Pia-FLOW: Deciphering hemodynamic maps of the pial vascular connectome and its response to arterial occlusion.

The pial vasculature is the sole source of blood supply to the neocortex. The brain is contained within the skull, a vascularized bone marrow with a unique anatomical connection to the brain meninges. Recent developments in tissue clearing have enabled detailed mapping of the entire pial and calvarial vasculature. However, what are the absolute flow rate values of those vascular networks? This information cannot accurately be retrieved with the commonly used bioimaging methods. Here, we introduce Pia-FLOW, a unique approach based on large-scale transcranial fluorescence localization microscopy, to attain hemodynamic imaging of the whole murine pial and calvarial vasculature at frame rates up to 1,000 Hz and spatial resolution reaching 5.4 µm. Using Pia-FLOW, we provide detailed maps of flow velocity, direction, and vascular diameters which can serve as ground-truth data for further studies, advancing our understanding of brain fluid dynamics. Furthermore, Pia-FLOW revealed that the pial vascular network functions as one unit for robust allocation of blood after stroke.

Pediatric non-galenic pial arteriovenous fistula's characteristics and outcomes: a systematic review.

INTRODUCTION: Pediatric non-galenic pial arteriovenous fistulas (pAVFs) are rare vascular malformations that are characterized by a pial arterial-venous connection without an intervening capillary bed. Outcomes and treatment strategies for pAVFs are highly individualized, owing to the rarity of the disease and lack of large-scale data guiding optimal treatment approaches. METHODS: We performed a systematic review of pediatric patients (< 18 years at diagnosis) diagnosed with a pAVF by digital subtraction angiogram (DSA). The demographics, treatment modalities, and outcomes were documented for each patient and clinical outcome data was collected. Descriptive information stratified by outcome scores were classified as follows: 1 = excellent (no deficit and full premorbid activity), 2 = good (mild deficit and full premorbid activity), 3 = fair (moderate deficit and impaired activity), 4 = poor (severe deficit and dependent on others), 5 = death. RESULTS: A total of 87 studies involving 231 patients were identified. Median age at diagnosis was 3 years (neonates to 18 years). There was slight male preponderance (55.4%), and 150 subjects (81.1%*) experienced excellent outcomes after treatment. Of the 189 patients treated using endovascular approaches, 80.3% experienced excellent outcomes and of the 15 patients surgically treated subjects 75% had an excellent outcome. The highest rate of excellent outcomes was achieved in patients treated with Onyx (95.2%) and other forms of EvOH (100%). High output heart failure and comorbid vascular lesions tended to result in worse outcomes, with only 54.2% and 68% of subjects experiencing an excellent outcome, respectively. *Outcomes were reported in only 185 patients. CONCLUSION: pAVFs are rare lesions, necessitating aggregation of patient data to inform natural history and optimal treatment strategies. This review summarizes the current literature on pAVF in children, where children presenting with heart failure as a result of high flow through the lesion were less likely to experience an excellent outcome. Prospective, large-scale studies would further characterize pediatric pAVFs and enable quantitative analysis of outcomes to inform best treatment practices.

Radio-pathologic correlation: no pial angioma-subarachnoid varicose network drainage pathway in Sturge-Weber syndrome.

PURPOSE: The traditional imaging findings reported in Sturge-Weber syndrome (SWS) include endpoints of cortical injury-cortical atrophy and cortical calcifications-but also what has been termed a "leptomeningeal angiomatosis," the latter recognized and reported as a leptomeningeal enhancement on magnetic resonance imaging (MRI). The objective of this study is to demonstrate through neuropathological correlation that the "leptomeningeal angiomatosis" in patients with Sturge-Weber syndrome (SWS), represents a re-opened primitive venous network in the subarachnoid space that likely acts as an alternative venous drainage pathway, seen separately to abnormal pial enhancement. MATERIALS AND METHODS: Retrospective review of MR imaging and surgical pathology of patients that underwent surgery for epilepsy at a tertiary, children's hospital. A pediatric radiologist with more than 20 years of experience reviewed the MR imaging. Surgically resected brain specimens that had been sectioned and fixed in 10% paraformaldehyde for histologic processing, following processing and paraffin embedding, were cut into 5-µm unstained slides which were subsequently stained with hematoxylin and eosin (H&E). Slides were re-examined by a board-certified pediatric neuropathologist, and histologic features specifically relating to cerebral surface and vascularity were documented for correlation with MR imaging of the resected region performed prior to resection. RESULTS: Five patients were reviewed (3 boys and 2 girls; the median age at the onset of seizures was 12 months (IQR, 7 to 45 months); the median age at surgery was 33 months (IQR, 23.5 to 56.5 months)). Surgical procedures included the following: 4, hemispherotomy (right: 2, left: 2) and 1, hemispherectomy (right). A subarachnoid space varicose network was present on both MRI and histology in 4 patients. Calcifications were seen on both MRI and histology in 3 patients. Abnormal leptomeningeal enhancement was present in 5 patients and seen separately from the subarachnoid vascular network in 4 patients. CONCLUSION: Histopathology confirmed the MRI findings of a subarachnoid space varicose network seen separately from leptomeningeal enhancement and presumed to represent an alternative venous drainage pathway to compensate for maldevelopment of cortical veins, the primary abnormality in SWS. No pial-based angioma was identified.

The role of surgical disconnection for posterior fossa pial arteriovenous fistulas and dural fistulas with pial supply: an illustrative case series.

BACKGROUND: Pial arteriovenous fistulas (pAVFs) are rare vascular malformations characterized by high-flow arteriovenous shunting involving a cortical arterial supply directly connecting to venous drainage without an intermediate nidus. Dural arteriovenous fistulas (dAVFs) can infrequently involve additional pial feeders which can introduce higher flow shunting and increase the associated treatment risk. In the posterior fossa, arteriovenous fistula (AVF) angioarchitecture tends to be particularly complex, involving either multiple arterial feeders-sometimes from both dural and pial origins-or small caliber vessels that are difficult to catheterize and tend to be intimately involved with functionally critical brainstem or upper cervical cord structures. Given their rarity, published experience on microsurgical or endovascular treatment strategies for posterior fossa pAVFs and dAVFs with pial supply remains limited. METHODS: Retrospective chart review from 2019-2023 at a high-volume center identified six adult patients with posterior fossa pAVFs that were unable to be fully treated endovascularly and required microsurgical disconnection. These cases are individually presented with a technical emphasis and supported by comprehensive angiographic and intraoperative images. RESULTS: One vermian (Case 1), three cerebellopontine angle (Cases 2-4) and two craniovertebral junction (Cases 5-6) posterior fossa pAVFs or dAVFs with pial supply are presented. Three cases involved mixed dural and pial arterial supply (Cases 1, 4, and 6), and one case involved a concomitant microAVM (Case 2). Endovascular embolization was attempted in four cases (Cases 1-4): The small caliber and tortuosity of the main arterial feeder prevented catheterization in two cases (Cases 1 and 3). Partial embolization was achieved in Cases 2 and 4. In Cases 5 and 6, involvement of the lateral spinal artery or anterior spinal artery created a prohibitive risk for endovascular embolization, and surgical clip ligation was pursued as primary management. In all cases, microsurgical disconnection resulted in complete fistula obliteration without evidence of recurrence on follow-up imaging (mean follow-up 27.1 months). Two patients experienced persistent post-treatment sensory deficits without significant functional limitation. CONCLUSIONS: This illustrative case series highlights the technical difficulties and anatomical limitations of endovascular management for posterior fossa pAVFs and dAVFs with pial supply and emphasizes the relative safety and utility of microsurgical disconnection in this context. A combined approach involving partial preoperative embolization-when the angioarchitecture is permissive-can potentially decrease surgical morbidity. Larger studies are warranted to better define the role for multimodal intervention and to assess associated long-term AVF obliteration rates in the setting of pial arterial involvement.

Expect the unexpected: a case of spontaneous thrombosis of a pial arteriovenous fistula in a preterm newborn with review of the literature.

INTRODUCTION: Pial arteriovenous fistulas (pAVF) are rare vascular malformations, especially in children and newborns. In neonates, the most common symptom is congestive heart failure. CASE PRESENTATION: We report a case of an asymptomatic preterm newborn incidentally diagnosed with pAVF during a routine cranial ultrasound (cUS) on the third day of life. Cerebral magnetic resonance (MRI) confirmed the diagnosis. A wait-and-see approach was chosen by the multidisciplinary team. The cUS and the MRI on day 14 of life showed the spontaneous resolution of the lesion. CONCLUSIONS: This case underlines the challenges in identifying pAVF in the first weeks of life and demonstrates a possible positive outcome for affected neonates.

Subpial Hemorrhage in Neonates: What Radiologists Need to Know.

OBJECTIVE. Subpial hemorrhages, typically seen in neonates, are rare but can harm the adjacent brain parenchyma. The purpose of this review is to summarize the anatomy and pathophysiology of subpial hemorrhage and highlight its characteristic neuro-imaging pattern. CONCLUSION. The distinctive neuroimaging pattern of subpial hemorrhage is best appreciated on brain MRI, which shows the morphology over the cortex and injury to adjacent cortex and subcortical white matter. These findings do not occur in subarachnoid and subdural hemorrhages. Recognizing the pattern of subpial hemorrhages should guide prognostic precision, prognostication, and counseling.

De Novo Dural Arteriovenous Fistula on Draining Veins of Previously Treated Pial Arteriovenous Malformation: a Case Report.

A 71-year-old man, with a pial micro-arteriovenous malformation (pAVM) draining into the confluence of the vein of Trolard and the vein of Labbé was surgically removed, sparing these cortical veins. 4-months MR and angiographic controls showed a de novo dural arteriovenous fistula (dAVF) draining into the previously spared cortical veins. It was removed using intraoperative motor evoked potentials (MEP). This is the first case of iatrogenic dAVF developing on the same draining vein of a previously treated pAVM. De novo dAVFs are generally iatrogenic. This case suggests that the unresected venous drainage of an AVM might be the substratum for neo-angiogenetic processes; moreover inflammation related to surgery might be the trigger factor for the development of the dAVF.

Estimates of cortical column orientation improve MEG source inversion.

Determining the anatomical source of brain activity non-invasively measured from EEG or MEG sensors is challenging. In order to simplify the source localization problem, many techniques introduce the assumption that current sources lie on the cortical surface. Another common assumption is that this current flow is orthogonal to the cortical surface, thereby approximating the orientation of cortical columns. However, it is not clear which cortical surface to use to define the current source locations, and normal vectors computed from a single cortical surface may not be the best approximation to the orientation of cortical columns. We compared three different surface location priors and five different approaches for estimating dipole vector orientation, both in simulations and visual and motor evoked MEG responses. We show that models with source locations on the white matter surface and using methods based on establishing correspondences between white matter and pial cortical surfaces dramatically outperform models with source locations on the pial or combined pial/white surfaces and which use methods based on the geometry of a single cortical surface in fitting evoked visual and motor responses. These methods can be easily implemented and adopted in most M/EEG analysis pipelines, with the potential to significantly improve source localization of evoked responses.

In utero alcohol exposure exacerbates endothelial protease activity from pial microvessels and impairs GABA interneuron positioning.

In utero alcohol exposure can induce severe neurodevelopmental disabilities leading to long-term behavioral deficits. Because alcohol induces brain defects, many studies have focused on nervous cells. However, recent reports have shown that alcohol markedly affects cortical angiogenesis in both animal models and infants with fetal alcohol spectrum disorder (FASD). In addition, the vascular system is known to contribute to controlling gamma-aminobutyric acid (GABA)ergic interneuron migration in the developing neocortex. Thus, alcohol-induced vascular dysfunction may contribute to the neurodevelopmental defects in FASD. The present study aimed at investigating the effects of alcohol on endothelial activity of pial microvessels. Ex vivo experiments on cortical slices from mouse neonates revealed that in endothelial cells from pial microvessels acute alcohol exposure inhibits both glutamate-induced calcium mobilization and activities of matrix metalloproteinase-9 (MMP-9) and tissue plasminogen activator (tPA). The inhibitory effect of alcohol on glutamate-induced MMP-9 activity was abrogated in tPA-knockout and Grin1flox/VeCadcre mice suggesting that alcohol interacts through the endothelial NMDAR/tPA/MMP-9 vascular pathway. Contrasting with the effects from acute alcohol exposure, in mouse neonates exposed to alcohol in utero during the last gestational week, glutamate exacerbated both calcium mobilization and endothelial protease activities from pial microvessels. This alcohol-induced vascular dysfunction was associated with strong overexpression of the N-methyl-d-aspartate receptor subunit GluN1 and mispositioning of the Gad67-GFP interneurons that normally populate the superficial cortical layers. By comparing several human control fetuses with a fetus chronically exposed to alcohol revealed that alcohol exposure led to mispositioning of the calretinin-positive interneurons, whose density was decreased in the superficial cortical layers II-III and increased in deepest layers. This study provides the first mechanistic and functional evidence that alcohol impairs glutamate-regulated activity of pial microvessels. Endothelial dysfunction is characterized by altered metalloproteinase activity and interneuron mispositioning, which was also observed in a fetus with fetal alcohol syndrome. These data suggest that alcohol-induced endothelial dysfunction may contribute in ectopic cortical GABAergic interneurons, that has previously been described in infants with FASD.

Spatial distribution of human arachnoid trabeculae.

Traumatic brain injury (TBI) is a common injury modality affecting a diverse patient population. Axonal injury occurs when the brain experiences excessive deformation as a result of head impact. Previous studies have shown that the arachnoid trabeculae (AT) in the subarachnoid space significantly influence the magnitude and distribution of brain deformation during impact. However, the quantity and spatial distribution of cranial AT in humans is unknown. Quantification of these microstructural features will improve understanding of force transfer during TBI, and may be a valuable dataset for microneurosurgical procedures. In this study, we quantify the spatial distribution of cranial AT in seven post-mortem human subjects. Optical coherence tomography (OCT) was used to conduct in situ imaging of AT microstructure across the surface of the human brain. OCT images were segmented to quantify the relative amounts of trabecular structures through a volume fraction (VF) measurement. The average VF for each brain ranged from 22.0% to 29.2%. Across all brains, there was a positive spatial correlation, with VF significantly greater by 12% near the superior aspect of the brain (p < .005), and significantly greater by 5%-10% in the frontal lobes (p < .005). These findings suggest that the distribution of AT between the brain and skull is heterogeneous, region-dependent, and likely contributes to brain deformation patterns. This study is the first to image and quantify human AT across the cerebrum and identify region-dependencies. Incorporation of this spatial heterogeneity may improve the accuracy of computational models of human TBI and enhance understanding of brain dynamics.

Hypertension and sympathetic nervous system overactivity rely on the vascular tone of pial vessels of the rostral ventrolateral medulla in spontaneously hypertensive rats.

NEW FINDINGS: What is the central question of this study? Is purinergic signalling in the pial vessels involved in the control of vascular tone in the ventral surface of the brainstem, affecting high blood pressure and sympathetic overactivity in spontaneously hypertensive rats? What is the main finding and its importance? The regulation of vascular tone in the ventral surface of the brainstem is tailored to support neuronal functions, arterial pressure and sympathetic activity. This adds one more piece in the complex puzzle to understand the central mechanisms underlying the genesis of hypertension. ABSTRACT: Evidence suggests the rostral ventrolateral medulla (RVLM) region is chronically hypoperfused and hypoxic in spontaneously hypertensive rats (SHR), which can facilitate ATP release throughout the brainstem. Thus, we hypothesized that purinergic signalling plays a key role in the increased vascular tone in the RVLM region, which in turn could be responsible for the high sympathetic tone and blood pressure in the SHR. The application of an antagonist of P2 receptors, pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (10 µm), or of P2Y1a receptors, MRS2179 (100 µm), on the surface of RVLM pial vessels of SHR produced an increase in the diameter of blood vessels (PPADS: 31 ± 1.4 µm or MRS2179: 32 ± 0.78 µm vs. saline: 27 ± 1.2 µm), an effect not observed in normotensive Wistar rats. In addition, the antagonism of P2 receptors was able to evoke a significant decrease in the arterial pressure, heart rate and splanchnic nerve activity in SHR, but not in Wistar rats. Our data show that SHR have higher vascular tone of pial vessels in the RVLM region when compared to the normotensive Wistar rats, a mechanism that relies on purinergic signalling through P2 receptors, suggesting a possible association with higher activity of sympathoexcitatory neurones, and sustained increases in blood pressure.

Localization of TRPA1 channels and characterization of TRPA1 mediated responses in dural and pial arteries in vivo after intracarotid infusion of Na2S.

BACKGROUND: The Transient Receptor Potential Ankyrin 1 (TRPA1) channel might play a role in migraine. However, different mechanisms for this have been suggested. The purpose of our study was to investigate the localization and significance of TRPA1 channels in rat pial and dural arteries. METHODS: Immunofluorescence microscopy was used to localize TRPA1 channels in dural arteries, pial arteries, dura mater and trigeminal ganglion. The genuine closed cranial window model was used to examine the effect of Na2S, a donor of the TRPA1 channel opener H2S, on the diameter of pial and dural arteries. Further, we performed blocking experiments with TRPA1 antagonist HC-030031, calcitonin gene-related peptide (CGRP) receptor antagonist olcegepant and KCa3.1 channel blocker TRAM-34. RESULTS: TRPA1 channels were localized to the endothelium of both dural and pial arteries and in nerve fibers in dura mater. Further, we found TRPA1 expression in the membrane of trigeminal ganglia neuronal cells, some of them also staining for CGRP. Na2S caused dilation of both dural and pial arteries. In dural arteries, this was inhibited by HC-030031 and olcegepant. In pial arteries, the dilation was inhibited by TRAM-34, suggesting involvement of the KCa3.1 channel. CONCLUSION: Na2S causes a TRPA1- and CGRP-dependent dilation of dural arteries and a KCa3.1 channel-dependent dilation of pial arteries in rats.

Formation and Resolution of Pial Microvascular Thrombosis in a Mouse Model of Thrombotic Thrombocytopenic Purpura.

OBJECTIVE: Microvascular thrombosis is the hallmark pathology of thrombotic thrombocytopenic purpura (TTP), a rare life-threatening disease. Neurological dysfunction is present in over 90% of patients with TTP, and TTP can cause long-lasting neurological damage or death. However, the pathophysiology of microvascular thrombosis in the brain is not well studied to date. Here, we investigate the formation and resolution of thrombosis in pial microvessels. Approach and Results: Using a cranial intravital microscopy in well-established mouse models of congenital TTP induced by infusion of recombinant VWF (von Willebrand factor), we found that soluble VWF, at high concentration, adheres to the endothelium of the vessel wall, self-associates, and initiates platelet adhesion resulting in the formation of pial microvascular thrombosis in ADAMTS13-/- (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) mice. Importantly, VWF-mediated pial microvascular thrombosis occurred without vascular injury to the brain, and thrombi consisted of resting platelets adhered onto ultra-large VWF without fibrin in the brain in rVWF (recombinant VWF) challenged ADAMTS13-/- mice. Prophylactic treatment with recombinant ADAMTS13 (BAX930) effectively prevented the onset of the VWF-mediated microvascular thrombosis and therapeutic treatment with BAX930 acutely resolved the preexisting or growing thrombi in the brain of ADAMTS13-/- mice after rVWF challenge. The absence of platelet activation and fibrin formation within VWF-mediated thrombi and efficacy of BAX930 was confirmed with an endothelial-driven VWF-mediated microvascular thrombosis model in mice. CONCLUSIONS: Our results provide important insight into the initiation and development of microvascular thrombi in mouse models that mimics TTP and indicate that rADAMTS13 could be an effective interventional therapy for microvascular thrombosis, the hallmark pathology in TTP.

Pediatric pial arteriovenous fistula located at the bottom of the callosal sulcus presenting with intraventricular hemorrhage: a case report and literature review.

BACKGROUND: A pial arteriovenous fistula (pAVF) is a rare condition characterized by a direct connection between a cerebral artery and cerebral vein without an intervening nidus. The prognosis is poor in untreated cases with hemorrhagic manifestations, indicating that surgical treatment is desirable. We describe a successful endovascular treatment for a pediatric case of ruptured pAVF located at the bottom of the sulcus. CLINICAL DESCRIPTION: An 11-year-old girl presented with severe headache and mild disturbance of consciousness. Head computed tomography showed hemorrhage in the callosal sulcus and ventricle. Cerebral angiography showed an arteriovenous shunt without a nidus. The branching artery from the pericallosal artery was connected directly to the thalamostriate vein without varix, and the shunt point was located at the bottom of the callosal sulcus. The patient was diagnosed with pAVF involving a single feeder and single drainer. Emergency endovascular transarterial embolization was performed using 20% N-butyl cyanoacrylate, and the shunt disappeared completely without complications. The patient was discharged with no neurological deficits. CONCLUSION: Endovascular treatment is feasible, safe, and effective for pediatric cases of deeply located pAVF.

How I do it: dorsolateral approach for ventrolateral intramedullary cavernoma.

BACKGROUND: For small and lateral lesions, in order to avoid postoperative sequelae related to dorso-median myelotomy, we propose to describe the use of a ventrolateral approach for intramedullary lesions. METHOD: Performing this approach entails that the denticulate ligament is cut from its dural attachment and retracted. Rotation of the spinal cord must be achieved with great caution and under electrophysiological monitoring. After pia mater incision, hydrodissection is useful to gently dissect the cavernoma and promote a cleavage plane. CONCLUSION: In the case of lateral intramedullary lesions, using this approach maximized the absence of postoperative deficit.

Unexpected and Sudden Death Due to Undiagnosed Moraxella catarrhalis Meningoencephalitis in a 40-day-old Infant: Case Report and Literature Review.

Acute bacterial meningitis in infants and newborns represents a medical emergency and a significant cause of mortality and morbidity worldwide. Moraxella catarrhalis has been considered a microorganism with low pathogenic potential, and only in exceptional cases has it been found to cause meningitis in infants and immunocompetent people. We will now document an unusual case of an unexpected and sudden death of a 40-day-old infant due to acute meningitis from M. catarrhalis, apparently asymptomatic and subsequently diagnosed by an autopsy. According to our knowledge this is the first case of unexpected infant death due to undiagnosed M. catarrhalis meningitis.The suggested case, as well as for the rarity of such a fatal event, should be considered a caution to pediatrics and neonatologists for M. catarrhalis can cause paucisymptomatic meningoencephalitis in infants which can be potentially fatal.From a forensic point of view, an autopsy accompanied by a multidisciplinary assessment is always necessary in cases of unexpected infant deaths to identify the causes.

Developmental biology of the meninges.

The meninges are membranous layers surrounding the central nervous system. In the head, the meninges lie between the brain and the skull, and interact closely with both during development. The cranial meninges originate from a mesenchymal sheath on the surface of the developing brain, called primary meninx, and undergo differentiation into three layers with distinct histological characteristics: the dura mater, the arachnoid mater, and the pia mater. While genetic regulation of meningeal development is still poorly understood, mouse mutants and other models with meningeal defects have demonstrated the importance of the meninges to normal development of the calvaria and the brain. For the calvaria, the interactions with the meninges are necessary for the progression of calvarial osteogenesis during early development. In later stages, the meninges control the patterning of the skull and the fate of the sutures. For the brain, the meninges regulate diverse processes including cell survival, cell migration, generation of neurons from progenitors, and vascularization. Also, the meninges serve as a stem cell niche for the brain in the postnatal life. Given these important roles of the meninges, further investigation into the molecular mechanisms underlying meningeal development can provide novel insights into the coordinated development of the head.

Dependence of resting-state fMRI fluctuation amplitudes on cerebral cortical orientation relative to the direction of B0 and anatomical axes.

Functional magnetic resonance imaging (fMRI) is now capable of sub-millimetre scale measurements over the entire human brain, however with such high resolutions each voxel is influenced by the local fine-scale details of the cerebral cortical vascular anatomy. The cortical vasculature is structured with the pial vessels lying tangentially along the grey matter surface, intracortical diving arterioles and ascending venules running perpendicularly to the surface, and a randomly oriented capillary network within the parenchyma. It is well-known that the amplitude of the blood-oxygenation level dependent (BOLD) signal emanating from a vessel depends on its orientation relative to the B0-field. Thus the vascular geometric hierarchy will impart an orientation dependence to the BOLD signal amplitudes and amplitude differences due to orientation differences constitute a bias for interpreting neuronal activity. Here, we demonstrate a clear effect of cortical orientation to B0 in the resting-state BOLD-fMRI amplitude (quantified as the coefficient of temporal signal variation) for 1.1 mm isotropic data at 7T and 2 mm isotropic at 3T. The maximum bias, i.e. the fluctuation amplitude difference between regions where cortex is perpendicular to vs. parallel to B0, is about +70% at the pial surface at 7T and +11% at 3T. The B0 orientation bias declines with cortical depth, becomes progressively smaller closer to the white matter surface, but then increases again to a local maximum within the white matter just beneath the cortical grey matter, suggesting a distinct tangential network of white matter vessels that also generate a BOLD orientation effect. We further found significant (negative) biases with the cortex orientation to the anterior-posterior anatomical axis of the head: a maximum negative bias of about -30% at the pial surface at 7T and about -13% at 3T. The amount of signal variance explained by the low frequency drift, motion and the respiratory cycle also showed a cortical orientation dependence; only the cardiac cycle induced signal variance was independent of cortical orientation, suggesting that the cardiac induced component of the image time-series fluctuations is not related to a significant change in susceptibility. Although these orientation effects represent a signal bias, and are likely to be a nuisance in high-resolution analyses, they may help characterize the vascular influences on candidate fMRI acquisitions and, thereby, may be exploited to improve the neuronal specificity of fMRI.

Activation of pial and dural macrophages and dendritic cells by cortical spreading depression.

OBJECTIVE: Cortical spreading depression (CSD) has long been implicated in migraine attacks with aura. The process by which CSD, a cortical event that occurs within the blood-brain barrier (BBB), results in nociceptor activation outside the BBB is likely mediated by multiple molecules and cells. The objective of this study was to determine whether CSD activates immune cells inside the BBB (pia), outside the BBB (dura), or in both, and if so, when. METHODS: Investigating cellular events in the meninges shortly after CSD, we used in vivo two-photon imaging to identify changes in macrophages and dendritic cells (DCs) that reside in the pia, arachnoid, and dura and their anatomical relationship to TRPV1 axons. RESULTS: We found that activated meningeal macrophages retract their processes and become circular, and that activated meningeal DCs stop migrating. We found that CSD activates pial macrophages instantaneously, pial, subarachnoid, and dural DCs 6-12 minutes later, and dural macrophages 20 minutes later. Dural macrophages and DCs can appear in close proximity to TRPV1-positive axons. INTERPRETATION: The findings suggest that activation of pial macrophages may be more relevant to cases where aura and migraine begin simultaneously, that activation of dural macrophages may be more relevant to cases where headache begins 20 to 30 minutes after aura, and that activation of dural macrophages may be mediated by activation of migratory DCs in the subarachnoid space and dura. The anatomical relationship between TRPV1-positive meningeal nociceptors, and dural macrophages and DCs supports a role for these immune cells in the modulation of head pain. Ann Neurol 2018;83:508-521.

Hyperglycemia-induced transcriptional regulation of ROCK1 and TGM2 expression is involved in small artery remodeling in obese diabetic Göttingen Minipigs.

Obesity and diabetes in humans are associated with hypertrophic remodeling and increased media:lumen ratio of small resistance arteries, which is an independent predictor of cardiovascular events. In order to minimize increases in media:lumen ratio, hypertrophic remodeling should be accompanied by outward remodeling. We aimed to investigate the mechanisms of structural remodeling in small pial arteries (PAs) and terminal mesenteric arteries (TMAs) from obese Göttingen Minipigs with or without diabetes. Göttingen Minipigs received either control diet (lean control (LC)), high fat/high fructose/high cholesterol diet (FFC), or FFC diet with streptozotocin (STZ)-induced diabetes (FFC/STZ) for 13 months. At the end of the study (20 months), we assessed body weight, fasting plasma biochemistry, passive vessel dimensions, mRNA expression (matrix metallopeptidases 2/9 (MMP2, MMP9), tissue inhibitor of metallopeptidase 1 (TIMP1), transglutaminase 2 (TGM2), Rho-kinase 1 (ROCK1), TGFß-receptor 2 (TGFBR2), and IGF1-receptor (IGFR1) genes), and immunofluorescence in PAs and TMAs. We performed multiple linear correlation analyses using plasma values, structural data, and gene expression data. We detected outward hypertrophic remodeling in TMAs and hypertrophic remodeling in PAs from FFC/STZ animals. ROCK1 and TGM2 genes were up-regulated in PAs and TMAs from the FFC/STZ group. Passive lumen diameter (PLD) of TMAs was correlated with plasma values of glucose (GLU), fructosamine (FRA), total cholesterol (TC), and triglycerides (TGs). ROCK1 and TGM2 expressions in TMAs were correlated with PLD, plasma GLU, fructosamine, and TC. ROCK1 and TGM2 proteins were immunolocalized in the media of PAs and TMAs, and their fluorescence levels were increased in the FFC/STZ group. Hyperglycemia/hyperlipidemia is involved in regulation of ROCK1 and TGM2 expression leading to outward remodeling of small resistance arteries in obese diabetic Göttingen Minipigs.