Search

Neurodegenerative diseases (ND) affect distinct populations of neurons and manifest various clinical and pathological symptoms. A subset of ND prognoses has been linked to vascular risk factors. Consequently, the current study investigated retinal vascular abnormalities in a murine model of Lafora neurodegenerative disease (LD), a fatal and genetic form of progressive myoclonus epilepsy that affects children. Here, arterial rigidity was evaluated by measuring pulse wave velocity and vasculature deformations in the retina. Our findings in the LD mouse model indicate altered pulse wave velocity, retinal vascular thinning, and convoluted retinal arteries.

The editorial discusses the importance of maintaining brain health through targeting the vasculature and metabolome to prevent brain aging and related diseases. It highlights the role of neurovascular coupling, the neurovascular unit, and the blood-brain barrier in ensuring brain homeostasis. Various studies presented in the editorial focus on different aspects of neurovascular health, such as the role of perivascular macrophages in ALS, neurotrophic factor receptor in diabetic macular edema, and pericytes in multiple sclerosis. The research emphasizes the significance of understanding and addressing disruptions in the neurovascular unit and metabolic processes to prevent cognitive decline and neurodegenerative diseases. [Extracted from the article]

Simple Summary: We discussed the reliability of fMRI for in vivo evaluation of eloquent cortex, which helps to reduce the risk of postsurgical morbidity. Task-based fMRI (tb-fMRI) is commonly utilized for the noninvasive, accurate evaluation of eloquent cortex implicated in sensorimotor, language, and visual function. Resting-state fMRI (rs-fMRI) is being increasingly employed in addition to tb-fMRI and may be able to serve as an adjunct for tb-fMRI for presurgical mapping in the future. There is, however, a need to confirm the reliability of rs-fMRI data in various clinical contexts, and more validation and standardization is necessary prior to adopting this tool for daily clinical care. Although tb-fMRI has been proved to be a trustworthy method, the problem of neurovascular uncoupling (NVU) needs to be addressed to give the most accurate functional evaluation in clinical practice. Breath-hold cerebrovascular reactivity (BH-CVR) methods can be used to assess risk of NVU. We hope that future research will investigate and overcome the problem of NVU encountered in presurgical brain mapping with BOLD fMRI. Functional magnetic resonance imaging (fMRI) with blood oxygen level-dependent (BOLD) technique is useful for preoperative mapping of brain functional networks in tumor patients, providing reliable in vivo detection of eloquent cortex to help reduce the risk of postsurgical morbidity. BOLD task-based fMRI (tb-fMRI) is the most often used noninvasive method that can reliably map cortical networks, including those associated with sensorimotor, language, and visual functions. BOLD resting-state fMRI (rs-fMRI) is emerging as a promising ancillary tool for visualization of diverse functional networks. Although fMRI is a powerful tool that can be used as an adjunct for brain tumor surgery planning, it has some constraints that should be taken into consideration for proper clinical interpretation. BOLD fMRI interpretation may be limited by neurovascular uncoupling (NVU) induced by brain tumors. Cerebrovascular reactivity (CVR) mapping obtained using breath-hold methods is an effective method for evaluating NVU potential. [ABSTRACT FROM AUTHOR]

The neurovascular unit (NVU) is involved in the pathological changes in Alzheimer's disease (AD). The NVU is a structural and functional complex that maintains microenvironmental homeostasis and metabolic balance in the central nervous system. As one of the most important components of the NVU, microglia not only induce blood-brain barrier breakdown by promoting neuroinflammation, the infiltration of peripheral white blood cells and oxidative stress but also mediate neurovascular uncoupling by inducing mitochondrial dysfunction in neurons, abnormal contraction of cerebral vessels, and pericyte loss in AD. In addition, microglia-mediated dysfunction of cellular components in the NVU, such as astrocytes and pericytes, can destroy the integrity of the NVU and lead to NVU impairment. Therefore, we review the mechanisms of microglia-mediated NVU dysfunction in AD. Furthermore, existing therapeutic advancements aimed at restoring the function of microglia and the NVU in AD are discussed. Finally, we predict the role of pericytes in microglia-mediated NVU dysfunction in AD is the hotspot in the future. [ABSTRACT FROM AUTHOR]

Impairment of moment-to-moment adjustment of cerebral blood flow (CBF) to the increased oxygen and energy requirements of active brain regions via neurovascular coupling (NVC) contributes to the genesis of age-related cognitive impairment. Aging is associated with marked deficiency in the vasoprotective hormone insulin-like growth factor-1 (IGF-1). Preclinical studies on animal models of aging suggest that circulating IGF-1 deficiency is causally linked to impairment of NVC responses. The present study was designed to test the hypotheses that decreases in circulating IGF-1 levels in older adults also predict the magnitude of age-related decline of NVC responses. In a single-center cross-sectional study, we enrolled healthy young (n = 31, 11 female, 20 male, mean age: 28.4 + / − 4.2 years) and aged volunteers (n = 32, 18 female, 14 male, mean age: 67.9 + / − 4.1 years). Serum IGF-1 level, basal CBF (phase contrast magnetic resonance imaging (MRI)), and NVC responses during the trail making task (with transcranial Doppler sonography) were assessed. We found that circulating IGF-1 levels were significantly decreased with age and associated with decreased basal CBF. Age-related decline in IGF-1 levels predicted the magnitude of age-related decline in NVC responses. In conclusion, our study provides additional evidence in support of the concept that age-related circulating IGF-1 deficiency contributes to neurovascular aging, impairing CBF and functional hyperemia in older adults. [ABSTRACT FROM AUTHOR]

To match the metabolic demands of the brain, mechanisms have evolved to couple neuronal activity to vasodilation, thus increasing local cerebral blood flow and delivery of oxygen and glucose to active neurons. Rather than relying on metabolic feedback signals such as the consumption of oxygen or glucose, the main signalling pathways rely on the release of vasoactive molecules by neurons and astrocytes, which act on contractile cells. Vascular smooth muscle cells and pericytes are the contractile cells associated with arterioles and capillaries, respectively, which relax and induce vasodilation. Much progress has been made in understanding the complex signalling pathways of neurovascular coupling, but issues such as the contributions of capillary pericytes and astrocyte calcium signal remain contentious. Study of neurovascular coupling mechanisms is especially important as cerebral blood flow dysregulation is a prominent feature of Alzheimer's disease. In this article we will discuss developments and controversies in the understanding of neurovascular coupling and finish by discussing current knowledge concerning neurovascular uncoupling in Alzheimer's disease. [ABSTRACT FROM AUTHOR]

What defines the rate of energy use by the brain, as well as per neurons of different sizes in different structures and animals, is one fundamental aspect of neuroscience for which much has been theorized, but very little data are available. The prevalent theories and models consider that energy supply from the vascular system to different brain regions is adjusted both dynamically and in the course of development and evolution to meet the demands of neuronal activity. In this perspective, we offer an alternative view: that regional rates of energy use might be mostly constrained by supply , given the properties of the brain capillary network, the highly stable rate of oxygen delivery to the whole brain under physiological conditions, and homeostatic constraints. We present evidence that these constraints, based on capillary density and tissue oxygen homeostasis, are similar between brain regions and mammalian species, suggesting they derive from fundamental biophysical limitations. The same constraints also determine the relationship between regional rates of brain oxygen supply and usage over the full physiological range of brain activity, from deep sleep to intense sensory stimulation, during which the apparent uncoupling of blood flow and oxygen use is still a predicted consequence of supply limitation. By carefully separating "energy cost" into energy supply and energy use, and doing away with the problematic concept of energetic "demands," our new framework should help shine a new light on the neurovascular bases of metabolic support of brain function and brain functional imaging. We speculate that the trade-offs between functional systems and even the limitation to a single attentional spot at a time might be consequences of a strongly supply-limited brain economy. We propose that a deeper understanding of brain energy supply constraints will provide a new evolutionary understanding of constraints on brain function due to energetics; offer new diagnostic insight to disturbances of brain metabolism; lead to clear, testable predictions on the scaling of brain metabolic cost and the evolution of brains of different sizes; and open new lines of investigation into the microvascular bases of progressive cognitive loss in normal aging as well as metabolic diseases. [ABSTRACT FROM AUTHOR]

What defines the rate of energy use by the brain, as well as per neurons of different sizes in different structures and animals, is one fundamental aspect of neuroscience for which much has been theorized, but very little data are available. The prevalent theories and models consider that energy supply from the vascular system to different brain regions is adjusted both dynamically and in the course of development and evolution to meet the demands of neuronal activity. In this perspective, we offer an alternative view: that regional rates of energy use might be mostly constrained by supply, given the properties of the brain capillary network, the highly stable rate of oxygen delivery to the whole brain under physiological conditions, and homeostatic constraints. We present evidence that these constraints, based on capillary density and tissue oxygen homeostasis, are similar between brain regions and mammalian species, suggesting they derive from fundamental biophysical limitations. The same constraints also determine the relationship between regional rates of brain oxygen supply and usage over the full physiological range of brain activity, from deep sleep to intense sensory stimulation, during which the apparent uncoupling of blood flow and oxygen use is still a predicted consequence of supply limitation. By carefully separating “energy cost” into energy supply and energy use, and doing away with the problematic concept of energetic “demands,” our new framework should help shine a new light on the neurovascular bases of metabolic support of brain function and brain functional imaging. We speculate that the trade-offs between functional systems and even the limitation to a single attentional spot at a time might be consequences of a strongly supply-limited brain economy. We propose that a deeper understanding of brain energy supply constraints will provide a new evolutionary understanding of constraints on brain function due to energetics; offer new diagnostic insight to disturbances of brain metabolism; lead to clear, testable predictions on the scaling of brain metabolic cost and the evolution of brains of different sizes; and open new lines of investigation into the microvascular bases of progressive cognitive loss in normal aging as well as metabolic diseases.

Age-related impairment of neurovascular coupling (NVC; or "functional hyperemia") compromises moment-to-moment adjustment of regional cerebral blood flow to increased neuronal activity and thereby contributes to the pathogenesis of vascular cognitive impairment (VCI). Previous studies established a causal link among age-related decline in circulating levels of insulin-like growth factor-1 (IGF-1), neurovascular dysfunction and cognitive impairment. Endothelium-mediated microvascular dilation plays a central role in NVC responses. To determine the functional consequences of impaired IGF-1 input to cerebromicrovascular endothelial cells, endothelium-mediated NVC responses were studied in a novel mouse model of accelerated neurovascular aging: mice with endothelium-specific knockout of IGF1R (VE-Cadherin-CreERT2/Igf1rf/f). Increases in cerebral blood flow in the somatosensory whisker barrel cortex (assessed using laser speckle contrast imaging through a cranial window) in response to contralateral whisker stimulation were significantly attenuated in VE-Cadherin-CreERT2/Igf1rf/f mice as compared to control mice. In VE-Cadherin-CreERT2/Igf1rf/f mice, the effects of the NO synthase inhibitor L-NAME were significantly decreased, suggesting that endothelium-specific disruption of IGF1R signaling impairs the endothelial NO-dependent component of NVC responses. Collectively, these findings provide additional evidence that IGF-1 is critical for cerebromicrovascular endothelial health and maintenance of normal NVC responses. [ABSTRACT FROM AUTHOR]

Functional magnetic resonance imaging for presurgical brain mapping enables neurosurgeons to identify viable tissue near a site of operable pathology which might be at risk of surgery-induced damage. However, focal brain pathology (e.g., tumors) may selectively disrupt neurovascular coupling while leaving the underlying neurons functionally intact. Such neurovascular uncoupling can result in false negatives on brain activation maps thereby compromising their use for surgical planning. One way to detect potential neurovascular uncoupling is to map cerebrovascular reactivity using either an active breath-hold challenge or a passive resting-state scan. The equivalence of these two methods has yet to be fully established, especially at a voxel level of resolution. To quantitatively compare breath-hold and resting-state maps of cerebrovascular reactivity, we first identified threshold settings that optimized coverage of gray matter while minimizing false responses in white matter. When so optimized, the resting-state metric had moderately better gray matter coverage and specificity. We then assessed the spatial correspondence between the two metrics within cortical gray matter, again, across a wide range of thresholds. Optimal spatial correspondence was strongly dependent on threshold settings which if improperly set tended to produce statistically biased maps. When optimized, the two CVR maps did have moderately good correspondence with each other (mean accuracy of 73.6%). Our results show that while the breath-hold and resting-state maps may appear qualitatively similar they are not quantitatively identical at a voxel level of resolution.

Functional magnetic resonance imaging for presurgical brain mapping enables neurosurgeons to identify viable tissue near a site of operable pathology which might be at risk of surgery-induced damage. However, focal brain pathology (e.g., tumors) may selectively disrupt neurovascular coupling while leaving the underlying neurons functionally intact. Such neurovascular un coupling can result in false negatives on brain activation maps thereby compromising their use for surgical planning. One way to detect potential neurovascular uncoupling is to map cerebrovascular reactivity using either an active breath-hold challenge or a passive resting-state scan. The equivalence of these two methods has yet to be fully established, especially at a voxel level of resolution. To quantitatively compare breath-hold and resting-state maps of cerebrovascular reactivity, we first identified threshold settings that optimized coverage of gray matter while minimizing false responses in white matter. When so optimized, the resting-state metric had moderately better gray matter coverage and specificity. We then assessed the spatial correspondence between the two metrics within cortical gray matter, again, across a wide range of thresholds. Optimal spatial correspondence was strongly dependent on threshold settings which if improperly set tended to produce statistically biased maps. When optimized, the two CVR maps did have moderately good correspondence with each other (mean accuracy of 73.6%). Our results show that while the breath-hold and resting-state maps may appear qualitatively similar they are not quantitatively identical at a voxel level of resolution. [ABSTRACT FROM AUTHOR]

Background: Potential neurovascular uncoupling (NVU) related to perinidal angiogenesis (PA) of brain arteriovenous malformations (AVMs) may cause inappropriate presurgical mapping using functional magnetic resonance imaging (fMRI), resulting in overconfident resection and postoperative morbidity. Purpose: To evaluate the potential impact of PA upon fMRI blood oxygen level‐dependent signal in the periphery of AVMs. Study Type: Prospective. Population: Twenty‐one patients with AVMs located in the primary sensorimotor cortex (SM1) undergoing task‐based fMRI (hand motor), and 19 patients with supratentorial AVMs undergoing resting‐state fMRI. Field Strength/Sequence: 3.0T, echo‐planar, time‐of‐flight, and magnetization‐prepared rapid gradient‐echo. Assessment: The presence of PA was determined by three observers (Y.C., J.W., and X.C.) according to digital subtraction angiography and MR angiography. Interhemispheric asymmetry of fMRI activations contralateral to hand movements was evaluated with the interhemispheric ratio of the average t‐value within ipsilesional SM1 to contralesional SM1. Regional homogeneity (ReHo) and fractional amplitude of low‐frequency fluctuations (fALFF) were extracted from ring‐shaped perinidal regions and contralateral homologous regions, and the corresponding interhemispheric ratios were calculated. The effect of PA on the interhemispheric asymmetry of motor activations, ReHo, and fALFF was estimated. Statistical Tests: Pearson analysis, paired and independent t‐test, multiple linear regression, Friedman test, and factorial analysis of variance were used. Results: Motor activations were significantly reduced in ipsilesional SM1 compared to contralesional SM1 (P < 0.05). The presence of PA was the independent predictor of activation loss in ipsilateral SM1(P < 0.05). Furthermore, perinidal regions exhibited reduced ReHo compared to the homologous regions (P < 0.05). PA was significantly associated with the decline of ReHo and fALFF in perinidal regions (P < 0.05, for both). Data Conclusion: The presence of PA can predict perinidal NVU that may confound the interpretation of both task‐based and resting‐state fMRI, highlighting the importance of alternative approaches of brain functional localization in improving treatment of AVMs. Level of Evidence: 2 Technical Efficacy Stage: 2 [ABSTRACT FROM AUTHOR]

Aging is associated with a significant deficiency in circulating insulin-like growth factor-1 (IGF-1), which has an important role in the pathogenesis of age-related vascular cognitive impairment (VCI). Impairment of moment-to-moment adjustment of regional cerebral blood flow via neurovascular coupling (NVC) importantly contributes to VCI. Previous studies established a causal link between circulating IGF-1 deficiency and neurovascular dysfunction. Release of vasodilator mediators from activated astrocytes plays a key role in NVC. To determine the impact of impaired IGF-1 signaling on astrocytic function, astrocyte-mediated NVC responses were studied in a novel mouse model of astrocyte-specific knockout of IGF1R (GFAP-CreERT2/Igf1rf/f) and accelerated neurovascular aging. We found that mice with disrupted astrocytic IGF1R signaling exhibit impaired NVC responses, decreased stimulated release of the vasodilator gliotransmitter epoxy-eicosatrienoic acids (EETs), and upregulation of soluble epoxy hydrolase (sEH), which metabolizes and inactivates EETs. Collectively, our findings provide additional evidence that IGF-1 promotes astrocyte health and maintains normal NVC, protecting cognitive health. [ABSTRACT FROM AUTHOR]

Components that comprise our brain parenchymal and cerebrovascular structures provide a homeostatic environment for proper neuronal function to ensure normal cognition. Cerebral insults (e.g. ischaemia, microbleeds and infection) alter cellular structures and physiologic processes within the neurovascular unit and contribute to cognitive dysfunction. COVID-19 has posed significant complications during acute and convalescent stages in multiple organ systems, including the brain. Cognitive impairment is a prevalent complication in COVID-19 patients, irrespective of severity of acute SARS-CoV-2 infection. Moreover, overwhelming evidence from in vitro, preclinical and clinical studies has reported SARS-CoV-2-induced pathologies in components of the neurovascular unit that are associated with cognitive impairment. Neurovascular unit disruption alters the neurovascular coupling response, a critical mechanism that regulates cerebromicrovascular blood flow to meet the energetic demands of locally active neurons. Normal cognitive processing is achieved through the neurovascular coupling response and involves the coordinated action of brain parenchymal cells (i.e. neurons and glia) and cerebrovascular cell types (i.e. endothelia, smooth muscle cells and pericytes). However, current work on COVID-19-induced cognitive impairment has yet to investigate disruption of neurovascular coupling as a causal factor. Hence, in this review, we aim to describe SARS-CoV-2's effects on the neurovascular unit and how they can impact neurovascular coupling and contribute to cognitive decline in acute and convalescent stages of the disease. Additionally, we explore potential therapeutic interventions to mitigate COVID-19-induced cognitive impairment. Given the great impact of cognitive impairment associated with COVID-19 on both individuals and public health, the necessity for a coordinated effort from fundamental scientific research to clinical application becomes imperative. This integrated endeavour is crucial for mitigating the cognitive deficits induced by COVID-19 and its subsequent burden in this especially vulnerable population., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Glioma growth can cause pervasive changes in the functional connectivity (FC) of brain networks, which has been associated with re-organization of brain functions and development of functional deficits in patients. Mechanisms underlying functional re-organization in brain networks are not understood and efforts to utilize functional imaging for surgical planning, or as a biomarker of functional outcomes are confounded by the heterogeneity in available human data. Here we apply multiple imaging modalities in a well-controlled murine model of glioma with extensive validation using human data to explore mechanisms of FC disruption due to glioma growth. We find gliomas cause both local and distal changes in FC. FC changes in networks proximal to the tumor occur secondary to hemodynamic alterations but surprisingly, remote FC changes are independent of hemodynamic mechanisms. Our data strongly implicate hemodynamic alterations as the main driver of local changes in measurements of FC in patients with glioma. [ABSTRACT FROM AUTHOR]

Functional MRI (fMRI) is well-established for the study of brain function in healthy populations, although its clinical application has proven more challenging. Specifically, cerebrovascular reactivity (CVR), which allows the assessment of the vascular response that serves as the basis for fMRI, has been shown to be reduced in healthy aging as well as in a range of diseases, including chronic stroke. However, the timing of when this occurs relative to the stroke event is unclear. We used a breath-hold fMRI task to evaluate CVR across gray matter in a group of acute stroke patients (

Patients with large artery intracranial occlusive disease (LAICOD) are at risk for both acute ischemia and chronic hypoperfusion. Collateral circulation plays an important role in prognosis, and imaging plays an essential role in diagnosis, treatment planning, and prognosis of patients with LAICOD. In addition to standard structural imaging, assessment of cerebral hemodynamic function is important to determine the adequacy of collateral supply. Among the currently available methods of assessment of cerebral hemodynamic function, measurement of cerebrovascular reactivity (CVR) using blood oxygen level-dependent (BOLD) MRI and precisely controlled CO2 has shown to be a safe, reliable, reproducible, and clinically useful method for long-term assessment of patients. Here, we report a case of long-term follow-up in a 28-year-old Caucasian female presented to the neurology clinic with a history of TIAs and LAICOD of the right middle cerebral artery (MCA). Initial structural MRI showed a right MCA stenosis and a small right coronal radiate lacunar infarct. Her CVR study showed a large area of impaired CVR with a paradoxical decrease in BOLD signal with hypercapnia involving the right MCA territory indicating intracerebral steal. The patient was managed medically with anticoagulant and antiplatelet therapy and was followed-up for over 9 years with both structural and functional imaging. Cortical thickness (CT) measures were longitudinally assessed from a region of interest that was applied to subsequent time points in the cortical region exhibiting steal physiology and in the same region of the contralateral healthy hemisphere. In the long-term follow-up, the patient exhibited improvement in her CVR as demonstrated by the development of collaterals with negligible changes to CT. Management of patients with LAICOD remains challenging since no revascularization strategies have shown efficacy except in patients with moyamoya disease. Management is well defined for acute ischemia where the presence and the adequacy of the collateralization dictate the need for intervention. Long-term assessment in neurovascular uncoupling (i.e., chronic ischemia) may reveal improvements in CVR as the durability of compensatory collaterals improve, even in cases with no intervention. Thus, assessment of cerebrovascular hemodynamics using CVR measurements coupled with time-of-flight MR angiography can be useful in the clinical management of patients with LAICOD. [ABSTRACT FROM AUTHOR]

Aging causes major alterations of all components of the neurovascular unit and compromises brain blood supply. Here, we tested how aging affects vascular reactivity in basilar arteries from young (<10 weeks; y-BA), old (>22 months; o-BA) and old (>22 months) heterozygous MYPT1-T-696A/+ knock-in mice. In isometrically mounted o-BA, media thickness was increased by ∼10% while the passive length tension relations were not altered. Endothelial denudation or pan-NOS inhibition (100 µmol/L L-NAME) increased the basal tone by 11% in y-BA and 23% in o-BA, while inhibition of nNOS (1 µmol/L L-NPA) induced ∼10% increase in both ages. eNOS expression was ∼2-fold higher in o-BA. In o-BA, U46619-induced force was augmented (pEC50 ∼6.9 vs. pEC50 ∼6.5) while responsiveness to DEA-NONOate, electrical field stimulation or nicotine was decreased. Basal phosphorylation of MLC20-S19 and MYPT1-T-853 was higher in o-BA and was reversed by apocynin. Furthermore, permeabilized o-BA showed enhanced Ca2+-sensitivity. Old T-696A/+ BA displayed a reduced phosphorylation of MYPT1-T696 and MLC20, a lower basal tone in response to L-NAME and a reduced eNOS expression. The results indicate that the vascular hypercontractility found in o-BA is mediated by inhibition of MLCP and is partially compensated by an upregulation of endothelial NO release. [ABSTRACT FROM AUTHOR]

Background: To demonstrate that the problem of brain tumor-related neurovascular uncoupling (NVU) is a significant issue with respect to resting state blood oxygen level dependent (BOLD) functional MRI (rsfMRI) similar to task-based BOLD fMRI, in which signal detectability can be compromised by breakdown of normal neurovascular coupling. Methods: We evaluated seven de novo brain tumor patients who underwent resting state fMRI as part of comprehensive clinical fMRI exams at 3 Tesla. For each of the seven patients who demonstrated evidence of NVU on task-based motor fMRI, we performed both an independent component analysis (ICA) and an atlas-based parcellation-based seed correlation analysis (SCA) of the resting state fMRI data. For each patient, ipsilesional (IL) and contralesional (CL) regions of interest (ROIs) comprising primary motor and somatosensory cortices were used to evaluate BOLD signal changes on Z score maps derived from both ICA and SCA analysis for evidence of NVU. A subsequent two-tailed t-test was performed to determine whether statistically significant differences between the two sides were present that were consistent with NVU. Results: In seven patients, overall decreased BOLD signal (based on suprathreshold voxels in ICA and SCA-derived Z-score maps) was noted in IL compared with CL ROIs (P < 0.01), consistent with NVU. Conclusion: We have demonstrated that NVU can result in false negative BOLD signal changes on rsfMRI comparable to previously published findings on standard motor task-based fMRI. [ABSTRACT FROM AUTHOR]

Aging is associated with marked deficiency in circulating IGF-1, which has been shown to contribute to age-related cognitive decline. Impairment of moment-to-moment adjustment of cerebral blood flow (CBF) via neurovascular coupling is thought to play a critical role in the genesis of age-related cognitive impairment. To establish the link between IGF-1 deficiency and cerebromicrovascular impairment, neurovascular coupling mechanisms were studied in a novel mouse model of IGF-1 deficiency (Igf1f/f-TBG-Cre-AAV8) and accelerated vascular aging. We found that IGF-1-deficient mice exhibit neurovascular uncoupling and show a deficit in hippocampal-dependent spatial memory test, mimicking the aging phenotype. IGF-1 deficiency significantly impaired cerebromicrovascular endothelial function decreasing NO mediation of neurovascular coupling. IGF-1 deficiency also impaired glutamate-mediated CBF responses, likely due to dysregulation of astrocytic expression of metabotropic glutamate receptors and impairing mediation of CBF responses by eicosanoid gliotransmitters. Collectively, we demonstrate that IGF-1 deficiency promotes cerebromicrovascular dysfunction and neurovascular uncoupling mimicking the aging phenotype, which are likely to contribute to cognitive impairment. [ABSTRACT FROM AUTHOR]

The blood oxygenation level-dependent (BOLD) phenomenon has profoundly revolutionized neuroscience, with applications ranging from normal brain development and aging, to brain disorders and diseases. While the BOLD effect represents an invaluable tool to map brain function, it does not measure neural activity directly; rather, it reflects changes in blood oxygenation resulting from the relative balance between cerebral oxygen metabolism (through neural activity) and oxygen supply (through cerebral blood flow and volume). As such, there are cases in which BOLD signals might be dissociated from neural activity, leading to misleading results. The emphasis of this review is to develop a critical perspective for interpreting BOLD results, through a comprehensive consideration of BOLD's metabolic and vascular underpinnings. We demonstrate that such an understanding is especially important under disease or resting conditions. We also describe state-of-the-art acquisition and analytical techniques to reveal physiological information on the mechanisms underlying measured BOLD signals. With these goals in mind, this review is structured to provide a fundamental understanding of: 1) the physiological and physical sources of the BOLD contrast; 2) the extraction of information regarding oxidative metabolism and cerebrovascular reactivity from the BOLD signal, critical to investigating neuropathology; and 3) the fundamental importance of metabolic and vascular mechanisms for interpreting resting-state BOLD measurements. [ABSTRACT FROM AUTHOR]

Purpose (i) to validate blood oxygenation level dependent (BOLD) breathhold cerebrovascular reactivity (BH CVR) mapping as an effective technique for potential detection of neurovascular uncoupling (NVU) in a cohort of patients with perirolandic low grade gliomas undergoing presurgical functional MRI (fMRI) for sensorimotor mapping, and (ii) to determine whether NVU potential, as assessed by BH CVR mapping, is prevalent in this tumor group. Materials and Methods We retrospectively evaluated 12 patients, with histological diagnosis of grade II glioma, who performed multiple motor tasks and a BH task. Sensorimotor activation maps and BH CVR maps were compared in two automatically defined regions of interest (ROIs), ipsilateral to the lesion (i.e., ipsilesional) and contralateral to the lesion (i.e., contralesional). Results Motor task mean T-value was significantly higher in the contralesional ROIs (6.00 ± 1.74 versus 4.34 ± 1.68; P = 0.00004) as well as the BH mean T-value (4.74 ± 2.30 versus 4.09 ± 2.50; P = 0.009). The number of active voxels was significantly higher in the contralesional ROIs (Z = 2.99; P = 0.03). Actual NVU prevalence was 75%. Conclusion Presurgical sensorimotor fMRI mapping can be affected by NVU-related false negative activation in low grade gliomas (76% of analyzed tasks). J. Magn. Reson. Imaging 2014;40:383-390. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Neurovascular uncoupling (NVU) is one of the most important confounds of blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMR imaging) in the setting of focal brain lesions such as brain tumors. This article reviews the assessment of NVU related to focal brain lesions with emphasis on the use of cerebrovascular reactivity mapping measurement methods and resting state BOLD fMR imaging metrics in the detection of NVU, as well as the use of amplitude of low-frequency fluctuation metrics to mitigate the effects of NVU on clinical fMR imaging activation., Competing Interests: Disclosure The authors report no financial conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Functional neuroimaging provides means to understand the relationship between brain structure and associated functions. Functional MR (fMR) imaging can offer a unique insight into preoperative planning for central nervous system (CNS) neoplasms by identifying areas of the brain effected or spared by the neoplasm. BOLD (blood-oxygen-level-dependent) fMR imaging can be reliably used to map eloquent cortex presurgically and is sufficiently accurate for neurosurgical planning. In patients with brain tumors undergoing neurosurgical intervention, fMR imaging can decrease postoperative morbidity. This article discusses the applications, significance, and interpretation of BOLD fMR imaging, and its applications in presurgical planning for CNS neoplasms., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Functional neuroimaging provides means to understand the relationship between brain structure and associated functions. Functional MR (fMR) imaging can offer a unique insight into preoperative planning for central nervous system (CNS) neoplasms by identifying areas of the brain effected or spared by the neoplasm. BOLD (blood-oxygen-level-dependent) fMR imaging can be reliably used to map eloquent cortex presurgically and is sufficiently accurate for neurosurgical planning. In patients with brain tumors undergoing neurosurgical intervention, fMR imaging can decrease postoperative morbidity. This article discusses the applications, significance, and interpretation of BOLD fMR imaging, and its applications in presurgical planning for CNS neoplasms., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The goal of this study was to demonstrate that a novel resting state BOLD ALFF (amplitude of low frequency fluctuations)-based correction method can substantially enhance the detectability of motor task activation in the presence of tumor-induced neurovascular uncoupling (NVU). Twelve de novo brain tumor patients who underwent comprehensive clinical BOLD fMRI exams including task fMRI and resting state fMRI (rsfMRI) were evaluated. Each patient displayed decreased/absent task fMRI activation in the ipsilesional primary motor cortex in the absence of corresponding motor deficit or suboptimal task performance, consistent with NVU. Z-score maps for the motor tasks were obtained from general linear model (GLM) analysis (reflecting motor activation vs. rest). ALFF maps were calculated from rsfMRI data. Precentral and postcentral gyri in contralesional (CL) and ipsilesional (IL) hemispheres were parcellated using an Automated Anatomical Labeling (AAL) template for each patient. A novel ALFF-based correction method was used to identify the NVU affected voxels in the ipsilesional primary motor cortex (PMC), and a correction factor was applied to normalize the baseline Z-scores for these voxels. In all cases, substantially greater activation was seen on post-ALFF correction motor activation maps within the ipsilesional precentral gyri than in the pre-ALFF correction activation maps. We have demonstrated the feasibility of a new resting state ALFF-based technique for effective correction of brain tumor-related NVU in the primary motor cortex.

Brain tumor patients often experience functional deficits that extend beyond the tumor site. While resting-state functional MRI (rsfMRI) has been used to map such functional connectivity changes in brain tumor patients, the interplay between abnormal tumor vasculature and the rsfMRI signal is still not well understood. Therefore, there is an exigent need for new tools to elucidate how the blood‑oxygenation-level-dependent (BOLD) rsfMRI signal is modulated in brain cancer. In this initial study, we explore the utility of a preclinical model for quantifying brain tumor-induced changes on the rsfMRI signal and resting-state brain connectivity. We demonstrate that brain tumors induce brain-wide alterations of resting-state networks that extend to the contralateral hemisphere, accompanied by global attenuation of the rsfMRI signal. Preliminary histology suggests that some of these alterations in brain connectivity may be attributable to tumor-related remodeling of the neurovasculature. Moreover, this work recapitulates clinical rsfMRI findings from brain tumor patients in terms of the effects of tumor size on the neurovascular microenvironment. Collectively, these results lay the foundation of a preclinical platform for exploring the usefulness of rsfMRI as a potential new biomarker in patients with brain cancer.

Methods of image acquisition and analysis for resting-state functional MR imaging (rsfMR imaging) are still evolving. Neurovascular uncoupling and susceptibility artifact are important confounds of rsfMR imaging in the setting of focal brain lesions such as brain tumors. This article reviews the detection of these confounds using rsfMR imaging metrics in the setting of focal brain lesions. In the near future, with the wide range of ongoing research in rsfMR imaging, these issues likely will be overcome and will open new windows into brain function and connectivity., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The aim of this study was to explore whether the phenomenon of brain tumor-related neurovascular uncoupling (NVU) in resting-state blood oxygen level-dependent functional magnetic resonance imaging (BOLD fMRI) (rsfMRI) may also affect the resting-state fMRI (rsfMRI) frequency domain metrics the amplitude of low-frequency fluctuation (ALFF) and fractional ALFF (fALFF). Twelve de novo brain tumor patients, who underwent clinical fMRI examinations, including task-based fMRI (tbfMRI) and rsfMRI, were included in this Institutional Review Board-approved study. Each patient displayed decreased/absent tbfMRI activation in the primary ipsilesional (IL) sensorimotor cortex in the absence of a corresponding motor deficit or suboptimal task performance, consistent with NVU. Z-score maps for the motor tasks were obtained from general linear model analysis (reflecting motor activation vs. rest). Seed-based correlation analysis (SCA) maps of sensorimotor network, ALFF, and fALFF were calculated from rsfMRI data. Precentral and postcentral gyri in contralesional (CL) and IL hemispheres were parcellated using an automated anatomical labeling template for each patient. Region of interest (ROI) analysis was performed on four maps: tbfMRI, SCA, ALFF, and fALFF. Voxel values in the CL and IL ROIs of each map were divided by the corresponding global mean of ALFF and fALFF in the cortical brain tissue. Group analysis revealed significantly decreased IL ALFF (p = 0.02) and fALFF (p = 0.03) metrics compared with CL ROIs, consistent with similar findings of significantly decreased IL BOLD signal for tbfMRI (p = 0.0005) and SCA maps (p = 0.0004). The frequency domain metrics ALFF and fALFF may be markers of lesion-induced NVU in rsfMRI similar to previously reported alterations in tbfMRI activation and SCA-derived resting-state functional connectivity maps.

The aim of this study is to determine whether regional homogeneity (ReHo) of resting-state blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (rsfMRI) data based on Kendall's coefficient of concordance (KCC-ReHo) and coherence (Cohe-ReHo) metrics may allow detection of brain tumor-induced neurovascular uncoupling (NVU) in the sensorimotor network similar to findings in standard motor task-based BOLD fMRI (tbfMRI) activation. Twelve de novo brain tumor patients undergoing clinical fMRI exams (tbfMRI and rsfMRI) were included in this Institutional Review Board (IRB)-approved study. Each patient displayed decreased/absent tbfMRI activation in the primary ipsilesional sensorimotor cortex in the absence of corresponding motor deficit or suboptimal task performance, consistent with NVU. Z-score maps for motor tasks were obtained from the general linear model (GLM) analysis (reflecting motor activation vs. rest). KCC-ReHo and Cohe-ReHo maps were calculated from rsfMRI data. Precentral and postcentral gyri in contralesional (CL) and ipsilesional (IL) hemispheres were parcellated using an automated anatomical labeling (AAL) template for each patient. Similar region of interest (ROI) analysis was performed on tbfMRI, KCC-ReHo, and Cohe-ReHo maps to allow direct comparison of results. Voxel values in CL and IL ROIs of each map were divided by the corresponding global mean of KCC-ReHo and Cohe-ReHo in bihemispheric cortical brain tissue. Group analysis revealed significantly decreased IL mean KCC-ReHo (p = 0.02) and Cohe-ReHo (p = 0.04) metrics compared with respective values in the CL ROIs, consistent with similar findings of significantly decreased ipsilesional BOLD signal for tbfMRI (p = 0.0005). Ipsilesional abnormalities in ReHo derived from rsfMRI may serve as potential indicators of NVU in patients with brain tumors and other resectable brain lesions; as such, ReHo findings may complement findings on tbfMRI used for presurgical planning.

To demonstrate in a small case series for the first time the phenomenon of brain tumor-related neurovascular uncoupling (NVU) in resting-state blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) at ultrahigh field (7T). Two de novo (i.e., untreated) brain tumor patients underwent both BOLD resting-state fMRI (rsfMRI) on a 7T MRI system and motor task-based BOLD fMRI at 3T. Ipsilesional (i.e., ipsilateral to tumor or IL) and contralesional (i.e., contralateral to tumor or CL) region of interest (ROI) analysis was performed on both 3T motor task-related general linear model-derived activation maps and on 7T rsfMRI independent component analysis (ICA)-derived sensorimotor network maps for each case. Asymmetry scores (ASs) were computed based on numbers of suprathreshold voxels in the IL and CL ROIs. In each patient, ASs derived from ROI analysis of suprathreshold voxels in IL and CL ROIs in task-related activation maps and rsfMRI ICA-derived sensorimotor component maps indicate greater number of suprathreshold voxels in contralesional than ipsilesional sensorimotor cortex in both maps. In patient 1, an AS of 0.2 was obtained from the suprathreshold Z-score spectrum (voxels with Z-scores >5.0) of the task-based activation map and AS of 1.0 was obtained from the suprathreshold Z-score spectrum (Z-scores >5.0) of the ICA-derived sensorimotor component map. Similarly, in patient 2, an AS of 1.0 was obtained from the suprathreshold Z-score spectrum (Z-scores >5.0) of the task-based activation map and an AS of 1.0 was obtained from the suprathreshold Z-score spectrum (Z-scores >5.0) of the ICA-derived sensorimotor component map. Overall, decreased BOLD signal was noted in IL compared with CL ROIs on both task-based activation maps and ultrahigh field resting-state maps, indicating the presence of NVU. We have demonstrated evidence of NVU on ultrahigh field 7T rsfMRI comparable with the findings on standard 3T motor task-based fMRI in both cases., Competing Interests: Author Disclosure Statement No competing financial interests exist.

Aim: To evaluate neurovascular uncoupling (NVU) associated with low grade gliomas (LGG) using blood oxygen level dependent (BOLD) cerebrovascular reactivity mapping., Methods: Seven patients with low grade gliomas referred by neurosurgeons for presurgical mapping were included in this pilot study. Cerebrovascular reactivity (CVR) mapping was performed by acquiring BOLD images while patients performed a block-design breath-hold (BH) hypercapnia task. CVR mapping was expressed as BOLD percentage signal change (PSC) from baseline associated with performance of the BH hypercapnia task. Standard T2* Dynamic Susceptibility Contrast perfusion imaging was performed and relative cerebral blood volume (rCBV) and relative cerebral blood flow (rCBF) maps were generated. Structural T1 weighted MR images were also acquired. A correlation analysis between intratumoral normalized (via ratio with contralateral homologous regions) BOLD BH PSC [referred to as (n(CVR))] and intratumoral normalized resting state rCBV (rCBF) values (i.e., n(CBV) and n(CBF), respectively) was performed., Results: No significant correlation was seen between the normalized BOLD BH PSC (i.e., n(CBV)) and n(CBV) or n(CBF). However, the average n(CVR) (median = 0.50, z = -2.28, P = 0.01) was significantly less than 1.0, indicating abnormally reduced vascular responses in the tumor regions relative to normal contralesional homologous regions, whereas the average n(CBV) (median = 0.94, z = -0.92, P = 0.375) and n(CBF) (median = 0.93, z = -1.16, P = 0.25) were not significantly higher or lower than 1.0, indicating iso-perfusion in the tumor regions relative to normal contralesional homologous regions. These findings suggest that in LGG, hyperperfusion that is seen in high grade gliomas is not present, but, nevertheless, abnormally decreased regional CVR is present within and adjacent to LGG. Since the patients all demonstrated at least some residual function attributable to the cortical regions of impaired CVR, but were incapable of producing a BOLD response in these regions regardless of the tasks performed, such regionally decreased CVR is indicative of NVU. The low n(CVR) ratios indicate high prevalence of NVU in this LGG cohort, which is an important consideration in the interpretation of clinical presurgical mapping with functional magnetic resonance (MR) imaging., Conclusion: Our preliminary study shows that BH CVR mapping is clinically feasible and demonstrates an unexpectedly high prevalence of NVU in patients with LGG.

This article provides a review of Blood Oxygen Level Dependent functional magnetic resonance imaging (BOLD fMRI) applications for presurgical mapping in patients with brain tumors who are being considered for lesion resection. Initially, the physical principle of the BOLD effect is discussed, followed by a general overview of the aims of presurgical planning. Subsequently, a review of sensorimotor, language and visual paradigms that are typically utilized in clinical fMRI is provided, followed by a brief description of studies demonstrating the clinical impact of preoperative BOLD fMRI. After this thorough introduction to presurgical fMRI, a detailed explanation of the phenomenon of neurovascular uncoupling (NVU), a major limitation of fMRI, is provided, followed by a discussion of the different approaches taken for BOLD cerebrovascular reactivity (CVR) mapping, which is an effective method of detecting NVU. We then include one clinical case which demonstrates the value of CVR mapping in clinical preoperative fMRI interpretation. The paper then concludes with a brief review of applications of CVR mapping other than for presurgical mapping.