Calcium channel blockade with nimodipine reverses MRI evidence of cerebral oedema following acute hypoxia

Acute cerebral hypoxia causes rapid calcium shifts leading to neuronal damage and death. Calcium channel antagonists improve outcomes in some clinical conditions, but mechanisms remain unclear. In 18 healthy participants we: (i) quantified with multiparametric MRI the effect of hypoxia on the thalamus, a region particularly sensitive to hypoxia, and on the whole brain in general; (ii) investigated how calcium channel antagonism with the drug nimodipine affects the brain response to hypoxia. Hypoxia resulted in a significant decrease in apparent diffusion coefficient (ADC), a measure particularly sensitive to cell swelling, in a widespread network of regions across the brain, and the thalamus in particular. In hypoxia, nimodipine significantly increased ADC in the same brain regions, normalizing ADC towards normoxia baseline. There was positive correlation between blood nimodipine levels and ADC change. In the thalamus, there was a significant decrease in the amplitude of low frequency fluctuations (ALFF) in resting state functional MRI and an apparent increase of grey matter volume in hypoxia, with the ALFF partially normalized towards normoxia baseline with nimodipine. This study provides further evidence that the brain response to acute hypoxia is mediated by calcium, and importantly that manipulation of intracellular calcium flux following hypoxia may reduce cerebral cytotoxic oedem

Opioid suppression of conditioned anticipatory brain responses to breathlessness

Opioid painkillers are a promising treatment for chronic breathlessness, but are associated with potentially fatal side effects. In the treatment of breathlessness, their mechanisms of action are unclear. A better understanding might help to identify safer alternatives. Learned associations between previously neutral stimuli (e.g. stairs) and repeated breathlessness induce an anticipatory threat response that may worsen breathlessness, contributing to the downward spiral of decline seen in clinical populations. As opioids are known to influence associative learning, we hypothesized that they may interfere with the brain processes underlying a conditioned anticipatory response to breathlessness in relevant brain areas, including the amygdala and the hippocampus. Healthy volunteers viewed visual cues (neutral stimuli) immediately before induction of experimental breathlessness with inspiratory resistive loading. Thus, an association was formed between the cue and breathlessness. Subsequently, this paradigm was repeated in two identical neuroimaging sessions with intravenous infusions of either low-dose remifentanil (0.7ng/ml target controlled infusion) or saline (randomised). During saline infusion, breathlessness anticipation activated the right anterior insula and the adjacent operculum. Breathlessness was associated with activity in a network including the insula, operculum, dorsolateral prefrontal cortex, anterior cingulate cortex and the primary sensory and motor cortices. Remifentanil reduced breathlessness unpleasantness but not breathlessness intensity. Remifentanil depressed anticipatory activity in the amygdala and the hippocampus that correlated with reductions in breathlessness unpleasantness. During breathlessness, remifentanil decreased activity in the anterior insula, anterior cingulate cortex and sensory motor cortices. Remifentanil-induced reduction in breathlessness unpleasantness was associated with increased activity in the rostral anterior cingulate cortex and nucleus accumbens, components of the endogenous opioid system known to decrease the perception of aversive stimuli. These findings suggest that in addition to effects on brainstem respiratory control, opioids palliate breathlessness through an interplay of altered associative learning mechanisms. These mechanisms provide potential targets for novel ways to develop and assess treatments for chronic breathlessness

Development of early predictors of cerebral ischaemia after subarachnoid haemorrhage

Aneurysmal subarachnoid haemorrhage (SAH) is a severe disease often leading to profound disability and death. There has been increasing interest in nitric oxide (NO) signalling after brain injury, as it appears to influence many of the cellular metabolic pathways that eventually result in apoptosis and neuronal dysfunction. Many animal studies have shown exogenous cerebral NO donation appears to confer neuroprotective effects. It has shown to particularly affect many of the pathophysiological processes that occur after SAH. The work presented here describes two studies. The first study correlates changes in quantitative electroencephalography (qEEG) with the infusion of a cerebral NO donor, sodium nitrite after severe (World Federation of Neurosurgeon’s grades 3, 4 and 5) SAH. There is a need for better cerebral function assessment tools in this patient cohort as the usefulness of neurological examination is limited. The second study investigates magnetic resonance imaging (MRI) methods of evaluating acute tissue blood flow changes that occur after severe SAH, namely vessel encoded pseudo-continuous arterial spin labelling (VEPCASL). The results from the first study demonstrate that qEEG changes in response to an NO donor correlate with the subsequent development of delayed cerebral ischaemia (DCI) and poor clinical outcomes. The results from the second study show that VEPCASL can be used to obtain measures of regional cerebral blood flow changes that occur over time in the acute stages of severe SAH. This thesis demonstrates that bedside EEG monitoring is an extremely useful tool to give additional information regarding neuronal health after severe SAH. We have offered a new insight into the mechanisms behind therapeutic repletion of NO, aiding its development as a potential new therapy. We have also shown that VEPCASL MRI is a useful tool in assessing cerebral perfusion in the acute stages of injury.</p

Development of early predictors of cerebral ischaemia after subarachnoid haemorrhage

Aneurysmal subarachnoid haemorrhage (SAH) is a severe disease often leading to profound disability and death. There has been increasing interest in nitric oxide (NO) signalling after brain injury, as it appears to influence many of the cellular metabolic pathways that eventually result in apoptosis and neuronal dysfunction. Many animal studies have shown exogenous cerebral NO donation appears to confer neuroprotective effects. It has shown to particularly affect many of the pathophysiological processes that occur after SAH. The work presented here describes two studies. The first study correlates changes in quantitative electroencephalography (qEEG) with the infusion of a cerebral NO donor, sodium nitrite after severe (World Federation of Neurosurgeonâs grades 3, 4 and 5) SAH. There is a need for better cerebral function assessment tools in this patient cohort as the usefulness of neurological examination is limited. The second study investigates magnetic resonance imaging (MRI) methods of evaluating acute tissue blood flow changes that occur after severe SAH, namely vessel encoded pseudo-continuous arterial spin labelling (VEPCASL). The results from the first study demonstrate that qEEG changes in response to an NO donor correlate with the subsequent development of delayed cerebral ischaemia (DCI) and poor clinical outcomes. The results from the second study show that VEPCASL can be used to obtain measures of regional cerebral blood flow changes that occur over time in the acute stages of severe SAH. This thesis demonstrates that bedside EEG monitoring is an extremely useful tool to give additional information regarding neuronal health after severe SAH. We have offered a new insight into the mechanisms behind therapeutic repletion of NO, aiding its development as a potential new therapy. We have also shown that VEPCASL MRI is a useful tool in assessing cerebral perfusion in the acute stages of injury.</p

Early brain injury and cognitive impairment after aneurysmal subarachnoid haemorrhage

The first 72 h following aneurysm rupture play a key role in determining clinical and cognitive outcomes after subarachnoid haemorrhage (SAH). Yet, very little is known about the impact of so called “early brain injury” on patents with clinically good grade SAH (as defined as World Federation of Neurosurgeons Grade 1 and 2). 27 patients with good grade SAH underwent MRI scanning were prospectively recruited at three time-points after SAH: within the first 72 h (acute phase), at 5–10 days and at 3 months. Patients underwent additional, comprehensive cognitive assessment 3 months post-SAH. 27 paired healthy controls were also recruited for comparison. In the first 72 h post-SAH, patients had significantly higher global and regional brain volume than controls. This change was accompanied by restricted water diffusion in patients. Persisting abnormalities in the volume of the posterior cerebellum at 3 months post-SAH were present to those patients with worse cognitive outcome. When using this residual abnormal brain area as a region of interest in the acute-phase scans, we could predict with an accuracy of 84% (sensitivity 82%, specificity 86%) which patients would develop cognitive impairment 3 months later, despite initially appearing clinically indistinguishable from those making full recovery. In an exploratory sample of good clinical grade SAH patients compared to healthy controls, we identified a region of the posterior cerebellum for which acute changes on MRI were associated with cognitive impairment. Whilst further investigation will be required to confirm causality, use of this finding as a risk stratification biomarker is promising