Objective Treatment of relapses in multiple sclerosis (MS) has not advanced beyond steroid use, which reduces acute loss of function, but has little effect on residual disability. Acute loss of function in an MS model (experimental autoimmune encephalomyelitis [EAE]) is partly due to central nervous system (CNS) hypoxia, and function can promptly improve upon breathing oxygen. Here, we investigate the cause of the hypoxia and whether it is due to a deficit in oxygen supply arising from impaired vascular perfusion. We also explore whether the CNS‐selective vasodilating agent, nimodipine, may provide a therapy to restore function, and protect from demyelination in 2 MS models. Methods A variety of methods have been used to measure basic cardiovascular physiology, spinal oxygenation, mitochondrial function, and tissue perfusion in EAE. Results We report that the tissue hypoxia in EAE is associated with a profound hypoperfusion of the inflamed spinal cord. Treatment with nimodipine restores spinal oxygenation and can rapidly improve function. Nimodipine therapy also reduces demyelination in both EAE and a model of the early MS lesion. Interpretation Loss of function in EAE, and demyelination in EAE, and the model of the early MS lesion, seem to be due, at least in part, to tissue hypoxia due to local spinal hypoperfusion. Therapy to improve blood flow not only protects neurological function but also reduces demyelination. We conclude that nimodipine could be repurposed to offer substantial clinical benefit in MS. ANN NEUROL 2020 ANN NEUROL 2020;88:123–136

was authored by IL and edited by NJR. Experiments performed by IL, CM, AAB and KM. Immunohistochemistry staining undertaken by MH; counting performed by IL, CM and KM. NIRS data collected with support from PK, CB and IT. MRS data acquisition led by XG. All co-authors have reviewed this manuscript.

We describe the development of a miniaturized broadband near-infrared spectroscopy system (bNIRS), which measures changes in cerebral tissue oxyhemoglobin (½HbO 2) and deoxyhemoglobin ([HHb]) plus tissue metabolism via changes in the oxidation state of cytochrome-c-oxidase ([oxCCO]). The system is based on a small light source and a customized mini-spectrometer. We assessed the instrument in a preclinical study in 27 newborn piglets undergoing transient cerebral hypoxia-ischemia (HI). We aimed to quantify the recovery of the HI insult and estimate the severity of the injury. The recovery in brain oxygenation (Δ½HbDiff ¼ Δ½HbO 2 − Δ½HHb), blood volume (Δ½HbT ¼ Δ½HbO 2 þ Δ½HHb), and metabolism (Δ½oxCCO) for up to 30 min after the end of HI were quantified in percentages using the recovery fraction (RF) algorithm, which quantifies the recovery of a signal with respect to baseline. The receiver operating characteristic analysis was performed on bNIRS-RF measurements compared to proton (1 H) magnetic resonance spectroscopic (MRS)-derived thalamic lactate/N-acetylaspartate (Lac/NAA) measured at 24-h post HI insult; Lac/NAA peak area ratio is an accurate surrogate marker of neurodevelopmental outcome in babies with neonatal HI encephalopathy. The Δ½oxCCO-RF cutoff threshold of 79% within 30 min of HI predicted injury severity based on Lac/NAA with high sensitivity (100%) and specificity (93%). A significant difference in thalamic Lac/NAA was noticed (p < 0.0001) between the two groups based on this cutoff threshold of 79% Δ½oxCCO-RF. The severe injury group (n ¼ 13) had ∼30% smaller recovery in Δ½HbDiff-RF (p ¼ 0.0001) and no significant difference was observed in Δ½HbT-RF between groups. At 48 h post HI, significantly higher 31 P-MRS-measured inorganic phosphate/exchangeable phosphate pool (epp) (p ¼ 0.01) and reduced phosphocreatine/epp (p ¼ 0.003) were observed in the severe injury group indicating persistent cerebral energy depletion. Based on these results, the bNIRS measurement of the oxCCO recovery fraction offers a noninvasive real-time biomarker of brain injury severity within 30 min following HI insult.

Mitochondria play a key role in ageing and disease. Their membrane potentials and ATP production decline with age and this is associated with progressive inflammation, cell loss and death. Here we use broadband Near-Infrared Spectroscopy (NIRS) to non-invasively measure in-vivo changes in aged retinal mitochondrial respiration following exposure to 670 nm, which improves mitochondrial performance and reduces inflammation. Low power NIR light was shone into the eye via a fibre optic and the reflection monitored to measure signature changes in the oxidation of cytochrome c oxidase (COX) in complex IV of the electron transport chain. Changes in retinal haemodynamics and oxygenation were also recorded simultaneously with COX by measuring changes in oxygenated and deoxygenated haemoglobin (Δ[HbO2] and Δ[HHb]). Retinae of aged rats exposed to 670 nm for 5 mins showed consistent progressive increases in oxidation of COX 5 mins post exposure. This remained significantly greater than baseline for up to 2 h. This was not seen when retinae were exposed to 420 nm light of the same power or when no light was applied. 670 nm exposure significantly increased total haemoglobin concentration (Δ[HbT] = Δ[HbO2] +Δ[HHb]) but not haemoglobin difference (Δ[HbDiff] = Δ[HbO2] -Δ[HHb]). There were no changes in blood metrics in association with 420 nm light or when no light exposure was given. Hence, brief 670 nm exposure that is associated with reduced inflammation has a significant positive impact on the redox state of COX in aged retinae. The relative redox state of retinal COX may provide a valuable biomarker in ageing and macular degeneration where declining mitochondrial function is implicated.

While near-infrared spectroscopy (NIRS) haemodynamic measures have proven to be vastly useful in investigating human brain development, the haemodynamic response function (HRF) in infants is not yet fully understood. NIRS measurements of the oxidation state of mitochondrial enzyme cytochrome-c-oxidase (oxCCO) have the potential to yield key information about cellular oxygen utilisation and therefore energy metabolism. We used a broadband NIRS system to measure changes in oxCCO, in addition to haemodynamic changes, during functional activation in a group of 33 typically developing infants aged between 4 and 6 months. The responses were recorded over the right temporal lobe while the infants were presented with engaging videos containing social content. A significant increase in oxCCO was found in response to the social stimuli, with maximum increase of 0.238 ± 0.13 μM. These results are the first reported significant change in oxCCO in response to stimulus-evoked activation in human infants and open new vistas for investigating human infant brain function and its energy metabolism.