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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., (© 2023. Crown.)

Background and Purpose- Poststroke fatigue affects a large proportion of stroke survivors and is associated with a poor quality of life. In a recent trial, modafinil was shown to be an effective agent in reducing poststroke fatigue; however, not all patients reported a significant decrease in fatigue with therapy. We sought to investigate clinical and radiological predictors of fatigue reduction with modafinil therapy in a stroke survivor cohort. Methods- Twenty-six participants with severe fatigue (multidimensional fatigue inventory-20 ≥60) underwent magnetic resonance imaging at baseline and during the last week of a 6-week treatment period of 200 mg modafinil taken daily. Resting-state functional magnetic resonance imaging and high-resolution structural imaging data were obtained, and functional connectivity and regional brain volumes within the fronto-striato-thalamic network were obtained. Linear regression analysis was used to identify predictors of modafinil-induced fatigue reduction. Results- Multiple regression analysis showed that baseline multidimensional fatigue inventory-20 score (β=0.576, P=0.006) and functional connectivity between the dorsolateral prefrontal cortex and the caudate nucleus (β=-0.424, P=0.008) were significant predictors of modafinil-associated decreases in poststroke fatigue (adjusted r 2 =0.52, area under the receiver operator characteristic curve=0.939). Conclusions- Fronto-striato-thalamic functional connectivity predicted modafinil response for poststroke fatigue. Fatigue in other neurological disease has been attributed to altered function of the fronto-striato-thalamic network and may indicate that poststroke fatigue has a similar mechanism to other neurological injury related fatigue. Self-reported fatigue in patients with normal fronto-striato-thalamic functional connectivity may have a different mechanism and require alternate therapeutic approaches. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: ACTRN12615000350527.

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 2 h. To define infarction thresholds at 1 h and 2 h post-stroke, separate groups of rats underwent 1 h (n = 6) and 2 h (n = 6) of middle cerebral artery occlusion followed by reperfusion. Infarct volumes were defined by histology at 24 h. 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 0.5 h (area under the curve = 0.660), 1 h (area under the curve = 0.659), 1.5 h (area under the curve = 0.636), and 2 h (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 1 h (area under the curve = 0.765) and at 2 h (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., (© 2013 The Authors. International Journal of Stroke © 2013 World Stroke Organization.)

In both the human and animal literature, it has largely been assumed that edema is the primary cause of intracranial pressure (ICP) elevation after stroke and that more edema equates to higher ICP. We recently demonstrated a dramatic ICP elevation 24 hours after small ischemic strokes in rats, with minimal edema. This ICP elevation was completely prevented by short-duration moderate hypothermia soon after stroke. Here, our aims were to determine the importance of edema in ICP elevation after stroke and whether mild hypothermia could prevent the ICP rise. Experimental stroke was performed in rats. ICP was monitored and short-duration mild (35 °C) or moderate (32.5 °C) hypothermia, or normothermia (37 °C) was induced after stroke onset. Edema was measured in three studies, using wet-dry weight calculations, T2-weighted magnetic resonance imaging, or histology. ICP increased 24 hours after stroke onset in all normothermic animals. Short-duration mild or moderate hypothermia prevented this rise. No correlation was seen between ΔICP and edema or infarct volumes. Calculated rates of edema growth were orders of magnitude less than normal cerebrospinal fluid production rates. These data challenge current concepts and suggest that factors other than cerebral edema are the primary cause of the ICP elevation 24 hours after stroke onset.

The aim of acute stroke treatment is to reperfuse the penumbra. However, not all posttreatment reperfusion is associated with a good outcome. Recent arterial spin labeling (ASL) studies suggest that patients with hyperperfusion after treatment have a better clinical recovery. This study aimed to determine whether there was a distinctive magnetic resonance spectroscopy (MRS) metabolite profile in hyperperfused tissue after stroke reperfusion therapy. We studied 77 ischemic stroke patients 24 hours after treatment using MRS (single voxel spectroscopy, point resolved spectroscopy, echo time 30 ms), ASL, and diffusion-weighted imaging (DWI). Magnetic resonance spectroscopy voxels were placed in cortical tissue that was penumbral on baseline perfusion imaging but had reperfused at 24 hours (and did not progress to infarction). Additionally, 20 healthy age matched controls underwent MRS. In all, 24 patients had hyperperfusion; 36 had reperfused penumbra without hyperperfusion, and 17 were excluded due to no reperfusion. Hyperperfusion was significantly related to better 3-month clinical outcome compared with patients without hyperperfusion (P=0.007). Patients with hyperperfusion showed increased glutamate (P<0.001), increased N-Acetylaspartate (NAA) (P=0.038), and increased lactate (P<0.002) in reperfused tissue compared with contralateral tissue and healthy controls. Hyperperfused tissue has a characteristic metabolite signature, suggesting that it is more metabolically active and perhaps more capable of later neuroplasticity.

Brain computed tomography perfusion imaging in acute stroke may help guide therapy. However, the perfusion thresholds defining potentially salvageable (penumbra) and irreversibly injured (infarct core) tissue require further validation. The aim of this study was to validate infarct core and penumbra perfusion thresholds in a rodent stroke model by developing and optimising perfusion computed tomography imaging, performing serial scanning and correlating scans with final histology. Stroke was induced in male Wistar rats (n=17) using the middle cerebral artery thread-occlusion method. Perfusion computed tomography scans were obtained immediately pre- and postocclusion, and every 30 min for 2.5 h. Histological changes of infarction were assessed after 24 h. High-quality maps of cerebral blood flow and cerebral blood volume were generated at multiple coronal planes after optimisation of contrast injection and scanning parameters. The prestroke absolute cerebral blood flow and cerebral blood volume values (mean ± SD) were 158.2 ± 49.94 ml/min per 100 g and 5.6 ± 1.13 ml per 100 g, respectively. Cerebral blood flow was significantly lower in the infarct region of interest than the contralateral hemisphere region of interest at all time points, except the 0.5 h postocclusion time point. However, cerebral blood volume was only significantly lower in the infarct region of interest than the contralateral hemisphere region of interest at the 1 h and the 1.5 h time points (postocclusion). This study has demonstrated for the first time the feasibility of performing perfusion computed tomography in the most commonly used animal model of stroke. The model will allow definitive studies to determine optimal thresholds and the reliability of perfusion computed tomography measures for infarct core and penumbra., (© 2011 The Authors. International Journal of Stroke © 2011 World Stroke Organization.)

The hypoxia tracer fluorine-18 fluoromisonidazole ([18F]FMISO) and its tritiated counterpart ([(3)H]FMISO) have been used as markers of potentially salvageable brain (ischemic penumbra) after stroke. In experimental models, the dynamics and half-life of [3H]FMISO allow concurrent histology after 24 h. Our aim was to further validate these techniques, by determining the optimum tracer exposure interval to delineate ischemic penumbra, and the effects of prolonged exposure on tracer retention in permanent ischemia. Middle cerebral artery occlusion (MCAO) of varying durations was created in rats using the thread occlusion model. Autoradiography using objective thresholding to define tracer-retention volume was performed to determine the time course of tracer retention in hypoxic tissues and the duration of ongoing retention after bolus administration. An ischemic duration of < or =90 min resulted in a tracer-retention volume underestimating 'tissue at risk' (histological infarction 24 h after permanent occlusion) by >1/2. Two hour ischemia resulted in a volume equal to 'tissue at risk'. Twenty-four hour permanent ischemia resulted in tracer-retaining tissue volumes greater than final infarction. However, the use of more stringent thresholding of autoradiographic signal produced a volume of FMISO retention closely approximating infarct volume. The findings indicate that the timing of imaging is crucial, with an optimal imaging time of 2 h using the current threshold. Earlier imaging is limited by tracer dynamics with this particular agent, however autoradiography with a longer ischemic interval (permanent occlusion) is feasible with modified thresholds. These findings support a role for hypoxia tracers in providing new insight into the ischemic penumbra.