Prognostic Neuroimaging Biomarkers in Acute Vascular Brain Injury and Traumatic Brain Injury.

Prognostic imaging biomarkers after acute brain injury inform treatment decisions, track the progression of intracranial injury, and can be used in shared decision-making processes with families. Herein, key established biomarkers and prognostic scoring systems are surveyed in the literature, and their applications in clinical practice and clinical trials are discussed. Biomarkers in acute ischemic stroke include computed tomography (CT) hypodensity scoring, diffusion-weighted lesion volume, and core infarct size on perfusion imaging. Intracerebral hemorrhage biomarkers include hemorrhage volume, expansion, and location. Aneurysmal subarachnoid biomarkers include hemorrhage grading, presence of diffusion-restricting lesions, and acute hydrocephalus. Traumatic brain injury CT scoring systems, contusion expansion, and diffuse axonal injury grading are reviewed. Emerging biomarkers including white matter disease scoring, diffusion tensor imaging, and the automated calculation of scoring systems and volumetrics are discussed.

Ultrasound, photoacoustic, and magnetic resonance imaging to study hyperacute pathophysiology of traumatic and vascular brain injury.

BACKGROUND AND PURPOSE: Cerebrovascular dynamics and pathomechanisms that evolve in the minutes and hours following traumatic vascular injury in the brain remain largely unknown. We investigated the pathophysiology evolution in mice within the first 3 hours after closed-head traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH), two significant traumatic vascular injuries. METHODS: We took a multimodal imaging approach using photoacoustic imaging, color Doppler ultrasound, and MRI to track injury outcomes using a variety of metrics. RESULTS: Brain oxygenation and velocity-weighted volume of blood flow (VVF) values significantly decreased from baseline to 15 minutes after both TBI and SAH. TBI resulted in 19.2% and 41.0% ipsilateral oxygenation and VVF reductions 15 minutes postinjury, while SAH resulted in 43.9% and 85.0% ipsilateral oxygenation and VVF reduction (p < .001). We found partial recovery of oxygenation from 15 minutes to 3 hours after injury for TBI but not SAH. Hemorrhage, edema, reduced perfusion, and altered diffusivity were evident from MRI scans acquired 90-150 minutes after injury in both injury models, although the spatial distribution was mostly focal for TBI and diffuse for SAH. CONCLUSIONS: The results reveal that the cerebral oxygenation deficits immediately following injuries are reversible for TBI and irreversible for SAH. Our findings can inform future studies on mitigating these early responses to improve long-term recovery.

Electrocardiogram properties and risk of covert brain infarction and other magnetic resonance imaging abnormalities in a stroke-free population.

OBJECTIVES: This study aimed to investigate the association between electrocardiogram (ECG) abnormalities and silent vascular brain injury as defined by cerebral magnetic resonance imaging (MRI) in a stroke-free community-based population. METHODS: A total of 5888 participants were studied from the Cardiovascular Health Study (CHS), a prospective cohort of community-living older adults. Standard 12-lead ECGs measured prior to MRI scan were used. MRI scans were conducted at years 4-6 and 10-11. The primary outcome was presence of incident covert brain infarcts (CBIs) on the 2nd MRI examination, excluding previous CBIs and stroke occurrence. Secondary outcomes included white matter, ventricular, and sulcal atrophy on the 1st MRI. Logistic and multiple linear regression models were used to assess the relationship between ECG findings and silent vascular brain injury. RESULTS: Left axis deviation before MRI scan was related to presence of incident CBIs (odds ratio [OR]: 1.45; 95% CI: 1.01-2.08, p = .047). A long QT interval was associated with severe white matter hyperintensity (OR: 1.36; 95% CI: 1.04-1.77, p = .024). Minor Q and QS waves with ST-T abnormalities were positively related to sulcal atrophy (ß: 0.43, 95% CI: 0.06-0.81, p = .023). CONCLUSIONS: Our study found that ECG abnormalities were related to presence of CBIs, white matter hyperintensity, and sulcal atrophy on MRI in a stroke-free relderly population. Specifically, those with left axis deviation had an increased risk of presence of CBIs.

Association between Anatomical Variations of the Circle of Willis and Covert Vascular Brain Injury in the General Population.

BACKGROUND AND PURPOSE: The circle of Willis (COW) is a circulatory anastomosis located at the base of the brain. Little is known about the association between covert vascular brain injury and COW configurations in the general population. We explored this relationship in a community-based Chinese sample. METHODS: A total of 1,055 patients (mean age, 54.8 ± 8.9 years; 36.0% men) without intracranial arterial stenosis were included in the analysis. Magnetic resonance imaging was performed to evaluate the presence of imaging markers of covert vascular brain injury, including white matter hyperintensities (WMHs), lacunes, cerebral microbleeds (CMBs), enlarged perivascular spaces, and brain atrophy. Magnetic resonance angiography was used to classify the COW configurations according to the completeness, symmetry, and presence of the fetal posterior cerebral artery (FTP). The association between vascular lesions and variations in COW was analyzed. RESULTS: Among the 1,055 patients, 104 (9.9%) had a complete COW. Completeness correlated with age (p = 0.001). Incomplete COW was positively associated with WMH severity (OR = 2.071; 95% CI, 1.004-4.270) and CMB presence (OR = 1.542; 95% CI, 1.012-2.348), independent of age and sex. The presence of FTP was associated with lacunes (OR = 1.878; 95% CI, 1.069-3.298), more severe WMHs (OR = 1.739; 95% CI, 1.064-2.842), and less severe enlarged perivascular spaces (OR = 0.562; 95% CI, 0.346-0.915). CONCLUSIONS: COW configuration was significantly related to various covert vascular brain injuries.

A Neuropathological Study of Diffuse Vascular Injury in Fatal Motor Vehicle Collisions.

In Canada, 42 929 people were involved in fatal motor vehicle collisions (MVCs) between 1999 and 2018. Traumatic brain injuries (TBIs), including diffuse vascular injury (DVI), were the most frequent cause of death. The neuroanatomical injury pattern and severity of DVI in relation to data on MVC dynamics and other MVC factors were the focus of the current study. Five cases of fatal MVCs investigated by Western University's Motor Vehicle Safety (MOVES) Research Team with the neuropathological diagnosis of DVI were reviewed. DVI was seen in single and multiple vehicle collisions, with/without rollover and with/without partial occupant ejection. DVI occurred regardless of seatbelt use and airbag deployment and in vehicles equipped with/without antilock brakes. All DVI cases sustained head impacts and had focal TBIs, including basal skull fractures and subarachnoid hemorrhages. DVI was seen in MVCs that ranged in severity based on the change in velocity (delta-V) during the crash (minimum 31 km/hour) and occupant compartment intrusion (minimum 25 cm). In all cases, DVI in frontal white matter, corpus callosum and pontine tegmentum were common. In cases with more extensive DVI, pronounced vehicle rotation occurred before the final impact. Extensive DVI was seen in drivers who experienced sudden acceleration during vehicle rotation and deceleration.

Plasma EFEMP1 Is Associated with Brain Aging and Dementia: The Framingham Heart Study.

BACKGROUND: Epidermal growth factor containing fibulin extracellular matrix protein-1 (EFEMP1) has been associated with increased white matter hyperintensities (WMH) burden and disorders of premature aging and may have a shared pathophysiological role in the development of WMH and dementia. OBJECTIVE: To determine the association between plasma EFEMP1 levels and MRI markers of vascular brain injury and incident all-cause and Alzheimer's disease (AD) dementia. METHODS: We measured plasma EFEMP1 levels in 1597 [53% women, mean age 68.7 (SD 5.7) years] dementia-free Framingham Offspring cohort participants between 1998-2001 and subsequently followed them for incident dementia. Secondary outcomes included stroke, structural MRI brain measures and neurocognitive test performance. RESULTS: During a median 11.8 [Q1, Q3 : 7.1, 13.3] year follow-up, 131 participants developed dementia. The highest quintile of plasma EFEMP1, compared to the bottom four quintiles, was associated with an increased risk of time to incident all-cause dementia (HR 1.77, 95% CI 1.18-2.64) and AD dementia (HR 1.76, 95% CI 1.11-2.81) but not with markers of vascular brain injury (WMH, covert brain infarcts or stroke). Higher circulating EFEMP1 concentrations were also cross-sectionally associated with lower total brain (ß±SE, -0.28±0.11, p = 0.01) and hippocampal volumes (-0.006±0.003, p = 0.04) and impaired abstract reasoning (Similarities test, -0.18±0.08, p = 0.018 per standard deviation increment in EFEMP1). CONCLUSION: Elevated circulating EFEMP1 is associated with an increased risk of all-cause and AD dementia, smaller hippocampal and total brain volumes, and poorer cognitive performance. EFEMP1 may play an important biological role in the development of AD dementia. Further studies to validate these findings are warranted.

Associations of Binge Drinking With Vascular Brain Injury and Atrophy in Older American Indians: The Strong Heart Study.

Objectives: American Indians (AIs) generally consume less alcohol than the US general population; however, the prevalence of alcohol use disorder is higher. This is the first large cohort study to examine binge drinking as a risk factor for vascular brain injury (VBI). Methods: We used linear and Poisson regression to examine the association of self-reported binge drinking with VBI, measured via magnetic resonance imaging (MRI), in 817 older AIs who participated in the Strong Heart and Cerebrovascular Disease and Its Consequences in American Indians studies. Results: Any binge drinking at multiple time-points was associated with increased sulcal (ß = 0.360, 95% CI [0.079, 0.641]) and ventricle dilatation (ß = 0.512, 95% CI [0.174, 0.850]) compared to no binge drinking. Discussion: These observed associations are consistent with previous findings. Identifying how binge drinking may contribute to VBI in older AIs may suggest modifiable health behaviors for neurological risk reduction and disease prevention.

Ischemia-reperfusion injury of brain induces endothelial-mesenchymal transition and vascular fibrosis via activating let-7i/TGF-ßR1 double-negative feedback loop.

Let-7i modulates the physical function and inflammation in endothelial cells (ECs). However, whether the let-7i of ECs involves in brain vasculature and ischemic stroke is unknown. Using inducible Cadherin5-Cre lineage-tracking mice, a loxp-RNA-sponge conditional knockdown of let-7 in ECs- induced increase of transforming growth factor-ß receptor type 1 (TGF-ßR1), endothelial-mesenchymal transition (endMT), vascular fibrosis, and opening of the brain-blood barrier (BBB). By this lineage-tracking mice, we found that ECs underwent endMT after transient middle cerebral artery occlusion (MCAO). Through specifically overexpressed let-7i in ECs, we found that it reduced TGF-ßR1, endMT, and vascular fibrosis. Furthermore, this overexpression reduced the infarct volume and leakage of the BBB, and improved the neurological function. Further, the expression of let-7i decreased after MCAO, but was reversed by antagonist of TGF-ßR1 or inhibition of Mek phosphorylation. And the inhibition of Mek attenuated the vascular fibrosis after MCAO. In summary, we concluded that ischemic stroke activates a let-7i/TGF-ßR1 double-negative feedback loop, thereby inducing endMT and vascular fibrosis. These results suggest that endMT is a potential target for the treatment of cerebral vascular fibrosis.

How Do Different Forms of Vascular Brain Injury Relate to Cognition in a Memory Clinic Population: The TRACE-VCI Study.

BACKGROUND: Memory clinic patients frequently present with different forms of vascular brain injury due to different etiologies, often co-occurring with Alzheimer's disease (AD) pathology. OBJECTIVE: We studied how cognition was affected by different forms of vascular brain injury, possibly in interplay with AD pathology. METHODS: We included 860 memory clinic patients with vascular brain injury on magnetic resonance imaging (MRI), receiving a standardized evaluation including cerebrospinal fluid (CSF) biomarker analyses (n = 541). The cognitive profile of patients with different forms of vascular brain injury on MRI (moderate/severe white matter hyperintensities (WMH) (n = 398), microbleeds (n = 368), lacunar (n = 188) and non-lacunar (n = 96) infarct(s), macrobleeds (n = 16)) was assessed by: 1) comparison of all these different forms of vascular brain injury with a reference group (patients with only mild WMH (n = 205) without other forms of vascular brain injury), using linear regression analyses also stratified for CSF biomarker AD profile and 2) multivariate linear regression analysis. RESULTS: The cognitive profile was remarkably similar across groups. Compared to the reference group effect sizes on all domains were <0.2 with narrow 95% confidence intervals, except for non-lacunar infarcts on information processing speed (age, sex, and education adjusted mean difference from reference group (ß: - 0.26, p = 0.05). Results were similar in the presence (n = 300) or absence (n = 241) of biomarker co-occurring AD pathology. In multivariate linear regression analysis, higher WMH burden was related to a slightly worse performance on attention and executive functioning (ß: - 0.08, p = 0.02) and working memory (ß: - 0.08, p = 0.04). CONCLUSION: Although different forms of vascular brain injury have different etiologies and different patterns of cerebral damage, they show a largely similar cognitive profile in memory clinic patients regardless of co-occurring AD pathology.

Simvastatin improves cerebrovascular injury caused by ischemia­reperfusion through NF­κB­mediated apoptosis via MyD88/TRIF signaling.

Cerebrovascular injury is the most prevalent human cerebrovascular disease and frequently results in ischemic stroke. Simvastatin may be a potential therapeutic agent for the treatment of patients with cerebrovascular injury. The present study aimed to investigate the efficacy of and the potential mechanisms regulated by simvastatin in a rat model of ischemia­reperfusion (I/R)­induced cerebrovascular injury. Cerebrovascular injury model rats were established and were subsequently treated with simvastatin or a vehicle control following I/R injury. Cell damage, neurological functions and neuronal apoptosis were examined, as well as the nuclear factor (NF)­κB­mediated myeloid differentiation primary response protein 88 (MyD88)/toll­interleukin­1 receptor domain­containing adapter molecule 1 (TRIF) signaling pathway following simvastatin treatment. The results of the present study demonstrated that simvastatin treatment led to a reduction in cell damage, improvement of neurological functions and decreased neuronal apoptosis compared with vehicle­treated I/R model rats, 14 days post­treatment. In addition, simvastatin treatment reduced cerebral water content and blood­brain barrier disruption in cerebrovascular injury induced by I/R. The results also revealed that simvastatin treatment inhibited neuronal apoptosis via the NF­κB­mediated MyD88/TRIF signaling pathway. In conclusion, simvastatin treatment may reduce I/R­induced neuronal apoptosis via inhibition of the NF­κB­mediated MyD88/TRIF signaling pathway.

Findings of Vascular Brain Injury and Structural Loss from Cranial Magnetic Resonance Imaging in Elderly American Indians: The Strong Heart Study.

BACKGROUND: The Cerebrovascular Disease and its Consequences in American Indians study conducted cranial MRI examination of surviving participants of the Strong Heart Study, a longitudinal cohort of elderly American Indians. METHODS: Of the 1,033 recruited participants, some were unable to complete the MRI (n = 22), some scans were unusable due to participant motion or technical errors (n = 13), and one community withdrew consent after data collection (n = 209), leaving 789 interpretable MRI scan images. Six image sequences were obtained in contiguous slices on 1.5T scanners. Neuroradiologists graded white matter hyperintensities (WMH), sulci, and ventricles on a 0- to 9-point scale, and recorded the presence of infarcts and hemorrhages. Intracranial, brain, hippocampal, and WMH volumes were estimated by automated image processing. RESULTS: The median scores for graded measures were 2 (WMH) and 3 (sulci, ventricles). About one-third of participants had lacunar (20%) or other infarcts (13%); few had hemorrhages (5.7%). Findings of cortical atrophy were also prevalent. Statistical analyses indicated significant associations between older age and findings of vascular injury and atrophy; male gender was associated with findings of cortical atrophy. CONCLUSIONS: Vascular brain injury is the likely explanation in this elderly American Indian population for brain infarcts, hemorrhages, WMH grade, and WMH volume. Although vascular brain injury may play a role in other findings, independent degenerative other disease processes may underlie abnormal sulcal widening, ventricular enlargement, hippocampal volume, and total brain volume. Further examination of risk factors and outcomes with these findings may expand the understanding of neurological conditions in this understudied population.

Alzheimer's disease neuropathologic change, Lewy body disease, and vascular brain injury in clinic- and community-based samples.

We examined the relationships between Alzheimer's disease neuropathologic change (ADNC), Lewy body disease (LBD), and vascular brain injury (VBI) in 2 large autopsy samples. Because findings may differ between study populations, data came from U.S. Alzheimer's Disease Centers contributing to the National Alzheimer's Coordinating Center (n = 2742) and from the population-based Adult Changes in Thought study (n = 499). Regardless of study population, over 50% of participants with ADNC had co-occurring LBD or VBI; the majority of whom had a clinical AD dementia diagnosis prior to death. Overlap of pathologies was similar between studies, especially after standardizing to the distribution of age and dementia status in the Adult Changes in Thought population. LBD, but not VBI, was positively associated with ADNC in both studies. Interestingly, cortical LBD was more common in those with intermediate ADNC compared to low or high ADNC, especially in the National Alzheimer's Coordinating Center (p < 0.001). High prevalence of co-occurring neuropathologies among older adults with dementia has implications for accurate diagnosis of dementia etiologies and development of disease-modifying strategies.

Long-term follow-up of blunt cerebrovascular injuries: Does time heal all wounds?

BACKGROUND: The short-term natural history of blunt cerebrovascular injuries (BCVIs) has been previously described in the literature, but the purpose of this study was to analyze long-term serial follow-up and lesion progression of BCVI. METHODS: This is a single institution's retrospective review of a prospectively collected database over four years (2009-2013). All patients with a diagnosis of BCVI by computed tomographic (CT) scan were identified, and injuries were graded based on modified Denver scale. Management followed institutional algorithm: initial whole-body contrast-enhanced CT scan, followed by CT angiography at 24 to 72 hours, 5 to 7 days, 4 to 6 weeks, and 3 months after injury. All follow-up imaging, medication management, and clinical outcomes through 6 months following injury were recorded. RESULTS: There were 379 patients with 509 injuries identified. Three hundred eighty-one injuries were diagnosed as BCVI on first CT (Grade 1 injuries, 126; Grade 2 injuries, 116; Grade 3 injuries, 69; and Grade 4 injuries, 70); 100 "indeterminate" on whole-body CT; 28 injuries were found in patients reimaged only for lesions detected in other vessels. Sixty percent were male, mean (SD) age was 46.5 (19.9) years, 65% were white, and 62% were victims of a motor vehicle crash. Most frequently, Grade 1 injuries were resolved at all subsequent time points. Up to 30% of Grade 2 injuries worsened, but nearly 50% improved or resolved. Forty-six percent of injuries originally not detected were subsequently diagnosed as Grade 3 injuries. Greater than 70% of all imaged Grade 3 and Grade 4 injuries remained unchanged at all subsequent time points. CONCLUSIONS: This study revealed that there are many changes in grade throughout the six-month time period, especially the lesions that start out undetectable or indeterminate, which become various grade injuries. Low-grade injuries (Grades 1 and 2) are likely to remain stable and eventually resolve. Higher-grade injuries (Grades 3 and 4) persist, many up to six months. Inpatient treatment with antiplatelet or anticoagulation did not affect BCVI progression. LEVEL OF EVIDENCE: Prognostic study, level III; therapeutic study, level IV.

Unbiased Stereological Analysis of Reactive Astrogliosis to Estimate Age-Associated Cerebral White Matter Injury.

Cerebral white matter injury (WMI) contributes to cognitive dysfunction associated with pathological aging. Because reactive astrocyte-related factors contribute to remyelination failure after WMI, we sought accurate, cost-effective, and reproducible histopathological approaches for quantification of morphometric features of reactive astrogliosis in aged human white matter in patients with vascular brain injury (VBI). We compared 7 distinct approaches to quantify the features of glial fibrillary acidic protein (GFAP)-labeled astrocytes in the prefrontal white matter of brains from patients with VBI (n = 17, mean age 88.8 years) and controls that did not exhibit VBI (n = 11, mean age 86.6 years). Only modern stereological techniques (ie, optical fractionator and spaceballs) and virtual process thickness measurements demonstrated significant changes in astrocyte number, process length, or proximal process thickness in cases with VBI relative to controls. The widely employed methods of neuropathological scoring, antibody capture assay (histelide), area fraction fractionator, and Cavalieri point counting failed to detect significant differences in GFAP expression between the groups. Unbiased stereological approaches and virtual thickness measurements provided the only sensitive and accurate means to quantify astrocyte reactivity as a surrogate marker of WMI in human brains with VBI.

Visualizing peroxynitrite fluxes in endothelial cells reveals the dynamic progression of brain vascular injury.

Accumulating evidence suggests that formation of peroxynitrite (ONOO(-)) in the cerebral vasculature contributes to the progression of ischemic damage, while the underlying molecular mechanisms remain elusive. To fully understand ONOO(-) biology, efficient tools that can realize the real-time tracing of endogenous ONOO(-) fluxes are indispensable. While a few ONOO(-) fluorescent probes have been reported, direct visualization of ONOO(-) fluxes in the cerebral vasculature of live mice remains a challenge. Herein, we present a fluorescent switch-on probe (NP3) for ONOO(-) imaging. NP3 exhibits good specificity, fast response, and high sensitivity toward ONOO(-) both in vitro and in vivo. Moreover, NP3 is two-photon excitable and readily blood-brain barrier penetrable. These desired photophysical and pharmacokinetic properties endow NP3 with the capability to monitor brain vascular ONOO(-) generation after injury with excellent temporal and spatial resolution. As a proof of concept, NP3 has enabled the direct visualization of neurovascular ONOO(-) formation in ischemia progression in live mouse brain by use of two-photon laser scanning microscopy. Due to these favorable properties, NP3 holds great promise for visualizing endogenous peroxynitrite fluxes in a variety of pathophysiological progressions in vitro and in vivo.

Lethal now or lethal later: The natural history of Grade 4 blunt cerebrovascular injury.

BACKGROUND: Grade 4 blunt cerebrovascular injury (BCVI4) has a known, significant rate of stroke. However, little is known about the natural history of BCVI4 and the pathophysiology of subsequent stroke formation. METHODS: A 4-year review of patients with BCVI4 at the R Adams Cowley Shock Trauma Center was performed. Rates of BCVI4-related stroke, stroke-related mortality, and overall mortality were calculated. The relationship of change in vessel characteristics and BCVI4-related stroke was examined, as was the mechanism of stroke formation. RESULTS: There were 82 BCVI4s identified, with 13 carotid artery (ICA) and 69 vertebral artery BCVI4s. BCVI4-related stroke rate was 2.9% in vertebral artery BCVI4 and 70% in ICA BCVI4 patients surviving to reimaging. Stroke mechanisms included embolic strokes, thrombotic strokes, and combined embolic and thrombotic strokes. Peristroke vessel recanalization and an embolic stroke mechanism were seen in 100% of ICA BCVI4-related strokes developing after admission. BCVI4-related stroke occurred within 10 hours of hospital admission in 67% of the patients with strokes. Contraindications to anticoagulation were present in most patients with BCVI4-related stroke developing after admission. CONCLUSION: Multiple etiologies of stroke formation exist in BCVI4. Early risk-benefit analysis for initiation of anticoagulation or antiplatelet agents should be performed in all patients with BCVI4, and the use of endovascular vessel occlusion should be considered in those with true contraindications to anticoagulation. However, more aggressive medical therapy may be needed to lessen BCVI4-related stroke development. LEVEL OF EVIDENCE: Prognostic study, level IV; therapeutic study, level V.

TGFß-activated Kinase 1 (TAK1) Inhibition by 5Z-7-Oxozeaenol Attenuates Early Brain Injury after Experimental Subarachnoid Hemorrhage.

Accumulating evidence suggests that activation of mitogen-activated protein kinases (MAPKs) and nuclear factor NF-κB exacerbates early brain injury (EBI) following subarachnoid hemorrhage (SAH) by provoking proapoptotic and proinflammatory cellular signaling. Here we evaluate the role of TGFß-activated kinase 1 (TAK1), a critical regulator of the NF-κB and MAPK pathways, in early brain injury following SAH. Although the expression level of TAK1 did not present significant alternation in the basal temporal lobe after SAH, the expression of phosphorylated TAK1 (Thr-187, p-TAK1) showed a substantial increase 24 h post-SAH. Intracerebroventricular injection of a selective TAK1 inhibitor (10 min post-SAH), 5Z-7-oxozeaenol (OZ), significantly reduced the levels of TAK1 and p-TAK1 at 24 h post-SAH. Involvement of MAPKs and NF-κB signaling pathways was revealed that OZ inhibited SAH-induced phosphorylation of p38 and JNK, the nuclear translocation of NF-κB p65, and degradation of IκBα. Furthermore, OZ administration diminished the SAH-induced apoptosis and EBI. As a result, neurological deficits caused by SAH were reversed. Our findings suggest that TAK1 inhibition confers marked neuroprotection against EBI following SAH. Therefore, TAK1 might be a promising new molecular target for the treatment of SAH.

Interhemispheric functional connectivity following prenatal or perinatal brain injury predicts receptive language outcome.

Early brain injury alters both structural and functional connectivity between the cerebral hemispheres. Despite increasing knowledge on the individual hemispheric contributions to recovery from such injury, we know very little about how their interactions affect this process. In the present study, we related interhemispheric structural and functional connectivity to receptive language outcome following early left hemisphere stroke. We used functional magnetic resonance imaging to study 14 people with neonatal brain injury, and 25 age-matched controls during passive story comprehension. With respect to structural connectivity, we found that increased volume of the corpus callosum predicted good receptive language outcome, but that this is not specific to people with injury. In contrast, we found that increased posterior superior temporal gyrus interhemispheric functional connectivity during story comprehension predicted better receptive language performance in people with early brain injury, but worse performance in typical controls. This suggests that interhemispheric functional connectivity is one potential compensatory mechanism following early injury. Further, this pattern of results suggests refinement of the prevailing notion that better language outcome following early left hemisphere injury relies on the contribution of the contralesional hemisphere (i.e., the "right-hemisphere-take-over" theory). This pattern of results was also regionally specific; connectivity of the angular gyrus predicted poorer performance in both groups, independent of brain injury. These results present a complex picture of recovery, and in some cases, such recovery relies on increased cooperation between the injured hemisphere and homologous regions in the contralesional hemisphere, but in other cases, the opposite appears to hold.