Objective Spontaneous intracerebral hemorrhage (ICH) is the commonest form of hemorrhagic stroke and is associated with a poor prognosis. Neurosurgical removal of intracerebral hematoma has limited benefit and no pharmacotherapies are available. In acute ICH, primary tissue damage is followed by secondary pathology, where the cellular and neuroinflammatory changes are poorly understood. Methods We studied histological changes in postmortem tissue from a cohort of spontaneous supra‐tentorial primary ICH cases (n = 27) with survival of 1–12 days, compared to a matched control group (n = 16) examined in corresponding regions. Hematoxylin–eosin and microglial (Iba1) immunolabelled sections were assessed at 0–2, 3–5, and 7–12 days post‐ICH. Results Peri‐hematoma, the observed ICH‐related changes include edema, tissue neutrophils and macrophages from day 1. Ischemic neurons and swollen endothelial cells were common at day 1 and universal after day 5, as were intramural erythrocytes within small vessel walls. Activated microglia were evident at day 1 post‐ICH. There was a significant increase in Iba1 positive area fraction at 0–2 (threefold), 3–5 (fourfold), and 7–12 days post ICH (ninefold) relative to controls. Giant microglia were detected peri‐hematoma from day 5 and consistently 7–12 days post‐ICH. Interpretation Our data indicate that neuroinflammatory processes commence from day 1 post‐ICH with changing microglial size and morphology following ICH and up to day 12. From day 5 some microglia exhibit a novel multiply nucleated morphology, which may be related to changing phagocytic function. Understanding the time course of neuroinflammatory changes, post‐ICH may reveal novel targets for therapy and brain restoration.

The controlled production of neurons in the postnatal dentate gyrus and thoughout life is important for hippocampal learning and memory. The mechanisms underlying the necessary coupling of neuronal activity to neural stem/progenitor cell (NSPC) function remain poorly understood. Within the dentate subgranular stem cell niche, local interneurons appear to play an important part in this excitation-neurogenesis coupling via GABAergic transmission, which promotes neuronal differentiation and integration. Here we show that vasoactive intestinal polypeptide, a neuropeptide coreleased with GABA under specific firing conditions, is uniquely trophic for proliferating postnatal nestin-positive dentate NSPCs, mediated via the VPAC 2 receptor. We also show that VPAC 2 receptor activation shifts the fate of symmetrically dividing NSPCs toward a nestin-only phenotype, independent of the trophic effect. In contrast, selective VPAC 1 receptor activation shifts NSPC fate toward granule cell neurogenesis without any trophism. We confirm a trophic role for VPAC 2 receptors in vivo, showing reduced progeny survival and dentate neurogenesis in adult Vipr2 2/2 mice. We also show a specific reduction in type 2 nestin-positive precursors in vivo, consistent with a role for VPAC 2 in maintaining this cell population. This work provides the first evidence of differential fate modulation of neurogenesis by neurotransmitter receptor subtypes and extends the fate-determining effects of neurotransmitters to maintaining the nestin-positive pool of NSPCs. This differential receptor effect may support the independent pharmacological manipulation of precursor pool expansion and neurogenic instruction for therapeutic application in the treatment of cognitive deficits associated with a decline in neurogenesis. STEM CELLS

Learning and memory dysfunction is the most common neuropsychological effect of mesial temporal lobe epilepsy, and because the underlying neurobiology is poorly understood, there are no pharmacological strategies to help restore memory function in these patients. We have demonstrated impairments in the acquisition of an allocentric spatial task, in patients with unilateral hippocampal sclerosis. We also show that patients have accelerated forgetting of the learned spatial task and that this is associated with damage to the non-dominant hippocampal formation. We go on to show a very similar pattern of chronic allocentric learning and accelerated forgetting in a status epilepticus model of mesial temporal lobe epilepsy in rats, which is associated with reduced and abnormal hippocampal neurogenesis. Finally, we show that reversal of the neurogenic deficit using fluoxetine is associated with reversal of the learning deficit but not the accelerated forgetting, pointing to a possible dissociation in the underlying mechanisms, as well as a potential therapeutic strategy for improving hippocampal-dependant learning in patients with mesial temporal lobe epilepsy.

Interest in promoting regeneration of the injured nervous system has recently turned toward the use of endogenous stem cells. Elucidating cues involved in driving these precursor cells out of quiescence following injury, and the signals that drive them toward neuronal and glial lineages, will help to harness these cells for repair. Using a biomechanically validated in vitro organotypic stretch injury model, cortico-hippocampal slices from postnatal mice were cultured and a stretch injury equivalent to a severe traumatic brain injury (TBI) applied. In uninjured cortex, proliferative potential under in vitro conditions is virtually absent in older slices (equivalent postnatal day 15 compared to 8). However, following a severe stretch injury, this potential is restored in injured outer cortex. Using slices from mice expressing a fluorescent reporter on the human glial fibrillary acidic protein (GFAP) promoter, we show that GFAP+ cells account for the majority of proliferating neurospheres formed, and that these cells are likely to arise from the cortical parenchyma and not from the subventricular zone. Moreover, we provide evidence for a correlation between upregulation of sonic hedgehog signaling, a pathway known to regulate stem cell proliferation, and this restoration of regenerative potential following TBI. Our results indicate that a source of quiescent endogenous stem cells residing in the cortex and subcortical tissue proliferate in vitro following TBI. Moreover, these proliferating cells are multipotent and are derived mostly from GFAP-expressing cells. This raises the possibility of using this endogenous source of stem cells for repair following TBI.

Introduction: There are few randomized clinical trials in vascular cognitive impairment (VCI). This trial tested the hypothesis that the PDE5 inhibitor tadalafil, a widely used vasodilator, increases cerebral blood flow (CBF) in older people with symptomatic small vessel disease, the main cause of VCI. Methods:In a double-blind, placebo-controlled, cross-over trial, participants received tadalafil (20 mg) and placebo on two visits ≥7 days apart (randomized to order of treatment). The primary endpoint, change in subcortical CBF, was measured by arterial spin labelling.Results: Tadalafil increased CBF non-significantly in all subcortical areas (N = 55, age: 66.8 (8.6) years) with greatest treatment effect within white matter hyperintensities (+9.8%, P = .0960). There were incidental treatment effects on systolic and diastolic blood pressure (-7.8, -4.9 mmHg; P < .001). No serious adverse events were observed.

Temporal lobe epilepsy alters adult neurogenesis. Existing experimental evidence is mainly from chronic models induced by an initial prolonged status epilepticus associated with substantial cell death. In these models, neurogenesis increases after status epilepticus. To test whether status epilepticus is necessary for this increase, we examined precursor cell proliferation and neurogenesis after the onset of spontaneous seizures in a model of temporal lobe epilepsy induced by unilateral intrahippocampal injection of tetanus toxin, which does not cause status or, in most cases, detectable neuronal loss. We found a 4.5 times increase in BrdU labeling (estimating precursor cells proliferating during the 2nd week after injection of toxin and surviving at least up to 7 days) in dentate gyri of both injected and contralateral hippocampi of epileptic rats. Radiotelemetry revealed that the rats experienced 112 ± 24 seizures, lasting 88 ± 11 s each, over a period of 8.6 ± 1.3 days from the first electrographic seizure. On the first day of seizures, their duration was a median of 103 s, and the median interictal period was 23 min, confirming the absence of experimentally defined status epilepticus. The total increase in cell proliferation/survival was due to significant population expansions of: radial glial-like precursor cells (type I; 7.2 ×), non-radial type II/III neural precursors in the dentate gyrus stem cell niche (5.6 ×), and doublecortin-expressing neuroblasts (5.1 ×). We conclude that repeated spontaneous brief temporal lobe seizures are sufficient to promote increased hippocampal neurogenesis in the absence of status epilepticus.

OBJECTIVEExternal ventricular drain (EVD) insertion is one of the most common emergency neurosurgical procedures. EVDs are traditionally inserted freehand (FH) in an emergency setting, but often result in suboptimal positioning. Image-guided surgery (IGS) is selectively used to assist placement. However, the accuracy and practicality of IGS use is yet to be reported. In this study, the authors set out to assess if IGS is practical and improves the accuracy of EVD placement.METHODSCase notes and images obtained in patients who underwent frontal EVD placement were retrospectively reviewed. Ventriculomegaly was determined by the measurement of the Evans index. EVD location was classified as optimal (ipsilateral frontal horn) or suboptimal (any other location). Propensity score matching of the two groups (IGS vs FH) for the Evans index was performed. Data were analyzed for patient age, diagnosis, number of EVDs, and complications. Those without postoperative CT scans were excluded.RESULTSA total of 607 patients with 760 EVDs placed were identified; 331 met inclusion criteria. Of these, 287 were inserted FH, and 44 were placed with IGS; 60.6% of all unmatched FH EVDs were optimal compared with 75% of the IGS group (p = 0.067). The IGS group had a significantly smaller Evans index (p < 0.0001). Propensity score matching demonstrated improved optimal position in the IGS group when compared with the matched FH group (75% vs 43.2%, OR 4.6 [1.5–14.6]; p = 0.002). Patients with an Evans index of ≥ 0.36 derived less benefit (75% in IGS vs 66% in FH, p = 0.5), and those with an Evans index < 0.36 derived more benefit (75% in IGS vs 53% in FH, p = 0.024). The overall EVD complication rate was 36% in the FH group versus 18% in the IGS group (p = 0.056). Revision rates were higher in the FH group (p = 0.035), and the operative times were similar (p = 0.69). Long intracranial EVD catheters were associated with tip malposition irrespective of the group.CONCLUSIONSImage guidance is practical and improves the accuracy of EVD placement in patients with small ventricles; thus, it should be considered for these patients.

Background and Purpose: Spontaneous intracerebral hemorrhage (sICH) is a common form of hemorrhagic stroke, with high mortality and morbidity. Pathophysiological mechanisms in sICH are poorly understood and treatments limited. Neuroinflammation driven by microglial-macrophage activation contributes to brain damage post-sICH. We aim to test the hypothesis that an anti-inflammatory (repair) process occurs in parallel with neuroinflammation in clinical sICH. Methods: We performed quantitative analysis of immunohistochemical markers for microglia and macrophages (Iba1, CD68, TMEM119, CD163, and CD206) in brain tissue biospecimens 1 to 12 days post-sICH and matched control cases. In a parallel, prospective group of patients, we assayed circulating inflammatory markers (CRP [C-reactive protein], total white cell, and monocyte count) over 1 to 12 days following sICH. Results: In 27 supratentorial sICH cases (n=27, median [interquartile range] age: 59 [52–80.5], 14F/13M) all microglia-macrophage markers increased post-sICH, relative to control brains. Anti-inflammatory markers (CD163 and CD206) were elevated alongside proinflammatory markers (CD68 and TMEM119). CD163 increased progressively post-sICH (15.0-fold increase at 7–12 days, P <0.001). CD206 increased at 3 to 5 days (5.2-fold, P <0.001) then returned to control levels at 7 to 12 days. The parenchymal immune response combined brain-derived microglia (TMEM119 positive) and invading monocyte-derived macrophages (CD206 positive). In a prospective sICH patient cohort (n=26, age 74 [66–79], National Institutes of Health Stroke Scale on admission: 8 [4–17]; 14F/12M) blood CRP concentration and monocyte density (but not white blood cell) increased post-sICH. CRP increased from 0 to 2 to 3 to 5 days (8.3-fold, P =0.020) then declined at 7 to 12 days. Monocytes increased from 0 to 2 to 3 to 5 days (1.8-fold, P <0.001) then declined at 7 to 12 days. Conclusions: An anti-inflammatory pathway, enlisting native microglia and blood monocytes, occurs alongside neuroinflammation post-sICH. This novel pathway offers therapeutic targets and a window of opportunity (3–5 days post-sICH) for delivery of therapeutics via invading monocytes.