Neurovascular Uncoupling Research Articles

Nrf2 deficiency exacerbates obesity‐induced neurovascular uncoupling in mice, mimicking the aging phenotype

Moment‐to‐moment adjustment of cerebral blood flow (CBF) via neurovascular coupling has a critical role in maintenance of healthy cognitive function. Previous studies demonstrate that obesity promotes cognitive impairment due to, at least in part, its deleterious effects on neurovascular coupling. Importantly, the effects of obesity are exacerbated in aging, but the underlying mechanisms remain elusive. There is increasing evidence that Nrf2/ARE signaling plays a critical role in vascular resilience to obesity and the metabolic syndrome and that aging is associated with progressive Nrf2 dysfunction, promoting microvascular oxidative stress. The present study was designed to test the hypothesis that Nrf2 deficiency contributes to neurovascular uncoupling and exacerbate cerebromicrovascular dysfunction induced by obesity. To test this hypothesis Nrf2+/+ and Nrf2−/− mice were fed a standard diet or an adipogenic high fat diet (HFD) and cortical neurovascular coupling responses were assessed. In control mice feeding HFD for 6 months significantly increased vascular oxidative stress and decreased endothelium‐mediated CBF responses (laser Doppler flowmetry) in the somatosensory cortex evoked by contralateral whisker stimulation. Nrf2 deficiency significantly exacerbated HFD‐induced neurovascular uncoupling, mimicking the aging phenotype. Together, these results provide additional evidence that intact Nrf2 signaling importantly contributes to cerebromicrovascular health, preserving neurovascular coupling mechanisms. Further studies are needed to elucidate the endothelial and astrocytic mechanisms impacted by Nrf2 deficiency and HFD‐induced obesity, determining the potential roles of oxidative stress and chronic low‐grade neuroinflammation.Support or Funding InformationThis work was supported by grants from the American Heart Association and the National Institute on Aging.

Treatment with the Mitochondrial‐targeted Antioxidant Peptide SS‐31 Improves Cerebromicrovascular Function in Aged Mice

Moment‐to‐moment adjustment of cerebral blood flow (CBF) via neurovascular coupling has a critical role in maintenance of healthy cognitive function. In advanced age increased oxidative stress and cerebromicrovascular endothelial dysfunction impair neurovascular coupling, likely contributing to age‐related decline of higher cortical functions. There is increasing evidence showing that mitochondrial oxidative stress plays a critical role in a range of age‐related cellular impairments, but its role in neurovascular uncoupling remains unexplored. The present study was designed to test the hypothesis that attenuation of mitochondrial oxidative stress may exert beneficial effects on neurovascular coupling in aging. To test this hypothesis 24 month old C57BL/6 mice were treated with a cell permeable, mitochondria‐targeted antioxidant peptide (SS‐31; 10 mg/kg/day, s.c.) or vehicle for 2 weeks. Neurovascular coupling was assessed by measuring CBF responses (laser Doppler flowmetry) and evoked field potentials in the somatosensory cortex evoked by contralateral electric whisker pad stimulation. We found that neurovascular coupling responses and ATP‐induced endothelium‐dependent CBF responses were significantly impaired in aged mice. Treatment with SS‐31 significantly improved neurovascular coupling responses, at least in part, by increasing NO‐mediated cerebromicrovascular dilation. These findings are paralleled by the protective effects of SS‐31 on mitochondrial production of reactive oxygen species in cultured cerebromicrovascular endothelial cells derived from aged animals. Thus, mitochondrial oxidative stress contributes to age‐related cerebromicovascular dysfunction. We propose that the antioxidant peptide SS‐31 should be considered for pharmacological microvascular protection for the prevention/treatments of age‐related diseases of the CNS.Support or Funding InformationThis work was supported by grants from the American Heart Association and the National Institute on Aging.

Abstract 220: Neurovascular Uncoupling in Acute Ischemic Stroke Correlates Well With Clinical Fluctuations in Acute Ischemic Stroke

Background and aims: Fluctuations in neurological status are frequently seen during first few days in thrombolysed acute ischemic stroke (AIS) patients. Underlying mechanisms for these fluctuations often remain unclear. Cerebral homeostatic balance is regulated by autoregulation and neurovascular coupling (NVC). We hypothesized that neurovascular uncoupling in AIS contributes to the fluctuations in neurological status. Methods: In this ongoing prospective study, consecutive and thrombolyzed AIS patients were recruited within 12 hours of symptom-onset. Serial CT perfusion (CTP) imaging (within 12 hours, at 24 and 72 hours after symptom-onset) were performed. Serial Quantitative EEG (QEEG) were performed, close to CTP imaging. Power within the alpha band (8-15Hz) was determined in each channel using epochs of 10-seconds % calculated for each hemisphere. Continuous transcranial Doppler (TCD) recording were obtained from both middle cerebral arteries, simultaneously with EEG. Neurological status was monitored with serial NIH stroke scale (NIHSS) scores. Neurovascular uncoupling was defined as a mismatch among CTP, QEEG and clinical findings. QEEG, CTP and TCD data were analysed independently by investigators blinded to the clinical findings. Results: A total of 32 patients (19 male, median age 68 years (range 56-86) were included. Median NIHSS score at recruitment was 8 points (range 1-24). NIHSS fluctuations by 4 or more points (deterioration followed by improvement or deterioration following improvement in absence of re-occlusion) were noted in 13 (40%) cases. Increasing cerebral edema (2 cases) and regional hyperperfusion (4 cases) were seen on serial CTP. Remaining 7 cases showed serial improvement in CTP. QEEG showed significantly increased inter-hemispheric alpha band power ratio (unaffected hemisphere/affected hemisphere ratio more than 1.5), irrespective of the CTP and TCD results, suggestive of neurovascular uncoupling as the underlying mechanism for early neurological fluctuations. Conclusion: Neurovascular uncoupling is a relatively frequent phenomenon during first few days of acute ischemic stroke. Multi-modal monitoring is useful in identifying these patients for appropriate therapeutic decision making.

Cocaine attenuates blood flow but not neuronal responses to stimulation while preserving neurovascular coupling for resting brain activity.

Cocaine affects neuronal activity and constricts cerebral blood vessels, making it difficult to determine whether cocaine-induced changes in cerebral blood flow (CBF) reflect neuronal activation or its vasoactive effects. Here we assessed the effects of acute cocaine on both resting-state and stimulation responses to investigate cocaine’s effects on neurovascular coupling and to differentiate its effects on neuronal activity from its vasoactive actions. We concurrently measured cortical field potentials via thinned skull EEG recordings and CBF with laser Doppler flowmetry in the rat’s somatosensory cortex for both resting state and forepaw stimulation prior to and following cocaine administration (1mg/kg, i.v.). Results show both resting-state field potentials and CBF were depressed after cocaine administration (19.8±4.7% and 52.1±13.4%, respectively) and these changes were strongly correlated with each other (r=0.81, p<0.001) indicating that cocaine did not affect neurovascular coupling at rest and that the reduction in resting CBF reflected reduction in synchronized spontaneous neuronal activity rather than vasoconstriction. In contrast, the forepaw-stimulation-evoked neuronal activity was not changed by cocaine (p=0.244) whereas the CBF to the stimulation was reduced 49.9±2.6% (p=0.028) gradually recovering ~20min post cocaine injection, indicating that neurovascular coupling during stimulation was temporarily disrupted by cocaine. Neurovascular uncoupling by cocaine during stimulation but not during rest indicates that distinct processes might underlie regulation of neurovascular coupling for spontaneous than for stimulation-induced activity. The greater reductions by cocaine to the stimulation-induced CBF increases than to the background CBF should be considered when interpreting fMRI studies comparing activation responses between controls and cocaine abusers. Neurovascular uncoupling could contribute to cocaine’s neurotoxicity particularly for stimulation conditions when CBF might be insufficient to cover for the energetic demands of neuronal tissue.

Purinergic glio-endothelial coupling during neuronal activity: role of P2Y1 receptors and eNOS in functional hyperemia in the mouse somatosensory cortex.

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 cognitive impairment associated with aging and pathological conditions associated with accelerated cerebromicrovascular aging (e.g., hypertension, obesity). Although previous studies demonstrate that endothelial dysfunction plays a critical role in neurovascular uncoupling in these conditions, the role of endothelial NO mediation in neurovascular coupling responses is not well understood. To establish the link between endothelial function and functional hyperemia, neurovascular coupling responses were studied in mutant mice overexpressing or deficient in endothelial NO synthase (eNOS), and the role of P2Y1 receptors in purinergic glioendothelial coupling was assessed. We found that genetic depletion of eNOS (eNOS(-/-)) and pharmacological inhibition of NO synthesis significantly decreased the CBF responses in the somatosensory cortex evoked by whisker stimulation and by administration of ATP. Overexpression of eNOS enhanced NO mediation of functional hyperemia. In control mice, the selective and potent P2Y1 receptor antagonist MRS2179 attenuated both whisker stimulation-induced and ATP-mediated CBF responses, whereas, in eNOS(-/-) mice, the inhibitory effects of MRS2179 were blunted. Collectively, our findings provide additional evidence for purinergic glio-endothelial coupling during neuronal activity, highlighting the role of ATP-mediated activation of eNOS via P2Y1 receptors in functional hyperemia.

Neurovascular uncoupling in resting state fMRI demonstrated in patients with primary brain gliomas.

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. 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. 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. 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.

Pharmacologically-induced neurovascular uncoupling is associated with cognitive impairment in mice.

There is increasing evidence that vascular risk factors, including aging, hypertension, diabetes mellitus, and obesity, promote cognitive impairment; however, the underlying mechanisms remain obscure. Cerebral blood flow (CBF) is adjusted to neuronal activity via neurovascular coupling (NVC) and this mechanism is known to be impaired in the aforementioned pathophysiologic conditions. To establish a direct relationship between impaired NVC and cognitive decline, we induced neurovascular uncoupling pharmacologically in mice by inhibiting the synthesis of vasodilator mediators involved in NVC. Treatment of mice with the epoxygenase inhibitor N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MSPPOH), the NO synthase inhibitor l-NG-Nitroarginine methyl ester (L-NAME), and the COX inhibitor indomethacin decreased NVC by over 60% mimicking the aging phenotype, which was associated with significantly impaired spatial working memory (Y-maze), recognition memory (Novel object recognition), and impairment in motor coordination (Rotarod). Blood pressure (tail cuff) and basal cerebral perfusion (arterial spin labeling perfusion MRI) were unaffected. Thus, selective experimental disruption of NVC is associated with significant impairment of cognitive and sensorimotor function, recapitulating neurologic symptoms and signs observed in brain aging and pathophysiologic conditions associated with accelerated cerebromicrovascular aging.

IGF-1 deficiency impairs neurovascular coupling in mice: implications for cerebromicrovascular aging.

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 (Igf1(f/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.

Imaging of the Functional and Dysfunctional Visual System

Functional magnetic resonance imaging (fMRI) is used clinically to map the visual cortex before brain surgery or other invasive treatments to achieve an optimal balance between therapeutic effect and the avoidance of postoperative vision deficits. Clinically optimized stimuli, analyses, and displays permit identification of cortical subregions supporting high-acuity central vision that is critical for reading and other essential visual functions. A novel data display permits instant appreciation of the functional relationship between the pattern of fMRI brain activation and the pattern of vision loss and preservation within the patient׳s field of view. Neurovascular uncoupling and its detection in the visual cortex are key issues for the interpretation of fMRI results in patients with existing brain pathology.

Experimental Neurovascular Uncoupling Promotes Cognitive Impairment in Mice: Implications for Brain and Cerebromicrovascular Aging

There is increasing evidence that vascular risk factors, including aging, hypertension, diabetes mellitus and obesity, promote cognitive impairment, however, the underlying mechanisms remain obscure. Cerebral blood flow (CBF) is adjusted to neuronal activity via neurovascular coupling (NVC) and this mechanism is known to be impaired in the aforementioned pathophysiological conditions. To establish a direct, causal relation between impaired NVC and cognitive decline, we induced neurovascular uncoupling pharmacologically in mice by inhibiting the synthesis of vasodilator mediators involved in NVC. Treatment of mice with the epoxygenase inhibitor MS-PPOH, the NOS inhibitor L-NAME and the COX inhibitor indomethacin decreased NVC by 75% mimicking the aging phenotype, which was associated with significantly impaired spatial working memory (Y-maze), recognition memory (Novel object recognition) and impairment in motor coordination (Rotarod). Blood pressure (tail cuff), basal cerebral perfusion (arterial spin labeling perfusion MRI) and synaptic activity (evoked field potential) were unaffected. Thus, targeted experimental disruption of NVC per se leads to significant impairment of cortical function, including cognitive decline, recapitulating neurological symptoms and signs observed in brain aging and pathophysiological conditions associated with accelerated cerebromicrovascular aging.

IGF‐1 Deficiency Promotes Neurovascular Uncoupling: Implications for Cerebromicrovascular Aging and Age‐Related Cognitive Decline

Aging is associated with marked deficiency in circulating IGF-1, which was shown to importantly contribute to age-related cognitive decline. Impairment of moment-to-moment adjustment of cerebral blood flow (CBF) via neurovascular coupling (NVC) 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, we compared NVC in IGF-1 deficient (Igf f/f-TBG-iCre-AAV8) and control mice. We found that glutamate (Glu)-dependent CBF responses to whisker stimulation were significantly decreased in IGF-1 deficient mice. IGF-1 deficiency did not affect neuronal activity-induced cerebral Glu release. Expression of Glu receptors (Grin1, Grin2A, Grm2, Grm4, Grm5) was down-regulated in astrocytes isolated from IGF-1 deficient mice. Glu-stimulated release of astrocyte-derived vasodilator arachidonic acid metabolites (EETs) and EET-dependent CBF responses elicited by whisker stimulation were significantly decreased in IGF-1 deficient mice. IGF-1 deficiency also increased production of the vasoconstrictor 20-HETE. Collectively, IGF-1 deficiency promotes neurovascular uncoupling mimicking the aging phenotype, which is likely causally linked to cognitive impairment.

Capillary transit time heterogeneity and flow-metabolism coupling after traumatic brain injury.

Most patients who die after traumatic brain injury (TBI) show evidence of ischemic brain damage. Nevertheless, it has proven difficult to demonstrate cerebral ischemia in TBI patients. After TBI, both global and localized changes in cerebral blood flow (CBF) are observed, depending on the extent of diffuse brain swelling and the size and location of contusions and hematoma. These changes vary considerably over time, with most TBI patients showing reduced CBF during the first 12 hours after injury, then hyperperfusion, and in some patients vasospasms before CBF eventually normalizes. This apparent neurovascular uncoupling has been ascribed to mitochondrial dysfunction, hindered oxygen diffusion into tissue, or microthrombosis. Capillary compression by astrocytic endfeet swelling is observed in biopsies acquired from TBI patients. In animal models, elevated intracranial pressure compresses capillaries, causing redistribution of capillary flows into patterns argued to cause functional shunting of oxygenated blood through the capillary bed. We used a biophysical model of oxygen transport in tissue to examine how capillary flow disturbances may contribute to the profound changes in CBF after TBI. The analysis suggests that elevated capillary transit time heterogeneity can cause critical reductions in oxygen availability in the absence of ‘classic' ischemia. We discuss diagnostic and therapeutic consequences of these predictions.

Angiogenesis in multiple sclerosis and experimental autoimmune encephalomyelitis.

Angiogenesis, the formation of new vessels, is found in Multiple Sclerosis (MS) demyelinating lesions following Vascular Endothelial Growth Factor (VEGF) release and the production of several other angiogenic molecules. The increased energy demand of inflammatory cuffs and damaged neural cells explains the strong angiogenic response in plaques and surrounding white matter. An angiogenic response has also been documented in an experimental model of MS, experimental allergic encephalomyelitis (EAE), where blood–brain barrier disruption and vascular remodelling appeared in a pre-symptomatic disease phase. In both MS and EAE, VEGF acts as a pro-inflammatory factor in the early phase but its reduced responsivity in the late phase can disrupt neuroregenerative attempts, since VEGF naturally enhances neuron resistance to injury and regulates neural progenitor proliferation, migration, differentiation and oligodendrocyte precursor cell (OPC) survival and migration to demyelinated lesions. Angiogenesis, neurogenesis and oligodendroglia maturation are closely intertwined in the neurovascular niches of the subventricular zone, one of the preferential locations of inflammatory lesions in MS, and in all the other temporary vascular niches where the mutual fostering of angiogenesis and OPC maturation occurs. Angiogenesis, induced either by CNS inflammation or by hypoxic stimuli related to neurovascular uncoupling, appears to be ineffective in chronic MS due to a counterbalancing effect of vasoconstrictive mechanisms determined by the reduced axonal activity, astrocyte dysfunction, microglia secretion of free radical species and mitochondrial abnormalities. Thus, angiogenesis, that supplies several trophic factors, should be promoted in therapeutic neuroregeneration efforts to combat the progressive, degenerative phase of MS.

Aging exacerbates obesity-induced cerebromicrovascular rarefaction, neurovascular uncoupling, and cognitive decline in mice.

Epidemiological studies show that obesity has deleterious effects on the brain and cognitive function in the elderly population. However, the specific mechanisms through which aging and obesity interact to promote cognitive decline remain unclear. To test the hypothesis that aging exacerbates obesity-induced cerebromicrovascular impairment, we compared young (7 months) and aged (24 months) high-fat diet-fed obese C57BL/6 mice. We found that aging exacerbates the obesity-induced decline in microvascular density both in the hippocampus and in the cortex. The extent of hippocampal microvascular rarefaction and the extent of impairment of hippocampal-dependent cognitive function positively correlate. Aging exacerbates obesity-induced loss of pericyte coverage on cerebral microvessels and alters hippocampal angiogenic gene expression signature, which likely contributes to microvascular rarefaction. Aging also exacerbates obesity-induced oxidative stress and induction of NADPH oxidase and impairs cerebral blood flow responses to whisker stimulation. Collectively, obesity exerts deleterious cerebrovascular effects in aged mice, promoting cerebromicrovascular rarefaction and neurovascular uncoupling. The morphological and functional impairment of the cerebral microvasculature in association with increased blood-brain barrier disruption and neuroinflammation (Tucsek Z, Toth P, Sosnowsk D, et al. Obesity in aging exacerbates blood-brain barrier disruption, neuroinflammation and oxidative stress in the mouse hippocampus: effects on expression of genes involved in beta-amyloid generation and Alzheimer's disease. J Gerontol Biol Med Sci. 2013. In press, PMID: 24269929) likely contribute to obesity-induced cognitive decline in aging.

Cerebrovascular reactivity mapping: an evolving standard for clinical functional imaging.

This review article explains the methodology of breath-hold cerebrovascular reactivity mapping, both in terms of acquisition and analysis, and reviews applications of this method to presurgical mapping, particularly with respect to blood oxygen level-dependent fMRI. Its main application in clinical fMRI is for the assessment of neurovascular uncoupling potential. Neurovascular uncoupling is potentially a major limitation of clinical fMRI, particularly in the setting of mass lesions in the brain such as brain tumors and intracranial vascular malformations that are associated with alterations in regional hemodynamics on either an acquired or congenital basis. As such, breath-hold cerebrovascular reactivity mapping constitutes an essential component of quality control analysis in clinical fMRI, particularly when performed for presurgical mapping of eloquent cortex. Exogenous carbon dioxide challenges used for cerebrovascular reactivity mapping will also be discussed, and their applications to the evaluation of cerebrovascular reserve and cerebrovascular disease will be described.

Angiogenesis in multiple sclerosis and experimental autoimmune encephalomyelitis

Angiogenesis, the formation of new vessels, is found in Multiple Sclerosis (MS) demyelinating lesions following Vascular Endothelial Growth Factor (VEGF) release and the production of several other angiogenic molecules. The increased energy demand of inflammatory cuffs and damaged neural cells explains the strong angiogenic response in plaques and surrounding white matter. An angiogenic response has also been documented in an experimental model of MS, experimental allergic encephalomyelitis (EAE), where blood–brain barrier disruption and vascular remodelling appeared in a pre-symptomatic disease phase. In both MS and EAE, VEGF acts as a pro-inflammatory factor in the early phase but its reduced responsivity in the late phase can disrupt neuroregenerative attempts, since VEGF naturally enhances neuron resistance to injury and regulates neural progenitor proliferation, migration, differentiation and oligodendrocyte precursor cell (OPC) survival and migration to demyelinated lesions. Angiogenesis, neurogenesis and oligodendroglia maturation are closely intertwined in the neurovascular niches of the subventricular zone, one of the preferential locations of inflammatory lesions in MS, and in all the other temporary vascular niches where the mutual fostering of angiogenesis and OPC maturation occurs. Angiogenesis, induced either by CNS inflammation or by hypoxic stimuli related to neurovascular uncoupling, appears to be ineffective in chronic MS due to a counterbalancing effect of vasoconstrictive mechanisms determined by the reduced axonal activity, astrocyte dysfunction, microglia secretion of free radical species and mitochondrial abnormalities. Thus, angiogenesis, that supplies several trophic factors, should be promoted in therapeutic neuroregeneration efforts to combat the progressive, degenerative phase of MS.

Vascular cognitive impairment, dementia, aging and energy demand. A vicious cycle

To a great extent, cognitive health depends on cerebrovascular health and a deeper understanding of the subtle interactions between cerebrovascular function and cognition is needed to protect humans from one of the most devastating affliction, dementia. However, the underlying biological mechanisms are still not completely clear. Many studies demonstrated that the neurovascular unit is compromised in cerebrovascular diseases and also in other types of dementia. The hemodynamic neurovascular coupling ensures a strong increase of the cerebral blood flow (CBF) and an acute increase in neuronal glucose uptake upon increased neural activity. Dysfunction of cerebral autoregulation with increasing age along with age-related structural and functional alterations in cerebral blood vessels including accumulation of amyloid-beta (Aβ) in the media of cortical arterioles, neurovascular uncoupling due to astrocyte endfeet retraction, impairs the CBF and increases the neuronal degeneration and susceptibility to hypoxia and ischemia. A decreased cerebral glucose metabolism is an early event in Alzheimer's disease (AD) pathology and may precede the neuropathological Aβ deposition associated with AD. Aβ accumulation in turn leads to further decreases in the CBF closing the vicious cycle. Alzheimer, aging and diabetes are also influenced by insulin/insulin-like growth factor-1 signaling, and accumulated evidence indicates sporadic AD is associated with disturbed brain insulin metabolism. Understanding how vascular and metabolic factors interfere with progressive loss of functional neuronal networks becomes essential to develop efficient drugs to prevent cognitive decline in elderly.

Cerebrovascular reactivity mapping in patients with low grade gliomas undergoing presurgical sensorimotor mapping with BOLD fMRI

(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. 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). 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%. Presurgical sensorimotor fMRI mapping can be affected by NVU-related false negative activation in low grade gliomas (76% of analyzed tasks).

BOLD Consistently Matches Electrophysiology in Human Sensorimotor Cortex at Increasing Movement Rates: A Combined 7T fMRI and ECoG Study on Neurovascular Coupling

Blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) is widely used to measure human brain function and relies on the assumption that hemodynamic changes mirror the underlying neuronal activity. However, an often reported saturation of the BOLD response at high movement rates has led to the notion of a mismatch in neurovascular coupling. We combined BOLD fMRI at 7T and intracranial electrocorticography (ECoG) to assess the relationship between BOLD and neuronal population activity in human sensorimotor cortex using a motor task with increasing movement rates. Though linear models failed to predict BOLD responses from the task, the measured BOLD and ECoG responses from the same tissue were in good agreement. Electrocorticography explained almost 80% of the mismatch between measured- and model-predicted BOLD responses, indicating that in human sensorimotor cortex, a large portion of the BOLD nonlinearity with respect to behavior (movement rate) is well predicted by electrophysiology. The results further suggest that other reported examples of BOLD mismatch may be related to neuronal processes, rather than to neurovascular uncoupling.

Neurovascular coupling during nociceptive processing in the primary somatosensory cortex of the rat

Neuroimaging methods such as functional magnetic resonance imaging (fMRI) have been used extensively to investigate pain-related cerebral mechanisms. However, these methods rely on a tight coupling of neuronal activity to hemodynamic changes. Because pain may be associated with hemodynamic changes unrelated to local neuronal activity (eg, increased mean arterial pressure [MAP]), it is essential to determine whether the neurovascular coupling is maintained during nociceptive processing. In this study, local field potentials (LFP) and cortical blood flow (CBF) changes evoked by electrical stimulation of the left hind paw were recorded concomitantly in the right primary somatosensory cortex (SI) in 15 rats. LFP, CBF, and MAP changes were examined in response to stimulus intensities ranging from 3 to 30mA. In addition, LFP, CBF, and MAP changes evoked by a 10-mA stimulation were examined during immersion of the tail in non-nociceptive or nociceptive hot water (counter-stimulation). SI neurovascular coupling was altered for stimuli of nociceptive intensities (P<0.001). This alteration was intensity-dependent and was strongly associated with MAP changes (r=0.98, P<0.001). However, when the stimulus intensity was kept constant, SI neurovascular coupling was not significantly affected by nociceptive counter-stimulation (P=0.4), which similarly affected the amplitude of shock-evoked LFP and CBF changes. It remains to be determined whether such neurovascular uncoupling occurs in humans, and whether it also affects other regions usually activated by painful stimuli. These results should be taken into account for accurate interpretation of fMRI studies that involve nociceptive stimuli associated with MAP changes.