Dr Rebecca Hood

Following ischemic stroke, substance P (SP)-mediated neurogenic inflammation is associated with profound blood-brain barrier (BBB) dysfunction, cerebral edema, and elevated intracranial pressure (ICP). SP elicits its effects by binding the neurokinin 1 tachykinin receptor (NK1-R), with administration of an NK1-R antagonist shown to ameliorate BBB dysfunction and cerebral edema in rodent and permanent ovine stroke models. Given the importance of reperfusion in clinical stroke, this study examined the efficacy of NK1-R antagonist treatment in reducing cerebral edema and ICP in an ovine model of transient middle cerebral artery occlusion (tMCAo). Anesthetized sheep (n = 24) were subject to 2-hours tMCAo and randomized (n = 6/group) to receive early NK1-R treatment (days 1¿3 post-stroke), delayed NK1-R treatment (day 5 post-stroke), or saline vehicle. At 6-days post-stroke animals were re-anaesthetized and ICP measured, followed by MRI to evaluate infarction, edema and BBB dysfunction. Following both early and delayed NK1-R antagonist administration, ICP was significantly reduced on day 6 compared to vehicle animals (p < 0.05), accompanied by a reduction in cerebral edema, midline shift and BBB dysfunction (p < 0.05). This study demonstrates that NK1-R antagonist treatment is an effective novel therapy for cerebral edema and elevated ICP following stroke in an ovine model, warranting future clinical evaluation.

Background: It has long been assumed that post-stroke intracranial pressure (ICP) elevation occurs because of large infarct and edema volumes. However, we have repeatedly shown ICP elevation at 24 h post-stroke in the presence of little to no edema in rats. Biological processes are often conserved across species and types of injury. Therefore, we aimed to determine if an ICP rise occurs at 24 h post-stroke in the presence of small infarct and edema volumes in mice. Methods: Mice were randomized by random number table to either photothrombotic stroke or sham surgery (n = 15). Epidural ICP was recorded using a fiber optic catheter at 1 h post-stroke (baseline) and between 23 and 24 h post-stroke. Results: ICP was significantly higher at 24 h compared to baseline in stroke animals (n = 6; 10.71 ± 6.45 mmHg vs. 3.74 ± 2.20 mmHg, respectively; p = 0.03). ICP at 24 h was also significantly higher in stroke mice compared to sham (n = 6; 3.45 ± 1.43 mmHg; p = 0.02). There was no change in ICP in sham mice (p = 0.9). Edema volumes in stroke animals were small (0.04 ± 0.04 mm3) and unlikely to have caused significant ICP elevation. Conclusion: This study provides¿evidence of an edema-independent ICP elevation following small ischemic stroke in mice. The occurrence of this rise supports our findings in other species and suggests it is caused by a previously undescribed mechanism.

We have previously demonstrated that a cortical stroke causes persistent impairment of hippocampal-dependent cognitive tasks concomitant with secondary neurodegenerative processes such as amyloid-ß accumulation in the hippocampus, a region remote from the primary infarct. Interestingly, there is emerging evidence suggesting that deposition of amyloid-ß around cerebral vessels may lead to cerebrovascular structural changes, neurovascular dysfunction, and disruption of blood¿brain barrier integrity. However, there is limited knowledge about the temporal changes of hippocampal cerebrovasculature after cortical stroke. In the current study, we aimed to characterise the spatiotemporal cerebrovascular changes after cortical stroke. This was done using the photothrombotic stroke model targeting the motor and somatosensory cortices of mice. Cerebrovascular morphology as well as the co-localisation of amyloid-ß with vasculature and blood¿brain barrier integrity were assessed in the cortex and hippocampal regions at 7, 28 and 84 days post-stroke. Our findings showed transient cerebrovascular remodelling in the peri-infarct area up to 28 days post-stroke. Importantly, the cerebrovascular changes were extended beyond the peri-infarct region to the ipsilateral hippocampus and were sustained out to 84 days post-stroke. When investigating vessel diameter, we showed a decrease at 84 days in the peri-infarct and CA1 regions that were exacerbated in vessels with amyloid-ß deposition. Lastly, we showed sustained vascular leakage in the peri-infarct and ipsilateral hippocampus, indicative of a compromised blood¿brain-barrier. Our findings indicate that hippocampal vasculature may represent an important therapeutic target to mitigate the progression of post-stroke cognitive impairment.

Background: Recent data indicates that cerebrospinal fluid (CSF) dynamics are disturbed after stroke. Our lab has previously shown that intracranial pressure rises dramatically 24¿h after experimental stroke and that this reduces blood flow to ischaemic tissue. CSF outflow resistance is increased at this time point. We hypothesised that reduced transit of CSF through brain parenchyma and reduced outflow of CSF via the cribriform plate at 24¿h after stroke may contribute to the previously identified post-stroke intracranial pressure elevation. Methods: Using a photothrombotic permanent occlusion model of stroke in C57BL/6 adult male mice, we examined the movement of an intracisternally infused 0.5% Texas Red dextran throughout the brain and measured tracer efflux into the nasal mucosa via the cribriform plate at 24¿h or two weeks after stroke. Brain tissue and nasal mucosa were collected ex vivo and imaged using fluorescent microscopy to determine the change in CSF tracer intensity in these tissues. Results: At 24¿h after stroke, we found that CSF tracer load was significantly reduced in brain tissue from stroke animals in both the ipsilateral and contralateral hemispheres when compared to sham. CSF tracer load was also reduced in the lateral region of the ipsilateral hemisphere when compared to the contralateral hemisphere in stroke brains. In addition, we identified an 81% reduction in CSF tracer load in the nasal mucosa in stroke animals compared to sham. These alterations to the movement of CSF-borne tracer were not present at two weeks after stroke. Conclusions: Our data indicates that influx of CSF into the brain tissue and efflux via the cribriform plate are reduced 24¿h after stroke. This may contribute to reported increases in intracranial pressure at 24¿h after stroke and thus worsen stroke outcomes.

Introduction: Virtual-reality (VR) technology has, over the last decade, quickly expanded from gaming into other sectors including training, education, and wellness. One of the most popular justifications for the use of VR over 2D is increased immersion and engagement. However, very little fundamental research has been produced evaluating the comparative impact of immersive VR on the user's cognitive, physiological, and emotional state. Methods: A within-subject cross-over study design was used to directly compare VR and 2D screen delivery of different subject matter content. Both physiological and self-report data were collected for scenes containing calming nature environments, aggressive social confrontations, and neutral content. Results: Compared to 2D, the VR delivery resulted in a higher sense of presence, higher ratings of engagement, fun, and privacy. Confrontational scenes were rated as more tense whilst calming scenes were rated as more relaxing when presented in VR compared to 2D. Physiological data indicated that the scenes promoted overall states of arousal and relaxation in accordance with the scene subject matter (both VR and 2D). However, heart rate (HR) and galvanic skin response (GSR) were consistently higher throughout the VR delivery condition compared to 2D, including responses during scenes of neutral and calming subject matter. Discussion: This discrepancy between emotional and physiological responses for calming and neutral content in VR suggest an elevated arousal response driven by VR immersion that is independent of the emotional and physiological responses to the subject matter itself. These findings have important implications for those looking to develop and utilize VR technology as a training and educational tool as they provide insights into the impact of immersion on the user.

White matter tract (WMT) degeneration has been reported to occur following a stroke, and it is associated with post-stroke functional disturbances. White matter pathology has been suggested to be an independent predictor of post-stroke recovery. However, the factors that influence WMT remodeling are poorly understood. Cortisol is a steroid hormone released in response to prolonged stress, and elevated levels of cortisol have been reported to interfere with brain recovery. The objective of this study was to investigate the influence of corticosterone (CORT; the rodent equivalent of cortisol) on WMT structure post-stroke. Photothrombotic stroke (or sham surgery) was induced in 8-week-old male C57BL/6 mice. At 72 h, mice were exposed to standard drinking water ± CORT (100 µg/mL). After two weeks of CORT administration, mice were euthanised and brain tissue collected for histological and biochemical analysis of WMT (particularly the corpus cal-losum and corticospinal tract). CORT administration was associated with increased tissue loss within the ipsilateral hemisphere, and modest and inconsistent WMT reorganization. Further, a structural and molecular analysis of the WMT components suggested that CORT exerted effects over axons and glial cells. Our findings highlight that CORT at stress-like levels can moderately influence the reorganization and microstructure of WMT post-stroke.

There is emerging evidence suggesting that a cortical stroke can cause delayed and remote hippocampal dysregulation, leading to cognitive impairment. In this study, we aimed to investigate motor and cognitive outcomes after experimental stroke, and their association with secondary neurodegenerative processes. Specifically, we used a photothrombotic stroke model targeting the motor and somatosensory cortices of mice. Motor function was assessed using the cylinder and grid walk tasks. Changes in cognition were assessed using a mouse touchscreen platform. Neuronal loss, gliosis and amyloid-ß accumulation were investigated in the peri-infarct and ipsilateral hippocampal regions at 7, 28 and 84 days post-stroke. Our findings showed persistent impairment in cognitive function post-stroke, whilst there was a modest spontaneous motor recovery over the investigated period of 84 days. In the peri-infarct region, we detected a reduction in neuronal loss and decreased neuroinflammation over time post-stroke, which potentially explains the spontaneous motor recovery. Conversely, we observed persistent neuronal loss together with concomitant increased neuroinflammation and amyloid-ß accumulation in the hippocampus, which likely accounts for the persistent cognitive dysfunction. Our findings indicate that cortical stroke induces secondary neurodegenerative processes in the hippocampus, a region remote from the primary infarct, potentially contributing to the progression of post-stroke cognitive impairment.

Triheptanoin, the medium-chain triglyceride of heptanoate, has been shown to be anticonvulsant and neuroprotective in several neurological disorders. In the gastrointestinal tract, triheptanoin is cleaved to heptanoate, which is then taken up by the blood and most tissues, including liver, heart and brain. Here we evaluated the neuroprotective effects of heptanoate and its effects on mitochondrial oxygen consumption in vitro. We also investigated the neuroprotective effects of triheptanoin compared to long-chain triglycerides when administered after stroke onset in rats. Heptanoate pre-treatment protected cultured neurons against cell death induced by oxygen glucose deprivation and N-methyl-D-aspartate. Incubation of cultured astrocytes with heptanoate for 2 h increased mitochondrial proton leak and also enhanced basal respiration and ATP turnover, suggesting that heptanoate protects against oxidative stress and is used as fuel. However, continuous 72 h infusion of triheptanoin initiated 1 h after middle cerebral artery occlusion in rats did not alter stroke volume at 3 days or neurological deficit at 1 and 3 days relative to long-chain triglyceride control treatment.

Background: Perfusion computed tomography is becoming more widely used as a clinical imaging tool to predict potentially salvageable tissue (ischemic penumbra) after ischemic stroke and guide reperfusion therapies. Aims: The study aims to determine whether there are important changes in perfusion computed tomography thresholds defining ischemic penumbra and infarct core over time following stroke. Methods: Permanent middle cerebral artery occlusion was performed in adult outbred Wistar rats (n=6) and serial perfusion computed tomography scans were taken every 30 mins for 2h. To define infarction thresholds at 1h and 2h post-stroke, separate groups of rats underwent 1h (n=6) and 2h (n=6) of middle cerebral artery occlusion followed by reperfusion. Infarct volumes were defined by histology at 24h. Co-registration with perfusion computed tomography maps (cerebral blood flow, cerebral blood volume, and mean transit time) permitted pixel-based analysis of thresholds defining infarction, using receiver operating characteristic curves. Results: Relative cerebral blood flow was the perfusion computed tomography parameter that most accurately predicted penumbra (area under the curve=0·698) and also infarct core (area under the curve=0·750). A relative cerebral blood flow threshold of <75% of mean contralateral cerebral blood flow most accurately predicted penumbral tissue at 0·5h (area under the curve=0·660), 1h (area under the curve=0·659), 1·5h (area under the curve=0·636), and 2h (area under the curve=0·664) after stroke onset. A relative cerebral blood flow threshold of <55% of mean contralateral most accurately predicted infarct core at 1h (area under the curve=0·765) and at 2h (area under the curve=0·689) after middle cerebral artery occlusion. Conclusions: The data provide perfusion computed tomography defined relative cerebral blood flow thresholds for infarct core and ischemic penumbra within the first two hours after experimental stroke in rats. These thresholds were shown to be stable to define the volume of infarct core and penumbra within this time window.