Three-dimensional simulations of embolic stroke and an equation for sizing emboli from imaging

Stroke simulations are needed to run in-silico trials, develop hypotheses for clinical studies and to interpret ultrasound monitoring and radiological imaging. We describe proof-of-concept three-dimensional stroke simulations, carrying out in silico trials to relate lesion volume to embolus diameter and calculate probabilistic lesion overlap maps, building on our previous Monte Carlo method. Simulated emboli were released into an in silico vasculature to simulate 1000 s of strokes. Infarct volume distributions and probabilistic lesion overlap maps were determined. Computer-generated lesions were assessed by clinicians and compared with radiological images. The key result of this study is development of a three-dimensional simulation for embolic stroke and its application to an in silico clinical trial. Probabilistic lesion overlap maps showed that the lesions from small emboli are homogeneously distributed throughout the cerebral vasculature. Mid-sized emboli were preferentially found in posterior cerebral artery (PCA) and posterior region of the middle cerebral artery (MCA) territories. For large emboli, MCA, PCA and anterior cerebral artery (ACA) lesions were comparable to clinical observations, with MCA, PCA then ACA territories identified as the most to least probable regions for lesions to occur. A power law relationship between lesion volume and embolus diameter was found. In conclusion, this article showed proof-of-concept for large in silico trials of embolic stroke including 3D information, identifying that embolus diameter could be determined from infarct volume and that embolus size is critically important to the resting place of emboli. We anticipate this work will form the basis of clinical applications including intraoperative monitoring, determining stroke origins, and in silico trials for complex situations such as multiple embolisation

Automated segmentation of haematoma and perihaematomal oedema in MRI of acute spontaneous intracerebral haemorrhage

BackgroundSpontaneous intracerebral haemorrhage (SICH) is a common condition with high morbidity and mortality. Segmentation of haematoma and perihaematoma oedema on medical images provides quantitative outcome measures for clinical trials and may provide important markers of prognosis in people with SICH.MethodsWe take advantage of improved contrast seen on magnetic resonance (MR) images of patients with acute and early subacute SICH and introduce an automated algorithm for haematoma and oedema segmentation from these images. To our knowledge, there is no previously proposed segmentation technique for SICH that utilises MR images directly. The method is based on shape and intensity analysis for haematoma segmentation and voxel-wise dynamic thresholding of hyper-intensities for oedema segmentation.ResultsUsing Dice scores to measure segmentation overlaps between labellings yielded by the proposed algorithm and five different expert raters on 18 patients, we observe that our technique achieves overlap scores that are very similar to those obtained by pairwise expert rater comparison. A further comparison between the proposed method and a state-of-the-art Deep Learning segmentation on a separate set of 32 manually annotated subjects confirms the proposed method can achieve comparable results with very mild computational burden and in a completely training-free and unsupervised way.ConclusionOur technique can be a computationally light and effective way to automatically delineate haematoma and oedema extent directly from MR images. Thus, with increasing use of MR images clinically after intracerebral haemorrhage this technique has the potential to inform clinical practice in the future

Feasibility of improving cerebral autoregulation in acute intracerebral hemorrhage (BREATHE-ICH) study: Results from an experimental interventional study.

BACKGROUND: Cerebral autoregulation is impaired in a multitude of neurological conditions. Increasingly, clinical studies are correlating the nature of this impairment with prognostic markers. In acute intracerebral hemorrhage, impairment of cerebral autoregulation has been associated with worsening clinical outcomes including poorer Glasgow Coma Score and larger hematoma volume. Hypocapnia has been shown to improve cerebral autoregulation despite concerns over hypoperfusion and consequent ischemic risks, and it is therefore hypothesized that hypocapnia (via hyperventilation) in acute intracerebral hemorrhage may improve cerebral autoregulation and consequently clinical outcome. AIMS: To assess the feasibility and acceptability of the first cerebral autoregulation-targeted intervention in acute intracerebral hemorrhage utilizing a simple bed-side hyperventilatory maneuver. METHODS: Twelve patients with acute intracerebral hemorrhage within 48 h of onset were enrolled. The experimental setup measured cerebral blood flow velocity (transcranial Doppler), blood pressure (Finometer), and end-tidal CO2 (EtCO2, capnography) at baseline, and in response to hypocapnia (-5 mmHg below baseline) achieved via a 90-s hyperventilatory maneuver. Cerebral autoregulation was evaluated with transfer function analysis and autoregulatory index calculations. RESULTS: We observed tolerance to the protocol in a cohort of mild (National Institutes of Health Scale 4) supratentorial intracerebral hemorrhage patients with small volume hematomas without intraventricular extension. Importantly, a significant difference was noted between ipsilateral autoregulatory index at baseline 4.8 (1.7) and autoregulatory index during hypocapnic intervention 7.0 (0.8) (p = 0.0004), reflecting improved cerebral autoregulation, though a dose-dependent effect of EtCO2 on autoregulatory index was not observed. CONCLUSIONS: In this small study, there was no observed effect on 14-day death and disability in recruited participants. This is the first report of improvement in cerebral autoregulation in acute intracerebral hemorrhage using a non-invasive interventional maneuver, through induction of hypocapnia via hyperventilation. ClinicalTrials.gov Identifier: NCT03324321 URL: https://clinicaltrials.gov/ct2/show/NCT03324321

Neuroimaging outcomes in studies of cognitive training in mild cognitive impairment and early alzheimer’s disease: A systematic review

Background: Cognitive Training (CT) has demonstrated some benefits to cognitive and psychosocial function in Mild Cognitive Impairment (MCI) and early dementia, but the certainty related to those findings remains unclear. Therefore, understanding the mechanisms by which CT improves cognitive functioning may help to understand the relationships between CT and cognitive function. The purpose of this review was to identify the evidence for neuroimaging outcomes in studies of CT in MCI and early Alzheimer’s Disease (AD). Methods: Medline, Embase, Web of Science, PsycINFO, CINAHL, and The Cochrane Library were searched with a predefined search strategy, which yielded 1778 articles. Studies were suitable for inclusion where a CT program was used in patients with MCI or AD, with a structural or functional Magnetic Resonance Imaging (MRI) outcome. Studies were assessed for quality using the Downs and Black criteria. Results: A total of 19 studies met the inclusion criteria. Quality of the included studies was variable and there was significant heterogeneity for studies included in this review. Task activation was generally increased post-training, but functional connectivity was both increased and decreased after training. Results varied by diagnosis, type of CT program, and brain networks examined. No effects were seen on hippocampal volumes post-training, but cortical thickening and increased grey matter volumes were demonstrated. Conclusions: CT resulted in variable functional and structural changes in dementia, and conclusions are limited by heterogeneity and study quality. Larger, more robust studies are required to correlate these findings with clinical benefits from CT.</div

Cerebrovascular tone and resistance measures differ between healthy control and patients with acute intracerebral haemorrhage: exploratory analyses from the BREATHE-ICH study

Objective. Cerebral autoregulation impairment in acute neurovascular disease is well described. The recent BREATHE-ICH study demonstrated improvements in dynamic cerebral autoregulation, by hypocapnia generated by hyperventilation, in the acute period following intracranial haemorrhage (ICH). This exploratory analysis of the BREATHE-ICH dataset aims to examine the differences in hypocapnic responses between healthy controls and patients with ICH, and determine whether haemodynamic indices differ between baseline and hypocapnic states. Approach. Acute ICH patients were recruited within 48 h of onset and healthy volunteers were recruited from a university setting. Transcranial Doppler measurements of the middle cerebral artery were obtained at baseline and then a hyperventilation intervention was used to induce hypocapnia. Patients with ICH were then followed up at 10–14 D post-event for repeated measurements. Main results. Data from 43 healthy controls and 12 patients with acute ICH met the criteria for statistical analysis. In both normocapnic and hypocapnic conditions, significantly higher critical closing pressure and resistance area product were observed in patients with ICH. Furthermore, critical closing pressure changes were observed to be sustained at 10–14 D follow up. During both the normocapnic and hypocapnic states, reduced autoregulation index was observed bilaterally in patients with ICH, compared to healthy controls. Significance. Whilst this exploratory analysis was limited by a small, non-age matched sample, significant differences between ICH patients and healthy controls were observed in factors associated with cerebrovascular tone and resistance. These differences suggest underlying cerebral autoregulation changes in ICH, which may play a pivotal role in the morbidity and mortality associated with ICH

Effect of Tranexamic Acid Administration on Remote Cerebral Ischemic Lesions in Acute Spontaneous Intracerebral Hemorrhage: A Substudy of a Randomized Clinical Trial

Importance: Hyperintense foci on diffusion-weighted imaging (DWI) that are spatially remote from the acute hematoma occur in 20% of people with acute spontaneous intracerebral hemorrhage (ICH). Tranexamic acid, a hemostatic agent that is under investigation for treating acute ICH, might increase DWI hyperintense lesions (DWIHLs). Objective: To establish whether tranexamic acid compared with placebo increased the prevalence or number of remote cerebral DWIHLs within 2 weeks of ICH onset. Design, Setting, and Participants: This prospective nested magnetic resonance imaging (MRI) substudy of a randomized clinical trial (RCT) recruited participants from the multicenter, double-blind, placebo-controlled, phase 3 RCT (Tranexamic Acid for Hyperacute Primary Intracerebral Hemorrhage [TICH-2]) from July 1, 2015, to September 30, 2017, and conducted follow-up to 90 days after participants were randomized to either the tranexamic acid or placebo group. Participants had acute spontaneous ICH and included TICH-2 participants who provided consent to undergo additional MRI scans for the MRI substudy and those who had clinical MRI data that were compatible with the brain MRI protocol of the substudy. Data analyses were performed on an intention-to-treat basis on January 20, 2020. Interventions: The tranexamic acid group received 1 g in 100-mL intravenous bolus loading dose, followed by 1 g in 250-mL infusion within 8 hours of ICH onset. The placebo group received 0.9% saline within 8 hours of ICH onset. Brain MRI scans, including DWI, were performed within 2 weeks. Main Outcomes and Measures: Prevalence and number of remote DWIHLs were compared between the treatment groups using binary logistic regression adjusted for baseline covariates. Results: A total of 219 participants (mean [SD] age, 65.1 [13.8] years; 126 men [57.5%]) who had brain MRI data were included. Of these participants, 96 (43.8%) were randomized to receive tranexamic acid and 123 (56.2%) were randomized to receive placebo. No baseline differences in demographic characteristics and clinical or imaging features were found between the groups. There was no increase for the tranexamic acid group compared with the placebo group in DWIHL prevalence (20 of 96 [20.8%] vs 28 of 123 [22.8%]; odds ratio [OR], 0.71; 95% CI, 0.33-1.53; P = .39) or mean (SD) number of DWIHLs (1.75 [1.45] vs 1.81 [1.71]; mean difference [MD], -0.08; 95% CI, -0.36 to 0.20; P = .59). In an exploratory analysis, participants who were randomized within 3 hours of ICH onset or those with chronic infarcts appeared less likely to have DWIHLs if they received tranexamic acid. Participants with probable cerebral amyloid angiopathy appeared more likely to have DWIHLs if they received tranexamic acid. Conclusions and Relevance: This substudy of an RCT found no evidence of increased prevalence or number of remote DWIHLs after tranexamic acid treatment in acute ICH. These findings provide reassurance for ongoing and future trials that tranexamic acid for acute ICH is unlikely to induce cerebral ischemic events. Trial Registration: isrctn.org Identifier: ISRCTN93732214

Effect of Tranexamic Acid Administration on Remote Cerebral Ischemic Lesions in Acute Spontaneous Intracerebral Hemorrhage: A Substudy of a Randomized Clinical Trial

Importance: Hyperintense foci on diffusion-weighted imaging (DWI) that are spatially remote from the acute hematoma occur in 20% of people with acute spontaneous intracerebral hemorrhage (ICH). Tranexamic acid, a hemostatic agent that is under investigation for treating acute ICH, might increase DWI hyperintense lesions (DWIHLs). Objective: To establish whether tranexamic acid compared with placebo increased the prevalence or number of remote cerebral DWIHLs within 2 weeks of ICH onset. Design, Setting, and Participants: This prospective nested magnetic resonance imaging (MRI) substudy of a randomized clinical trial (RCT) recruited participants from the multicenter, double-blind, placebo-controlled, phase 3 RCT (Tranexamic Acid for Hyperacute Primary Intracerebral Hemorrhage [TICH-2]) from July 1, 2015, to September 30, 2017, and conducted follow-up to 90 days after participants were randomized to either the tranexamic acid or placebo group. Participants had acute spontaneous ICH and included TICH-2 participants who provided consent to undergo additional MRI scans for the MRI substudy and those who had clinical MRI data that were compatible with the brain MRI protocol of the substudy. Data analyses were performed on an intention-to-treat basis on January 20, 2020. Interventions: The tranexamic acid group received 1 g in 100-mL intravenous bolus loading dose, followed by 1 g in 250-mL infusion within 8 hours of ICH onset. The placebo group received 0.9% saline within 8 hours of ICH onset. Brain MRI scans, including DWI, were performed within 2 weeks. Main Outcomes and Measures: Prevalence and number of remote DWIHLs were compared between the treatment groups using binary logistic regression adjusted for baseline covariates. Results: A total of 219 participants (mean [SD] age, 65.1 [13.8] years; 126 men [57.5%]) who had brain MRI data were included. Of these participants, 96 (43.8%) were randomized to receive tranexamic acid and 123 (56.2%) were randomized to receive placebo. No baseline differences in demographic characteristics and clinical or imaging features were found between the groups. There was no increase for the tranexamic acid group compared with the placebo group in DWIHL prevalence (20 of 96 [20.8%] vs 28 of 123 [22.8%]; odds ratio [OR], 0.71; 95% CI, 0.33-1.53; P = .39) or mean (SD) number of DWIHLs (1.75 [1.45] vs 1.81 [1.71]; mean difference [MD], -0.08; 95% CI, -0.36 to 0.20; P = .59). In an exploratory analysis, participants who were randomized within 3 hours of ICH onset or those with chronic infarcts appeared less likely to have DWIHLs if they received tranexamic acid. Participants with probable cerebral amyloid angiopathy appeared more likely to have DWIHLs if they received tranexamic acid. Conclusions and Relevance: This substudy of an RCT found no evidence of increased prevalence or number of remote DWIHLs after tranexamic acid treatment in acute ICH. These findings provide reassurance for ongoing and future trials that tranexamic acid for acute ICH is unlikely to induce cerebral ischemic events. Trial Registration: isrctn.org Identifier: ISRCTN93732214