Dietary nitrate supplementation and cognitive health: the nitric oxide-dependent neurovascular coupling hypothesis.

Diet is currently recognized as a major modifiable agent of human health. In particular, dietary nitrate has been increasingly explored as a strategy to modulate different physiological mechanisms with demonstrated benefits in multiple organs, including gastrointestinal, cardiovascular, metabolic, and endocrine systems. An intriguing exception in this scenario has been the brain, for which the evidence of the nitrate benefits remains controversial. Upon consumption, nitrate can undergo sequential reduction reactions in vivo to produce nitric oxide (•NO), a ubiquitous paracrine messenger that supports multiple physiological events such as vasodilation and neuromodulation. In the brain, •NO plays a key role in neurovascular coupling, a fine process associated with the dynamic regulation of cerebral blood flow matching the metabolic needs of neurons and crucial for sustaining brain function. Neurovascular coupling dysregulation has been associated with neurodegeneration and cognitive dysfunction during different pathological conditions and aging. We discuss the potential biological action of nitrate on brain health, concerning the molecular mechanisms underpinning this association, particularly via modulation of •NO-dependent neurovascular coupling. The impact of nitrate supplementation on cognitive performance was scrutinized through preclinical and clinical data, suggesting that intervention length and the health condition of the participants are determinants of the outcome. Also, it stresses the need for multimodal quantitative studies relating cellular and mechanistic approaches to function coupled with behavior clinical outputs to understand whether a mechanistic relationship between dietary nitrate and cognitive health is operative in the brain. If proven, it supports the exciting hypothesis of cognitive enhancement via diet.

Application and advantages of zebrafish model in the study of neurovascular unit.

The concept of "Neurovascular Unit" (NVU) was put forward, so that the research goal of Central Nervous System (CNS) diseases gradually transitioned from a single neuron to the structural and functional integrity of the NVU. Zebrafish has the advantages of high homology with human genes, strong reproductive capacity and visualization of neural circuits, so it has become an emerging model organism for NVU research and has been applied to a variety of CNS diseases. Based on CNKI (https://www.cnki.net/) and PubMed (https://pubmed.ncbi.nlm.nih.gov/about/) databases, the author of this article sorted out the relevant literature, analyzed the construction of a zebrafish model of various CNS diseases，and the use of diagrams showed the application of zebrafish in the NVU, revealed its relationship, which would provide new methods and references for the treatment and research of CNS diseases.

Integrative analysis of the human brain mural cell transcriptome.

Brain mural cells, including pericytes and vascular smooth muscle cells, are important for vascular development, blood-brain barrier function, and neurovascular coupling, but the molecular characteristics of human brain mural cells are incompletely characterized. Single cell RNA-sequencing (scRNA-seq) is increasingly being applied to assess cellular diversity in the human brain, but the scarcity of mural cells in whole brain samples has limited their molecular profiling. Here, we leverage the combined power of multiple independent human brain scRNA-seq datasets to build a transcriptomic database of human brain mural cells. We use this combined dataset to determine human-mouse species differences in mural cell transcriptomes, culture-induced dedifferentiation of human brain pericytes, and human mural cell organotypicity, with several key findings validated by RNA fluorescence in situ hybridization. Together, this work improves knowledge regarding the molecular constituents of human brain mural cells, serves as a resource for hypothesis generation in understanding brain mural cell function, and will facilitate comparative evaluation of animal and in vitro models.

Cortical and subcortical hemodynamic changes during sleep slow waves in human light sleep.

EEG slow waves, the hallmarks of NREM sleep are thought to be crucial for the regulation of several important processes, including learning, sensory disconnection and the removal of brain metabolic wastes. Animal research indicates that slow waves may involve complex interactions within and between cortical and subcortical structures. Conventional EEG in humans, however, has a low spatial resolution and is unable to accurately describe changes in the activity of subcortical and deep cortical structures. To overcome these limitations, here we took advantage of simultaneous EEG-fMRI recordings to map cortical and subcortical hemodynamic (BOLD) fluctuations time-locked to slow waves of light sleep. Recordings were performed in twenty healthy adults during an afternoon nap. Slow waves were associated with BOLD-signal increases in the posterior brainstem and in portions of thalamus and cerebellum characterized by preferential functional connectivity with limbic and somatomotor areas, respectively. At the cortical level, significant BOLD-signal decreases were instead found in several areas, including insula and somatomotor cortex. Specifically, a slow signal increase preceded slow-wave onset and was followed by a delayed, stronger signal decrease. Similar hemodynamic changes were found to occur at different delays across most cortical brain areas, mirroring the propagation of electrophysiological slow waves, from centro-frontal to inferior temporo-occipital cortices. Finally, we found that the amplitude of electrophysiological slow waves was positively related to the magnitude and inversely related to the delay of cortical and subcortical BOLD-signal changes. These regional patterns of brain activity are consistent with theoretical accounts of the functions of sleep slow waves.

Tailored haemodynamic response function increases detection power of fMRI in awake dogs (Canis familiaris).

Functional magnetic resonance imaging (fMRI) of awake and unrestrained dogs (Canis familiaris) has been established as a novel opportunity for comparative neuroimaging, promising important insights into the evolutionary roots of human brain function and cognition. However, data processing and analysis pipelines are often derivatives of methodological standards developed for human neuroimaging, which may be problematic due to profound neurophysiological and anatomical differences between humans and dogs. Here, we explore whether dog fMRI studies would benefit from a tailored dog haemodynamic response function (HRF). In two independent experiments, dogs were presented with different visual stimuli. BOLD signal changes in the visual cortex during these experiments were used for (a) the identification and estimation of a tailored dog HRF, and (b) the independent validation of the resulting dog HRF estimate. Time course analyses revealed that the BOLD signal in the primary visual cortex peaked significantly earlier in dogs compared to humans, while being comparable in shape. Deriving a tailored dog HRF significantly improved the model fit in both experiments, compared to the canonical HRF used in human fMRI. Using the dog HRF yielded significantly increased activation during visual stimulation, extending from the occipital lobe to the caudal parietal cortex, the bilateral temporal cortex, into bilateral hippocampal and thalamic regions. In sum, our findings provide robust evidence for an earlier onset of the dog HRF in two visual stimulation paradigms, and suggest that using such an HRF will be important to increase fMRI detection power in canine neuroimaging. By providing the parameters of the tailored dog HRF and related code, we encourage and enable other researchers to validate whether our findings generalize to other sensory modalities and experimental paradigms.

Effect of acupuncture on neurovascular units after cerebral infarction in rats through PI3K/AKT signaling pathway.

OBJECTIVE: To study the effect of acupuncture on neurovascular units after cerebral infarction (CI) in rats through the phosphatidylinositol 3-hydroxy kinase/protein kinase B (PI3K/AKT) signaling pathway. METHODS: A total of 36 Sprague-Dawley rats were randomly divided into sham group (n = 12), model group (n = 12) and acupuncture group (n = 12). The external carotid artery was only exposed in model group, while the post-CI ischemia-reperfusion model was established using the suture method in the other 2 groups. After modeling, the rats in sham group and model group were fixed and sampled, while those in acupuncture group were treated with acupuncture intervention for 2 weeks and sampled. The neurological deficits of rats were evaluated using the Zea-Longa score, and the spatial learning and memory of rats were detected via water maze test. Moreover, the expressions of vascular endothelial growth factor (VEGF), growth associated protein-43 (GAP-43) and synuclein (SYN) in brain tissues were detected via immunohistochemistry, and the relative protein expressions of PI3K p85, PI3K p110 and p-AKT were detected via Western blotting. The messenger ribonucleic acid (mRNA) expressions of VEGF, GAP-43 and SYN were detected via quantitative polymerase chain reaction (qPCR). RESULTS: The Zea-Longa score was significantly increased in model group and acupuncture group compared with that in sham group (p < 0.05), while it significantly declined in acupuncture group compared with that in model group (p < 0.05). The escape latency was significantly prolonged and the times of crossing platform were significantly reduced in model group and acupuncture group compared with those in sham group (p < 0.05), while the escape latency was significantly shortened and the times of crossing platform were significantly increased in acupuncture group compared with those in model group (p < 0.05). The positive expressions of VEGF, GAP-43 and SYN were obviously increased in model group and acupuncture group compared with those in sham group (p < 0.05), while they were obviously increased in acupuncture group compared with those in model group (p < 0.05). Besides, model group and acupuncture group had significantly higher relative protein expressions of PI3K p85, PI3K p110 and p-AKT than sham group (p < 0.05), while acupuncture group also had significantly higher relative protein expressions of PI3K p85, PI3K p110 and p-AKT than model group (p < 0.05). The relative mRNA expressions of VEGF, GAP-43 and SYN were remarkably increased in model group and acupuncture group compared with those in sham group (p < 0.05), while they were remarkably increased in acupuncture group compared with those in model group (p < 0.05). CONCLUSION: Acupuncture promotes the repair of neurovascular units after CI in rats through activating the PI3K/AKT signaling pathway, thereby exerting a protective effect on neurovascular units.

Neurovascular coupling during deep brain stimulation.

BACKGROUND: Deep brain stimulation (DBS) is an effective treatment for movement disorders, yet its mechanisms of action remain unclear. One method used to study its circuit-wide neuromodulatory effects is functional magnetic resonance imaging (fMRI) which measures hemodynamics as a proxy of neural activity. To interpret functional imaging data, we must understand the relationship between neural and vascular responses, which has never been studied with the high frequencies used for DBS. OBJECTIVE: To measure neurovascular coupling in the rat motor cortex during thalamic DBS. METHOD: Simultaneous intrinsic optical imaging and extracellular electrophysiology was performed in the motor cortex of urethane-anesthetized rats during thalamic DBS at 7 different frequencies. We related Maximum Change in Reflectance (MCR) from the imaging data to Integrated Evoked Potential (IEP) and change in broadband power of multi-unit (MU) activity, computing Spearman's correlation to determine the strength of these relationships. To determine the source of these effects, we studied the contributions of antidromic versus orthodromic activation in motor cortex perfusion using synaptic blockers. RESULTS: MCR, IEP and change in MU power increased linearly to 60 Hz and saturated at higher frequencies of stimulation. Blocking orthodromic transmission only reduced the DBS-induced change in optical signal by ∼25%, suggesting that activation of corticofugal fibers have a major contribution in thalamic-induced cortical activation. CONCLUSION: DBS-evoked vascular response is related to both evoked field potentials as well as multi-unit activity.

Cerebral haemodynamics during motor imagery of self-feeding with chopsticks: differences between dominant and non-dominant hand.

Purpose: Motor imagery is defined as a dynamic state during which a subject mentally simulates a given action without overt movements. Our aim was to use near-infrared spectroscopy to investigate differences in cerebral haemodynamics during motor imagery of self-feeding with chopsticks using the dominant or non-dominant hand.Materials and methods: Twenty healthy right-handed people participated in this study. The motor imagery task involved eating sliced cucumber pickles using chopsticks with the dominant (right) or non-dominant (left) hand. Activation of regions of interest (pre-supplementary motor area, supplementary motor area, pre-motor area, pre-frontal cortex, and sensorimotor cortex was assessed.Results: Motor imagery vividness of the dominant hand tended to be significantly higher than that of the non-dominant hand. The time of peak oxygenated haemoglobin was significantly earlier in the right pre-frontal cortex than in the supplementary motor area and left pre-motor area. Haemodynamic correlations were detected in more regions of interest during dominant-hand motor imagery than during non-dominant-hand motor imagery.Conclusions: Haemodynamics might be affected by differences in motor imagery vividness caused by variations in motor manipulation.

Consequence of intraventricular hemorrhage on neurovascular coupling evoked by speech syllables in preterm neonates.

Intraventricular Hemorrhage (IVH) is the leading cause of neurological and cognitive impairment in preterm neonates with an incidence that increases with increasing prematurity. In the present study, we tested how preterm neonates with IVH react to external stimulation (i.e. speech syllables). We compared their neural responses measured by electroencephalography (EEG), and hemodynamic responses measured by functional near-infrared spectroscopy (fNIRS), with those of healthy preterms. A neural response to syllables was observed in these infants, but did not induce a vascular response in contrast with healthy neonates. These results clearly demonstrate that the cerebral vascular network in IVH preterm neonates was unable to compensate for the increased metabolism resulting from neuronal activation in response to external stimulation. Optical imaging is thus a sensitive tool to identify altered cerebral hemodynamic in critically ill preterms before behavioral changes are manifested or when only minor abnormalities on other functional monitoring techniques such as EEG are visible. We propose that a multi-modal approach provides unique opportunities for early monitoring of cognitive functions and opens up new possibilities for clinical care and recommended practices by studying the difficulties of the premature brain to adapt to its environment.

Investigating the role of temporal lobe activation in speech perception accuracy with normal hearing adults: An event-related fNIRS study.

Functional near infrared spectroscopy (fNIRS) is a safe, non-invasive, relatively quiet imaging technique that is tolerant of movement artifact making it uniquely ideal for the assessment of hearing mechanisms. Previous research demonstrates the capacity for fNIRS to detect cortical changes to varying speech intelligibility, revealing a positive relationship between cortical activation amplitude and speech perception score. In the present study, we use an event-related design to investigate the hemodynamic response in the temporal lobe across different listening conditions. We presented participants with a speech recognition task using sentences in quiet, sentences in noise, and vocoded sentences. Hemodynamic responses were examined across conditions and then compared when speech perception was accurate compared to when speech perception was inaccurate in the context of noisy speech. Repeated measures, two-way ANOVAs revealed that the speech in noise condition (-2.8dB signal-to-noise ratio/SNR) demonstrated significantly greater activation than the easier listening conditions on multiple channels bilaterally. Further analyses comparing correct recognition trials to incorrect recognition trials (during the presentation phase of the trial) revealed that activation was significantly greater during correct trials. Lastly, during the repetition phase of the trial, where participants correctly repeated the sentence, the hemodynamic response demonstrated significantly higher deoxyhemoglobin than oxyhemoglobin, indicating a difference between the effects of perception and production on the cortical response. Using fNIRS, the present study adds meaningful evidence to the body of knowledge that describes the brain/behavior relationship related to speech perception.

Disruption of Brain-Heart Coupling in Sepsis.

PURPOSE: To investigate heart rate and EEG variability and their coupling in patients with sepsis and determine their relationship to sepsis severity and severity of sepsis-associated brain dysfunction. METHODS: Fifty-two patients with sepsis were prospectively identified, categorized as comatose (N = 30) and noncomatose (N = 22), and compared with 11 control subjects. In a 30-minute EEG and electrocardiogram recording, heart rate variability and EEG variability (measured by the variability of relative power in a modified alpha band = RAP) and their coupled oscillations were quantified using linear (least-square periodogram and magnitude square coherence) and nonlinear (Shannon entropy and mutual information) measures. These measures were compared between the three groups and correlated with outcome, adjusting for severity of sepsis. RESULTS: Several measures of heart rate variability and EEG variability and of their coupled oscillations were significantly lower in patients with sepsis compared with controls and correlated with outcome. This correlation was not independent when adjusting for severity of sepsis. CONCLUSIONS: Sepsis is associated with lower variability of both heart rate and RAP on EEG and reduction of their coupled oscillations. This uncoupling is associated with the severity of encephalopathy. Combined EEG and electrocardiogram monitoring may be used to gain insight in underlying mechanisms of sepsis and quantify brainstem or thalamic dysfunction.

Altered Coupling Between Resting-State Cerebral Blood Flow and Functional Connectivity in Schizophrenia.

Background: Respective changes in resting-state cerebral blood flow (CBF) and functional connectivity in schizophrenia have been reported. However, their coupling alterations in schizophrenia remain largely unknown. Methods: 89 schizophrenia patients and 90 sex- and age-matched healthy controls underwent resting-state functional MRI to calculate functional connectivity strength (FCS) and arterial spin labeling imaging to compute CBF. The CBF-FCS coupling of the whole gray matter and the CBF/FCS ratio (the amount of blood supply per unit of connectivity strength) of each voxel were compared between the 2 groups. Results: Whole gray matter CBF-FCS coupling was decreased in schizophrenia patients relative to healthy controls. In schizophrenia patients, the decreased CBF/FCS ratio was predominantly located in cognitive- and emotional-related brain regions, including the dorsolateral prefrontal cortex, insula, hippocampus and thalamus, whereas an increased CBF/FCS ratio was mainly identified in the sensorimotor regions, including the putamen, and sensorimotor, mid-cingulate and visual cortices. Conclusion: These findings suggest that the neurovascular decoupling in the brain may be a possible neuropathological mechanism of schizophrenia.

Functional neuroimaging of sex differences in autobiographical memory recall in depression.

BACKGROUND: Females are more likely than males to develop major depressive disorder (MDD). The current study used fMRI to compare the neural correlates of autobiographical memory (AM) recall between males and females diagnosed with MDD. AM overgenerality is a persistent cognitive deficit in MDD, the magnitude of which is correlated with depressive severity only in females. Delineating the neurobiological correlates of this deficit may elucidate the nature of sex-differences in the diathesis for developing MDD. METHODS: Participants included unmedicated males and females diagnosed with MDD (n = 20/group), and an age and sex matched healthy control group. AM recall in response to positive, negative, and neutral cue words was compared with a semantic memory task. RESULTS: The behavioral properties of AMs did not differ between MDD males and females. In contrast, main effects of sex on cerebral hemodynamic activity were observed in left dorsolateral prefrontal cortex and parahippocampal gyrus during recall of positive specific memories, and middle prefrontal cortex (mPFC), and precuneus during recall of negative specific memories. Moreover, main effects of diagnosis on regional hemodynamic activity were observed in left ventrolateral prefrontal cortex and mPFC during positive specific memory recall, and dorsal anterior cingulate cortex during negative specific memory recall. Sex × diagnosis interactions were evident in the dorsomedial prefrontal cortex, caudate, and precuneus during positive memory recall, and in the posterior cingulate cortex, insula, precuneus and thalamus during negative specific memory recall. CONCLUSIONS: The differential hemodynamic changes conceivably may reflect sex-specific cognitive strategies during recall of AMs irrespective of the phenomenological properties of those memories.

Association of Concurrent fNIRS and EEG Signatures in Response to Auditory and Visual Stimuli.

Functional near-infrared spectroscopy (fNIRS) has been proven reliable for investigation of low-level visual processing in both infants and adults. Similar investigation of fundamental auditory processes with fNIRS, however, remains only partially complete. Here we employed a systematic three-level validation approach to investigate whether fNIRS could capture fundamental aspects of bottom-up acoustic processing. We performed a simultaneous fNIRS-EEG experiment with visual and auditory stimulation in 24 participants, which allowed the relationship between changes in neural activity and hemoglobin concentrations to be studied. In the first level, the fNIRS results showed a clear distinction between visual and auditory sensory modalities. Specifically, the results demonstrated area specificity, that is, maximal fNIRS responses in visual and auditory areas for the visual and auditory stimuli respectively, and stimulus selectivity, whereby the visual and auditory areas responded mainly toward their respective stimuli. In the second level, a stimulus-dependent modulation of the fNIRS signal was observed in the visual area, as well as a loudness modulation in the auditory area. Finally in the last level, we observed significant correlations between simultaneously-recorded visual evoked potentials and deoxygenated hemoglobin (DeoxyHb) concentration, and between late auditory evoked potentials and oxygenated hemoglobin (OxyHb) concentration. In sum, these results suggest good sensitivity of fNIRS to low-level sensory processing in both the visual and the auditory domain, and provide further evidence of the neurovascular coupling between hemoglobin concentration changes and non-invasive brain electrical activity.

Estudio estadístico de la acción terapéutica del ácido retinoico tópico en los trastornos de queratinización / A statistical study of the topical retinoid´s therapeutic action in keratin disorders

Los retinoides han adquirido con el paso del tiempo la condición de fármaco indispensable en la práctica clínica diaria tras la observación de un gran número de resultados efectivos en un amplio abanico de procesos cutáneos. De hecho, los retinoides son los fármacos de elección en el tratamiento de los trastornos importantes de la queratinización. Ello se debe al amplio espectro de acción que poseen, el cual a su vez se explica por la gran diversidad de actividades farmacológicas que tienen los retinoides debido a los efectos que se derivan de la acción que ejercen sobre receptores celulares. Estas acciones incluyen, entre otras, la normalización de los desórdenes de queratinización al inducir el crecimiento de una nueva población de queratinocitos de apariencia normal. El presente estudio tiene como objetivo principal demostrar la efectividad que tiene la aplicación de ácido retinoico al 0,1% para el tratamiento del heloma neurovascular, una lesión dérmica que si bien su primera opción terapéutica es actualmente la extirpación quirúrgica, en ciertas ocasiones nos veremos obligados a recurrir a otra estrategia terapéutica. Será en estos casos en los que los retinoides tópicos constituirán un fármaco de elección para el tratamiento del trastorno de queratinización que se desarrolla durante la formación del heloma neuro vascular. Asimismo, otro objetivo de este estudio es valorar la efectividad de la aplicación de retinoides por via tópica como elemento coadyuvante al tratamiento ortopodológico (AU)

The success of retinoids in dermatology and skin care has made these chemical compounds to be a potential treatment for skin and dermatological diseases, being a key compound in the treatment of keratin disorders. Retinoids work by triggering molecular switches in skin cells called retinoid receptors. These switches affect many intracellular processes including the control of cell proliferation and cell differentiation. All these functions determine their usefulness in clinical dermatology being effective in the treatment of a number of dermatological conditions. The principal objective of the following article is to show retinoid acid cream 0,1% effect in the treatment of a specific keratin disorder, the neurovascular corn. The neurovascular corn is a dermatological disease whose principal treatment is the surgical excision. However, we should resort to others therapeutic strategies in different cases. Is in these situations when the retinoid acid will be a key compound for the treatment of the keratin disorder that takes place during the neurovascular corn evolution. Another objective of this study is to value the effectiveness of the retinoid acid cream as an adjuvant treatment of foot orthoses. An exploration protocol has been developed to covers from statistical dates to a clinical and dermoscopic exam of each neurovascular corn. Finally, a pain scale has been designed to value the degree of pain before starting the treatment and once topic treatment is completed. Based on the results we can conclude that topical retinoids are a very effective therapeutic tool in the treatment of dermatological conditions that are accompanied by a keratin disorder (AU)