Anxiety-related disorders have a significant effect on the welfare of pet dogs, often leading to behavioral problems and straining the human-animal bond. Conventional treatments sometimes prove inadequate, highlighting the need for a more objective understanding of the neurobiological pathways underlying canine anxiety disorders. Therefore, this study aimed to investigate anxiety disorders in dogs using 99mTc-HMPAO single photon emission computed tomography (SPECT), focusing on the left frontal region, subcortical region, and cerebellum. While a frequentist approach found no significant differences in brain perfusion between patient and healthy dogs, Bayesian analyses indicated underpowered results. Subsequent correlational analyses were performed and revealed significant positive associations between cerebellar perfusion and aggression, social fear, and nonsocial fear C-BARQ cluster scores (Canine Behavioral Assessment and Research Questionnaire), as well as a negative correlation between subcortical perfusion and nonsocial fear C-BARQ cluster scores in dogs with an anxiety disorder. This study supports the involvement of subcortical regions in anxious dogs and emphasizes the emerging role of the cerebellum in canine anxiety disorders. This study deepens our understanding of the neural correlates of canine anxiety and underscores the potential of nuclear neuroimaging in clinical practice. Future research into broader neural functioning is warranted for improved diagnostic and therapeutic strategies in veterinary behavioral medicine.

Wearable noninvasive brain-computer interface (BCI) technologies, such as electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS), have experienced significant progress since their inception. However, these technologies have not achieved revolutionary advancements, largely because of their inherently low signal-to-noise ratio and limited penetration depth. In recent years, the application of quantum-theory-based optically pumped (OP) technologies, particularly optical pumped magnetometers (OPMs) for magnetoencephalography (MEG) and photoacoustic imaging (PAI) utilizing OP pulsed laser sources, has opened new avenues for development in noninvasive BCIs. These advanced technologies have garnered considerable attention owing to their high sensitivity in tracking neural activity and detecting blood oxygen saturation. This paper represents the first attempt to discuss and compare technologies grounded in OP theory by examining the technical advantages of OPM-MEG and PAI over traditional EEG and fNIRS. Furthermore, the paper investigates the theoretical and structural feasibility of hardware reuse in OPM-MEG and PAI applications.

Advancements in magnetic resonance imaging (MRI) analysis over the past decades have significantly reshaped the field of neuroradiology. The ability to extract multiple quantitative measures from each MRI scan, alongside the development of extensive data repositories, has been fundamental to the emergence of advanced methodologies such as radiomics and artificial intelligence (AI). This educational review aims to delineate the importance of image analysis, highlight key paradigm shifts, examine their implications, and identify existing constraints that must be addressed to facilitate integration into clinical practice. Particular attention is given to aiding junior neuroradiologists in navigating this complex and evolving landscape.

A comprehensive review of the available analysis toolboxes was conducted, focusing on major technological advancements in MRI analysis, the evolution of data repositories, and the rise of AI and radiomics in neuroradiology. Stakeholders within the field were identified and their roles examined. Additionally, current challenges and barriers to clinical implementation were analyzed.

The analysis revealed several pivotal shifts, including the transition from qualitative to quantitative imaging, the central role of large datasets in developing AI tools, and the growing importance of interdisciplinary collaboration. Key stakeholders-including academic institutions, industry partners, regulatory bodies, and clinical practitioners-were identified, each playing a distinct role in advancing the field. However, significant barriers remain, particularly regarding standardization, data sharing, regulatory approval, and integration into clinical workflows.

While advancements in MRI analysis offer tremendous potential to enhance neuroradiology practice, realizing this potential requires overcoming technical, regulatory, and practical barriers. Education and structured support for junior neuroradiologists are essential to ensure they are well-equipped to participate in and drive future developments. A coordinated effort among stakeholders is crucial to facilitate the seamless translation of these technological innovations into everyday clinical practice.

The brain's resting-state energy consumption is expected to be driven by spontaneous activity. We previously used 50 resting-state fMRI (rs-fMRI) features to predict [18F]FDG SUVR as a proxy of glucose metabolism. Here, we expanded on our effort by estimating [18F]FDG kinetic parameters Ki (irreversible uptake), K1 (delivery), k3 (phosphorylation) in a large healthy control group (n = 47). Describing the parameters' spatial distribution at high resolution (216 regions), we showed that K1 is the least redundant (strong posteromedial pattern), and Ki and k3 have relevant differences (occipital cortices, cerebellum, thalamus). Using multilevel modeling, we investigated how much spatial variance of [18F]FDG parameters could be explained by a combination of a) rs-fMRI variables, b) cerebral blood flow (CBF) and metabolic rate of oxygen (CMRO2) from 15O PET. Rs-fMRI-only models explained part of the individual variance in Ki (35%), K1 (14%), k3 (21%), while combining rs-fMRI and CMRO2 led to satisfactory description of Ki (46%) especially. Ki was sensitive to both local rs-fMRI variables (ReHo) and CMRO2, k3 to ReHo, K1 to CMRO2. This work represents a comprehensive assessment of the complex underpinnings of brain glucose consumption, and highlights links between 1) glucose phosphorylation and local brain activity, 2) glucose delivery and oxygen consumption.

Attention plays a vital part in the cognitive process, where different kinds of attention are associated with separate brain mechanisms. The objective of this research was to investigate the patterns of brain activation and functional connectivity in middle-aged and elderly individuals, while they were engaged in various attentional tasks, with the intention of establishing a reference foundation for the clinical treatment of attention disorders.

A total of 44 healthy middle-aged and elderly persons (47.1% women) aged over 40 were enrolled in this study. The digital cancellation test (DCT), the paced auditory serial addition test (PASAT), the Stroop colour-word test, and the trail making test (TMT) are, respectively, associated with four types of attention tasks: sustained attention, divided attention, selective attention, and attention shifting. Functional near-infrared spectroscopic imaging was employed to measure the concentration of brain oxyhaemoglobin in the subjects, while they were performing these four attention tasks.

In this study, we found distinct activation patterns in brain areas, such as BA-3, BA-4, BA-6, and others. Functional connectivity analysis revealed that the frontal and right parietal lobes consistently showed higher density and strength of connections across tasks, with the PASAT task exhibiting the highest number of connections exceeding the threshold. Notably, the DCT task demonstrated significant correlations in oxygen fluctuations among several brain regions, while the TMT-B task highlighted strong functional connectivity within the bilateral frontal and parietal lobes.

This research provides evidence that middle-aged and elderly people have different brain activation and functional connectivity patterns in different attentional tasks, suggesting individualized treatment for attention disorder patients based on impairment type and location.

This study has been registered through the Chinese Clinical Trial Registry (ChiCTR2400087755).

The neurovascular unit (NVU) is composed of neurons, glial cells, brain microvascular endothelial cells (BMECs), pericytes, and the extracellular matrix. The NVU controls the permeability of the blood-brain barrier (BBB) and protects the brain from harmful blood-borne and endogenous and exogenous substances. Among these, neurons transmit signals, astrocytes provide nutrients, microglia regulate inflammation, and BMECs and pericytes strengthen barrier tightness and coverage. These cells, due to their physical structure, anatomical location, or physiological function, maintain the microenvironment required for normal brain function. In this review, the BBB structure and mechanisms are examined to obtain a better understanding of the factors that influence BBB permeability. The findings may aid in safeguarding the BBB and provide potential therapeutic targets for drugs affecting the central nervous system.

Neuroglial cells perform numerous physiological functions and contribute to the pathogenesis of all diseases of the nervous system. Neuroglial neuroprotection defines the resilience of the nervous tissue to exo- and endogenous pathological challenges, while neuroglial defence determines the progression and outcome of neurological disorders. IN this paper, we overview previously unknown but recently discovered roles of various types of neuroglial cells in diverse physiological and pathological processes. First, we describe the role of ependymal glia in the regulation of cerebrospinal fluid flow from the spinal cord to peripheral tissues through the spinal nerves. This newly discovered pathway provides a highway for the CNS-body volume transmission. Next, we present the mechanism by which astrocytes control migration and differentiation of oligodendrocyte precursor cells (OPCs). In pre- and early postnatal CNS, OPCs migrate using vasculature (which is yet free from glia limitans perivascularis) as a pathfinder. Newly forming astrocytic perivascular endfeet signal (through semaphorin-plexin cascade) to OPCs that detach from the vessels and start to differentiate into myelinating oligodendrocytes. We continue the astrocyte theme by demonstrating the neuroprotective role of APOE-laden astrocytic extracellular vesicles in neuromyelitis optica. Next, we explore the link between astrocytic morphology and stress-induced depression. We discuss the critical role of astrocytic ezrin, the cytosolic linker defining terminal astrocyte arborisation and resilience to stress: overexpression of ezrin in prefrontal cortical astrocytes makes mice resistant to stress, whereas ezrin knockdown increases animals vulnerability to stress. Subsequently, we highlight the pathophysiological role of oligodendroglial lineage in schizophrenia by describing novel hypertrophied OPCs in the post-mortem patient's tissue and in a mouse model with OPCs overexpressing alternative splice variant DISC1-Δ3. These DISC1-Δ3-OPCs demonstrated overactivated Wnt/β-catenin signalling pathway and were sufficient to trigger pathological behaviours. Finally, we deliberate on the pathological role of astrocytic and microglial connexin 43 hemichannels in Alzheimer's disease and present a new formula of Cx43 hemichannel inhibitor with increased blood-brain barrier penetration and brain retention.

Experience level correlates with motor cortex and supplementary motor area activation during laparoscopy. Whether brain activation patterns correlate with cognitive surgical task expertise is unknown. We compared the functional neuroimaging responses during simulated operative dictation-a cognitive surgical task-by experience level.

Junior (postgraduate years 1-3) and senior (postgraduate years 4-5) residents and attendings were recruited over 1 year. After a baseline rest period, participants were asked to dictate a simulated operative note for an open inguinal hernia repair with mesh. Functional near-infrared spectroscopy data were recorded from the prefrontal, sensorimotor, and occipital brain areas. The hemodynamic response based on changes in oxyhemoglobin and deoxyhemoglobin concentrations during the task relative to the pre-task baseline for each participant were calculated. Group-level differences in oxyhemoglobin were evaluated using a general linear model.

Thirty participants, 10 from each of the 3 experience levels, were recruited. In the left prefrontal cortex, senior activation (-182) was stronger than both junior (14) and attending (27) activation (P < .001). In the left premotor cortex, senior activation (-147) was stronger than both junior (-52) and attending (15) activation (P = .008). In the left parietal cortex, senior activation (-255) was stronger than both junior (-41) and attending (12) activation (P < .001).

Functional neuroimaging responses during the cognitive task of simulated operative dictation differ by skill level. This study represents the first brain imaging analysis of cognitive function connecting mental imagery, brain activation, and a cognitive surgical task linked to previously performed motor tasks. Functional neuroimaging may act as a nonbiased assessment tool of cognitive skill.

Neurovascular coupling (NVC) refers to the dynamic regulation of cerebral blood flow via neuronal activity, a mechanism crucial for maintaining normal brain function. This review elucidates the intricate physiological mechanisms underlying NVC, emphasizing the coordinated roles of neurons, glial cells, and vascular cells in mediating activity-induced changes in blood flow. We examine how NVC is impaired in neurological disorders such as Alzheimer's disease and stroke, where the dysfunction of this coupling contributes to neurodegeneration and neurological deficits. A broad range of techniques for assessing NVC is discussed-encompassing the established modalities like transcranial Doppler, near-infrared spectroscopy, and functional magnetic resonance imaging (fMRI), as well as emerging technologies such as functional ultrasound imaging and miniaturized endoscopy that enable high-resolution monitoring in deep brain regions. We also highlight the computational modeling approaches for simulating NVC dynamics and identify the novel biomarkers of NVC dysfunction with potential utility in early diagnosis. Finally, emerging translational applications-including neuromodulation techniques and targeted pharmacological interventions-are explored as means to restore normal neurovascular function. These advancements underscore the clinical significance of NVC research, paving the way for improved diagnostic tools and therapeutic strategies in neurological disorders.

Crosstalk mechanisms between retinas were never documented in humans despite being documented for several other species, including non-human primates. Results of the first-in-human study that documents the crosstalk between retinas by measuring the vascular response in one retina to the photic stimulation of the contralateral eye in health and disease are reported herein. A stimulation apparatus was developed and integrated into an adaptive-optics fundus camera to image 32 healthy control (HC) subjects and 20 type 1 diabetes mellitus (DM) patients. Ipsilateral and contralateral neurovascular coupling effects were documented, and criteria were established to consider an actual response and find positive and negative responses. Ten (31.2%) and two (6.2%) subjects of the HC group presented contralateral positive and negative responses, respectively, and three (15.0%) positive and four (20.0%) negative responses were found for the DM group. Also, statistically significant differences in the ipsilateral (p < 0.001) and contralateral (p = 0.027) responses were found for the HC group, rejecting the null (non-response) hypothesis. This finding raises the need to revisit the current knowledge of neurovascular coupling mechanisms and the association between its dysregulation and neurological disorders. Further studies involving distinct populations and imaging centers are necessary to validate the findings herein.

Intracranial pressure (ICP) is pressure within the cranium, between 5 and 15 mmHg in a normal brain, and is influenced by the dynamic balance between brain tissue, cerebrospinal fluid (CSF) and cerebral blood volume. ICP is vital for cerebral health, impacting outcomes in various neurological conditions. Disruptions, such as cerebral haemorrhage, hydrocephalus and malignant hypertension, can lead to elevated ICP, a dangerous condition known as intracranial hypertension (IH). Systemic hypertension significantly impacts cerebral health by causing microvascular damage, dysfunction of the blood-brain barrier (BBB) and impairment of intracranial compliance (ICC). This increases the risk of IH), cerebral ischaemia, neuroinflammation and lacunar infarction, further worsening neurological dysfunction. This review describes the complex relationship between hypertension and ICP regulation, focusing on the mechanisms underlying ICP and ICC adjustments in hypertensive conditions and emphasizing the role of BBB integrity and cerebral blood flow (CBF) dynamics. It discusses how the sympathetic output might change the regulation of CBF and the maintenance of ICP, highlighting how hypertensive conditions can impair this mechanism, increasing the risk of cerebral ischaemia. The neurovascular unit, including astrocytes and microglia, plays a significant role in this process, contributing to IH in hypertensive patients. Understanding the effects of hypertension on ICP and ICC could lead to therapies aimed at preserving BBB integrity, reducing inflammation and improving cerebral compliance, potentially preventing brain dysfunction and reducing stroke risk in hypertensive patients. This review underscores the need for early detection and intervention to mitigate the severe consequences of uncontrolled hypertension on cerebral health.

Proper formation of the complex neurovascular unit (NVU) along with the blood-brain barrier is critical for building and sustaining a healthy, functioning central nervous system. The RNA binding protein argonaute2 (Ago2) mediates microRNA (miRNA)-mediated gene silencing, which is critical for many facets of brain development, including NVU development. Here, we found that Ago2 in glutamatergic neurons was critical for NVU formation in the developing cortices of mice. Glutamatergic neuron-specific loss of Ago2 diminished synaptic formation, neuronal-to-endothelial cell contacts, and morphogenesis of the brain vasculature, ultimately compromising the integrity of the blood-brain barrier. Ago2 facilitated miRNA targeting of phosphatase and tensin homolog (Pten) mRNA, which encodes a phosphatase that modulates reelin-dependent phosphatidylinositol 3-kinase (PI3K)-Akt signaling within the glutamatergic subpopulation. Conditionally deleting Pten in Ago2-deficient neurons restored Akt2 phosphorylation as well as postnatal development and survival. Several mutations in AGO2 impair small RNA silencing and are associated with Lessel-Kreienkamp syndrome, a neurodevelopmental disorder. When expressed in a neuronal cell line, these human AGO2 loss-of-function variants failed to suppress PTEN, resulting in attenuated PI3K-Akt signaling, further indicating that dysregulation of Ago2 function may contribute to both impaired development and neurological disorders. Together, these results identify Ago2 as central to the engagement of neurons with blood vessels in the developing brain.

Local control of blood flow depends on signaling to arterioles via upstream conducted responses. Here, the objective is to examine how electrical properties of gap junctions between endothelial cells (EC) affect the spread of conducted responses in microvascular networks of the brain cortex, using a theoretical model based on EC electrophysiology.

Modeled EC currents are an inward-rectifying potassium current, a non-voltage-dependent potassium current, a leak current, and a gap junction current between adjacent ECs. Effects of varying gap junction conductance are considered, including asymmetric conductance, with higher conductance for forward currents (positive currents from upstream to downstream, based on blood flow direction). The response is initiated by a local increase in extracellular potassium concentration. The model is applied to a 45-segment synthetic network and a 4881-segment network from mouse brain cortex.

The conducted response propagates preferentially to upstream arterioles when the conductance for forward currents is at least 20 times that for backward currents. The response depends strongly on the site of stimulation. With symmetric gap junction conductance, the network acts as a syncytium and the conducted response is dissipated.

Upstream propagation of conducted responses may depend on the asymmetric conductance of EC gap junctions.

Cerebrovascular regulation is critically dependent upon the arterial partial pressure of carbon dioxide (P aC O 2 ${P_{{\mathrm{aC}}{{\mathrm{O}}_{\mathrm{2}}}}}$ ), owing to its effect on cerebral blood flow, tissueP C O 2 ${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ , tissue proton concentration, cerebral metabolism and cognitive and neuronal function. In normal environments and in the absence of pathology, at least over acute time frames, hypercapnia is usually managed readily via the respiratory chemoreflex arcs and/or acid-base buffering capacity, such that there is minimal impact on cerebrovascular and neurological function. However, in non-normal environments, such as enclosed spaces, or with pathology, extended exposures to elevations inP aC O 2 ${P_{{\mathrm{aC}}{{\mathrm{O}}_{\mathrm{2}}}}}$ can be detrimental to cerebral health. Given the direct effect of protons on cellular function, even if pH is normalized, it is feasible that higher proton concentrations could still produce detrimental effects. Although it seems that humans can work safely in mildly hypercapnic environments for extended periods, chronic respiratory acidosis can cause bone demineralization, renal calcification, perinatal developmental abnormalities, systemic inflammation and impairments in cognitive function and visuomotor skills and can produce cerebral acidosis, potentially inducing sustained alterations in cerebral function. With the advancement of new initiatives in spaceflight, including proposed long-duration missions to Mars, the study of the effects of chronic inspired CO2 on human health is relevant. In this review, we draw on evidence from preclinical, physiological and clinical research in humans to summarize the cerebral ramifications of prolonged and chronic exposures to elevated partial pressures of inspired CO2 and respiratory acidosis.

Diffusion MRI was introduced in 1985, showing how the diffusive motion of molecules, especially water, could be spatially encoded with MRI to produce images revealing the underlying structure of biologic tissues at a microscopic scale. Diffusion is one of several Intravoxel Incoherent Motions (IVIM) accessible to MRI together with blood microcirculation. Diffusion imaging first revolutionized the management of acute cerebral ischemia by allowing diagnosis at an acute stage when therapies can still work, saving the outcomes of many patients. Since then, the field of diffusion imaging has expanded to the whole body, with broad applications in both clinical and research settings, providing insights into tissue integrity, structural and functional abnormalities from the hindered diffusive movement of water molecules in tissues. Diffusion imaging is particularly used to manage many neurologic disorders and in oncology for detecting and classifying cancer lesions, as well as monitoring treatment response at an early stage. The second major impact of diffusion imaging concerns the wiring of the brain (Diffusion Tensor Imaging, DTI), allowing to obtain from the anisotropic movement of water molecules in the brain white-matter images in 3 dimensions of the brain connections making up the Connectome. DTI has opened up new avenues of clinical diagnosis and research to investigate brain diseases, neurogenesis and aging, with a rapidly extending field of application in psychiatry, revealing how mental illnesses could be seen as Connectome spacetime disorders. Adding that water diffusion is closely associated to neuronal activity, as shown from diffusion fMRI, one may consider that diffusion MRI is ideally suited to investigate both brain structure and function. This article retraces the early days and milestones of diffusion MRI which spawned over 40 years, showing how diffusion MRI emerged and expanded in the research and clinical fields, up to become a pillar of modern clinical imaging.

Neurovascular coupling (NVC) is the mechanism that drives the neurovascular response to neural activation, and NVC dysfunction has been implicated in various neurologic diseases. NVC is driven by (1) nonmetabolic feedforward mechanisms that are mediated by various signaling pathways and (2) metabolic feedback mechanisms that involve metabolic factors. However, the interplay between these feedback and feedforward mechanisms remains unresolved. We propose that feedforward mechanisms normally drive a swift, neural activation-induced regional cerebral blood flow (rCBF) overshoot, which floods the tissue beds, leading to local hypocapnia and hyperoxia. The feedback mechanisms are triggered by the resultant hypocapnia (not hyperoxia), which causes cerebral vasoconstriction in the neurovascular unit that counterbalances the rCBF overshoot and returns rCBF to a level that matches the metabolic activity. If feedforward mechanisms function improperly (eg, in a disease state), the rCBF overshoot, tissue-bed flooding, and local hypocapnia fail to occur or occur on a smaller scale. Consequently, the neural activation-related increase in metabolic activity results in local hypercapnia and hypoxia, both of which drive cerebral vasodilation and increase rCBF. Thus, feedback mechanisms ensure the brain milieu's stability when feedforward mechanisms are impaired. Our proposal integrates the feedforward and feedback mechanisms underlying NVC and suggests that these 2 mechanisms work like a fail-safe system, to a certain degree. We also discussed the difference between NVC and cerebral metabolic rate-CBF coupling and the clinical implications of our proposed framework.

Niels Lassen's seminal 1959 cerebral autoregulation plot, a cornerstone in understanding the relationship between mean arterial pressure (MAP) and cerebral blood flow (CBF), was based on preexisting literature. However, this work has faced criticism for selective data presentation, leading to inaccurate interpretation. This review revisits and validates Lassen's original plot using contemporary data published since 2000. Additionally, we aim to understand the impact of vasoactive drug treatments on CBF, as Lassen's referenced studies used various drugs for blood pressure manipulation. Our findings confirm Lassen's concept of a plateau where CBF remains relatively stable across a specific MAP range in awake humans with normal brains. However, significant variations in cerebral autoregulation among different populations are evident. In critically ill patients and those with traumatic brain injury, the autoregulatory plateau dissipates, necessitating tight blood pressure control to avoid inadequate or excessive cerebral perfusion. A plateau is observed in patients anesthetized with intravenous agents but not with volatile agents. Vasopressor treatments have population-dependent effects, with contemporary data showing increased CBF in critically ill patients but not in awake humans with normal brains. Vasopressor treatment results in a greater increase in CBF during volatile than intravenous anesthesia. Modern antihypertensives do not significantly impact CBF based on contemporary data, exerting a smaller impact on CBF compared to historical data. These insights underscore the importance of individualized blood pressure management guided by modern data in the context of cerebral autoregulation across varied patient populations.

Functional near-infrared spectroscopy was used to record spontaneous hemodynamic fluctuations form the bilateral temporal lobes in 25 children with autism spectrum disorder (ASD) and 22 typically developing (TD) children. The coupling between oxygenated hemoglobin (HbO) and deoxygenated hemoglobin (Hb) was calculated by Pearson correlation coefficient, showing significant difference between ASD and TD, thus the coupling could be a characteristic feature for ASD. To evaluate the discrimination ability of the feature obtained in different acquisition times, the receiver operating characteristic curve (ROC) was constructed and the area under curve (AUC) was calculated. The results showed AUC > 0.8 when the time duration was longer than 1.5 min, but longer than 4 min, AUC value (~0.87) hardly varied, implying the maximal discrimination ability reached. This study demonstrated the coupling could be one of characteristic features for ASD even acquired in a short measurement time.

Our understanding of the relationship between neural activity and psychological states has advanced greatly in recent decades. But we are still unable to explain conscious experience in terms of physical processes occurring in our brains.

This paper introduces a conceptual framework that may contribute to an explanation. All physical processes entail the transfer, transduction, and transformation of energy between portions of matter as work is performed in material systems. If the production of consciousness in nervous systems is a physical process, then it must entail the same. Here the nervous system, and the brain in particular, is considered as a material system that transfers, transduces, and transforms energy as it performs biophysical work.

Evidence from neuroscience suggests that conscious experience is produced in the organic matter of nervous systems when they perform biophysical work at classical and quantum scales with a certain level of dynamic complexity or organization. An empirically grounded, falsifiable, and testable hypothesis is offered to explain how energy processing in nervous systems may produce conscious experience at a fundamental physical level.

The brain's resting-state energy consumption is expected to be mainly driven by spontaneous activity. In our previous work, we extracted a wide range of features from resting-state fMRI (rs-fMRI), and used them to predict [18F]FDG PET SUVR as a proxy of glucose metabolism. Here, we expanded upon our previous effort by estimating [18F]FDG kinetic parameters according to Sokoloff's model, i.e.,K i (irreversible uptake rate),K 1 (delivery),k 3 (phosphorylation), in a large healthy control group. The parameters' spatial distribution was described at a high spatial resolution. We showed that whileK 1 is the least redundant, there are relevant differences betweenK i andk 3 (occipital cortices, cerebellum and thalamus). Using multilevel modeling, we investigated how much of the regional variability of [18F]FDG parameters could be explained by a combination of rs-fMRI variables only, or with the addition of cerebral blood flow (CBF) and metabolic rate of oxygen (CMRO2), estimated from 15O PET data. We found that combining rs-fMRI and CMRO2 led to satisfactory prediction of individualK i variance (45%). Although more difficult to describe,K i andk 3 were both most sensitive to local rs-fMRI variables, whileK 1 was sensitive to CMRO2. This work represents the most comprehensive assessment to date of the complex functional and metabolic underpinnings of brain glucose consumption.

The brain is the most complex organ in the human body and, as such, its study entails great challenges (methodological, theoretical, etc.). Nonetheless, there is a remarkable amount of studies about the consequences of pathological conditions on its development and functioning. This bibliographic review aims to cover mostly findings related to changes in the physical distribution of neurons and their connections-the connectome-both structural and functional, as well as their modelling approaches. It does not intend to offer an extensive description of all conditions affecting the brain; rather, it presents the most common ones. Thus, here, we highlight the need for accurate brain modelling that can subsequently be used to understand brain function and be applied to diagnose, track, and simulate treatments for the most prevalent pathologies affecting the brain.

Glaucoma is the leading cause of irreversible blindness globally. The disease causes vision loss due to neurodegeneration of the retinal ganglion cell (RGC) projection to the brain through the optic nerve. Glaucoma is associated with sensitivity to intraocular pressure (IOP). Thus, mainstay treatments seek to manage IOP, though many patients continue to lose vision. To address neurodegeneration directly, numerous preclinical studies seek to develop protective or reparative therapies that act independently of IOP. These include growth factors, compounds targeting metabolism, anti-inflammatory and antioxidant agents, and neuromodulators. Despite success in experimental models, many of these approaches fail to translate into clinical benefits. Several factors contribute to this challenge. Firstly, the anatomic structure of the optic nerve head differs between rodents, nonhuman primates, and humans. Additionally, animal models do not replicate the complex glaucoma pathophysiology in humans. Therefore, to enhance the success of translating these findings, we propose two approaches. First, thorough evaluation of experimental targets in multiple animal models, including nonhuman primates, should precede clinical trials. Second, we advocate for combination therapy, which involves using multiple agents simultaneously, especially in the early and potentially reversible stages of the disease. These strategies aim to increase the chances of successful neuroprotective treatment for glaucoma.

Biomedical research on the brain has led to many discoveries and developments, such as understanding human consciousness and the mind and overcoming brain diseases. However, historical biomedical research on the brain has unique characteristics that differ from those of conventional biomedical research. For example, there are different scientific interpretations due to the high complexity of the brain and insufficient intercommunication between researchers of different disciplines owing to the limited conceptual and technical overlap of distinct backgrounds. Therefore, the development of biomedical research on the brain has been slower than that in other areas. Brain biomedical research has recently undergone a paradigm shift, and conducting patient-centered, large-scale brain biomedical research has become possible using emerging high-throughput analysis tools. Neuroimaging, multiomics, and artificial intelligence technology are the main drivers of this new approach, foreshadowing dramatic advances in translational research. In addition, emerging interdisciplinary cooperative studies provide insights into how unresolved questions in biomedicine can be addressed. This review presents the in-depth aspects of conventional biomedical research and discusses the future of biomedical research on the brain.

Both the retina and brain exhibit neurovascular coupling, increased blood flow during increased neural activity. In the retina increased blood flow can be evoked by flickering light, but the magnitude of the metabolic change that underlies this is not known. Local changes in oxygen consumption (QO2) are difficult to measure in vivo when both supply and demand are changing. Here we isolated the C57BL/6J mouse retina and supplied it with oxygen from both sides of the tissue. Microelectrode recordings of PO2 were made in darkness and during 20 s of high scotopic flickering light at 1 Hz. Flicker led to a PO2 increase in the outer retina and a decrease in the inner retina, indicating that outer retinal QO2 (QOR) decreased and inner retinal QO2 (QIR) increased. A four-layer oxygen diffusion model was fitted to PO2 values obtained in darkness and at the end of flicker to determine the values of QOR and QIR. QOR in flicker was 76 ± 14% (mean and SD, n = 10) of QOR in darkness. The increase in QIR was smaller, 6.4 ± 5.0%. These metabolic changes are likely smaller than the maximum changes, because with no regeneration of pigment in the isolated retina, we limited the illumination. Further modeling indicated that at high illumination, QIR could increase by up to 45%, which is comparable to the magnitude of flow changes. This suggests that the blood flow increase is at least roughly matched to the increased metabolic demands of activity in the retina.

Sleep is a physiological process that preserves the integrity of the neuro-immune-endocrine network to maintain homeostasis. Sleep regulates the production and secretion of hormones, neurotransmitters, cytokines and other inflammatory mediators, both at the central nervous system (CNS) and at the periphery. Sleep promotes the removal of potentially toxic metabolites out of the brain through specialized systems such as the glymphatic system, as well as the expression of specific transporters in the blood-brain barrier. The blood-brain barrier maintains CNS homeostasis by selectively transporting metabolic substrates and nutrients into the brain, by regulating the efflux of metabolic waste products, and maintaining bidirectional communication between the periphery and the CNS. All those processes are disrupted during sleep loss. Brain endothelial cells express the blood-brain barrier phenotype, which arises after cell-to-cell interactions with mural cells, like pericytes, and after the release of soluble factors by astroglial endfeet. Astroglia, pericytes and brain endothelial cells respond differently to sleep loss; evidence has shown that sleep loss induces a chronic low-grade inflammatory state at the CNS, which is associated with blood-brain barrier dysfunction. In animal models, blood-brain barrier dysfunction is characterized by increased blood-brain barrier permeability, decreased tight junction protein expression and pericyte detachment from the capillary wall. Blood-brain barrier dysfunction may promote defects in brain clearance of potentially neurotoxic metabolites and byproducts of neural physiology, which may eventually contribute to neurodegenerative diseases. This chapter aims to describe the cellular and molecular mechanisms by which sleep loss modifies the function of the blood-brain barrier.

Functional connectivity is a critical aspect of brain function and is essential for understanding, diagnosing, and treating neurological and psychiatric disorders. It refers to the synchronous activity between different regions of the brain, which gives rise to communication and information processing. Resting-state functional connectivity is a subarea of study that allows researchers to examine brain activity in the absence of a task or stimulus. This can provide insight into the brain's intrinsic functional architecture and help identify neural networks that are active during rest. Thus, determining functional connectivity topography is valuable both clinically and in research. Traditional methods using functional magnetic resonance imaging have proven to be effective, however, they have their limitations. In this review, we investigate the feasibility of using functional near-infrared spectroscopy (fNIRS) as a low-cost, portable alternative for measuring functional connectivity. We first establish fNIRS' ability to detect localized brain activity during task-based experiments. Next, we verify its use in resting-state studies with results showing a high degree of correspondence with resting-state functional magnetic resonance imaging (rs-fMRI). Also discussed are various data-processing methods and the validity of filtering the global signal, which is the current standard for analysis. We consider the possible origins of the global signal, if it contains pertinent neuronal information that could be of importance in better understanding neuronal networks, and what we believe is the best method of approaching signal analysis and regression.

Resting-state functional magnetic resonance imaging (rsfMRI) has been developed as a method of investigating spontaneous neural activity. Based on its low-frequency signal synchronization, rsfMRI has made it possible to identify multiple macroscopic structures termed resting-state networks (RSNs) on a single scan of less than 10 minutes. It is easy to implement even in clinical practice, in which assigning tasks to patients can be challenging. These advantages have accelerated the adoption and growth of rsfMRI. Recently, studies on the global rsfMRI signal have attracted increasing attention. Because it primarily arises from physiological events, less attention has hitherto been paid to the global signal than to the local network (i.e., RSN) component. However, the global signal is not a mere nuisance or a subsidiary component. On the contrary, it is quantitatively the dominant component that accounts for most of the variance in the rsfMRI signal throughout the brain and provides rich information on local hemodynamics that can serve as an individual-level diagnostic biomarker. Moreover, spatiotemporal analyses of the global signal have revealed that it is closely and fundamentally associated with the organization of RSNs, thus challenging the basic assumptions made in conventional rsfMRI analyses and views on RSNs. This review introduces new concepts emerging from rsfMRI spatiotemporal analyses focusing on the global signal and discusses how they may contribute to future clinical medicine. EVIDENCE LEVEL: 5 TECHNICAL EFFICACY: Stage 1.

The brain's unique characteristics make it exceptionally susceptible to oxidative stress, which arises from an imbalance between reactive oxygen species (ROS) production, reactive nitrogen species (RNS) production, and antioxidant defense mechanisms. This review explores the factors contributing to the brain's vascular tone's vulnerability in the presence of oxidative damage, which can be of clinical interest in critically ill patients or those presenting acute brain injuries. The brain's high metabolic rate and inefficient electron transport chain in mitochondria lead to significant ROS generation. Moreover, non-replicating neuronal cells and low repair capacity increase susceptibility to oxidative insult. ROS can influence cerebral vascular tone and permeability, potentially impacting cerebral autoregulation. Different ROS species, including superoxide and hydrogen peroxide, exhibit vasodilatory or vasoconstrictive effects on cerebral blood vessels. RNS, particularly NO and peroxynitrite, also exert vasoactive effects. This review further investigates the neuroprotective effects of antioxidants, including superoxide dismutase (SOD), vitamin C, vitamin E, and the glutathione redox system. Various studies suggest that these antioxidants could be used as adjunct therapies to protect the cerebral vascular tone under conditions of high oxidative stress. Nevertheless, more extensive research is required to comprehensively grasp the relationship between oxidative stress and cerebrovascular tone, and explore the potential benefits of antioxidants as adjunctive therapies in critical illnesses and acute brain injuries.

Historically, clinical evaluation of unresponsive patients following brain injury has relied principally on serial behavioral examination to search for emerging signs of consciousness and track recovery. Advances in neuroimaging and electrophysiologic techniques now enable clinicians to peer into residual brain functions even in the absence of overt behavioral signs. These advances have expanded clinicians' ability to sub-stratify behaviorally unresponsive and seemingly unaware patients following brain injury by querying and classifying covert brain activity made evident through active or passive neuroimaging or electrophysiologic techniques, including functional MRI, electroencephalography (EEG), transcranial magnetic stimulation-EEG, and positron emission tomography. Clinical research has thus reciprocally influenced clinical practice, giving rise to new diagnostic categories including cognitive-motor dissociation (i.e. 'covert consciousness') and covert cortical processing (CCP). While covert consciousness has received extensive attention and study, CCP is relatively less understood. We describe that CCP is an emerging and clinically relevant state of consciousness marked by the presence of intact association cortex responses to environmental stimuli in the absence of behavioral evidence of stimulus processing. CCP is not a monotonic state but rather encapsulates a spectrum of possible association cortex responses from rudimentary to complex and to a range of possible stimuli. In constructing a roadmap for this evolving field, we emphasize that efforts to inform clinicians, philosophers, and researchers of this condition are crucial. Along with strategies to sensitize diagnostic criteria and disorders of consciousness nosology to these vital discoveries, democratizing access to the resources necessary for clinical identification of CCP is an emerging clinical and ethical imperative.

Neurovascular coupling (NVC) is important for brain function and its dysfunction underlies many neuropathologies. Although cell-type specificity has been implicated in NVC, how active neural information is conveyed to the targeted arterioles in the brain remains poorly understood. Here, using two-photon focal optogenetics in the mouse cerebral cortex, we demonstrate that single glutamatergic axons dilate their innervating arterioles via synaptic-like transmission between neural-arteriolar smooth muscle cell junctions (NsMJs). The presynaptic parental-daughter bouton makes dual innervations on postsynaptic dendrites and on arteriolar smooth muscle cells (aSMCs), which express many types of neuromediator receptors, including a low level of glutamate NMDA receptor subunit 1 (Grin1). Disruption of NsMJ transmission by aSMC-specific knockout of GluN1 diminished optogenetic and whisker stimulation-caused functional hyperemia. Notably, the absence of GluN1 subunit in aSMCs reduced brain atrophy following cerebral ischemia by preventing Ca2+ overload in aSMCs during arteriolar constriction caused by the ischemia-induced spreading depolarization. Our findings reveal that NsMJ transmission drives NVC and open up a new avenue for studying stroke.

Recent thermodynamic modelling indicates that maintaining the brain tissue ratio of O2 to CO2 (abbreviated tissue O2 /CO2 ) is critical for preserving the entropy increase available from oxidative metabolism of glucose, with a fall of that available entropy leading to a reduction of the phosphorylation potential and impairment of brain energy metabolism. This provides a novel perspective for understanding physiological responses under different conditions in terms of preserving tissue O2 /CO2 . To enable estimation of tissue O2 /CO2 in the human brain, a detailed mathematical model of O2 and CO2 transport was developed, and applied to reported physiological responses to different challenges, asking: how well is tissue O2 /CO2 preserved? Reported experimental results for increased neural activity, hypercapnia and hypoxia due to high altitude are consistent with preserving tissue O2 /CO2 . The results highlight two physiological mechanisms that control tissue O2 /CO2 : cerebral blood flow, which modulates tissue O2 ; and ventilation rate, which modulates tissue CO2 . The hypoxia modelling focused on humans at high altitude, including acclimatized lowlanders and Tibetan and Andean adapted populations, with a primary finding that decreasing CO2 by increasing ventilation rate is more effective for preserving tissue O2 /CO2 than increasing blood haemoglobin content to maintain O2 delivery to tissue. This work focused on the function served by particular physiological responses, and the underlying mechanisms require further investigation. The modelling provides a new framework and perspective for understanding how blood flow and other physiological factors support energy metabolism in the brain under a wide range of conditions. KEY POINTS: Thermodynamic modelling indicates that preserving the O2 /CO2 ratio in brain tissue is critical for preserving the entropy change available from oxidative metabolism of glucose and the phosphorylation potential underlying energy metabolism. A detailed model of O2 and CO2 transport was developed to allow estimation of the tissue O2 /CO2 ratio in the human brain in different physiological states. Reported experimental results during hypoxia, hypercapnia and increased oxygen metabolic rate in response to increased neural activity are consistent with maintaining brain tissue O2 /CO2 ratio. The hypoxia modelling of high-altitude acclimatization and adaptation in humans demonstrates the critical role of reducing CO2 with increased ventilation for preserving tissue O2 /CO2 . Preservation of tissue O2 /CO2 provides a novel perspective for understanding the function of observed physiological responses under different conditions in terms of preserving brain energy metabolism, although the mechanisms underlying these functions are not well understood.

To investigate macular and peripapillary vascular density (VD) in patients with anorexia nervosa (AN) compared to healthy controls. Methods:Whole face scans of the superficial and deep macular layers and whole face and peripapillary scans of the radial peripapillary capillaries (RPC) were obtained using optical coherence tomography angiography (OCTA, AngioVueR, Optovue) in ten patients with AN and ten age-matched controls.The primary objective was to determine whether there was a difference between the vessel density (VD) in the above areas in AN and controls. P-values ≤ 0.0125 were considered statistically significant. Results: VD in the superficialmacular en-face OCTA image was significantly lower in the study group compared to the control group. Neither the deepmacula nor the radial peripapillary capillary (RPC) in the whole-face image nor the RPC-peripapillary imaging appeared to be significantly different. Conclusion: Patients with AN showed reduced VD in the superficialmacular layers compared to healthy controls, which can be discussed as a consequence of the malnutrition. OCTA could be a useful non- invasive tool to detect reduced peripheral blood supply to show vascular changes that occur before ocular symptoms.

The blood-brain barrier (BBB) is a remarkable and intricate barrier that controls the exchange of molecules between the bloodstream and the brain. Its role in maintaining the stability of the central nervous system cannot be overstated. Over the years, advancements in neuroscience and technology have enabled us to delve into the cellular and molecular components of the BBB, as well as its regulation. Yet, there is a scarcity of comprehensive reviews that follow a logical framework of structure-function-regulation, particularly focusing on the nuances of BBB regulation under both normal and pathological conditions. This review sets out to address this gap by taking a historical perspective on the discovery of the BBB and highlighting the major observations that led to its recognition as a distinct brain barrier. It explores the intricate cellular elements contributing to the formation of the BBB, including endothelial cells, pericytes, astrocytes, and neurons, emphasizing their collective role in upholding the integrity and functionality of the BBB. Furthermore, the review delves into the dynamic regulation of the BBB in physiological states, encompassing neural, humoral, and auto-regulatory mechanisms. By shedding light on these regulatory processes, a deeper understanding of the BBB's response to various physiological cues emerges. This review also investigates the disruption of the BBB integrity under diverse pathological conditions, such as ischemia, infection, and toxin exposure. It elucidates the underlying mechanisms that contribute to BBB dysfunction and explores potential therapeutic strategies that aim to restore the BBB integrity and function. Overall, this recapitulation provides valuable insights into the structure, functions, and regulation of the BBB. By integrating historical perspectives, cellular elements, regulatory mechanisms, and pathological implications, this review contributes to a more comprehensive understanding of the BBB and paves the way for future research and therapeutic interventions.

Opioids are important tools for pain management, but abuse can result in serious health complications. Of these complications, respiratory depression that leads to brain hypoxia is the most dangerous, resulting in coma and death. Although all opioids at large doses induce brain hypoxia, danger is magnified with synthetic opioids such as fentanyl and structurally similar analogs. These drugs are highly potent, act rapidly, and are often not effectively treated by naloxone, the standard of care for opioid-induced respiratory depression. The goal of this review paper is to present and discuss brain oxygen responses induced by opioids, focusing on heroin and fentanyl. In contrast to studying drug-induced changes in respiratory activity, we used chronically implanted oxygen sensors coupled with high-speed amperometry to directly evaluate physiological and drug-induced fluctuations in brain oxygen levels in awake, freely moving rats. First, we provide an overview of brain oxygen responses to physiological stimuli and discuss the mechanisms regulating oxygen entry into brain tissue. Next, we present data on brain oxygen responses induced by heroin and fentanyl and review underlying mechanisms. These data allowed us to compare the effects of these drugs on brain oxygen in terms of their potency, time-dependent response pattern, and potentially lethal effect at high doses. Then, we present the interactive effects of opioids during polysubstance use (alcohol, ketamine, xylazine) on brain oxygenation. Finally, we consider factors that affect the therapeutic potential of naloxone, focusing on dosage, timing of drug delivery, and contamination of opioids by other neuroactive drugs. The latter issue is considered chiefly with respect to xylazine, which strongly potentiates the hypoxic effects of heroin and fentanyl. Although this work was done in rats, the data are human relevant and will aid in addressing the alarming rise in lethality associated with opioid misuse.

Epilepsy is now considered a network disease that affects the brain across multiple levels of spatial and temporal scales. The paradigm shift from an epileptic focus-a discrete cortical area from which seizures originate-to a widespread epileptic network-spanning lobes and hemispheres-considerably advanced our understanding of epilepsy and continues to influence both research and clinical treatment of this multi-faceted high-impact neurological disorder. The epileptic network, however, is not static but evolves in time which requires novel approaches for an in-depth characterization. In this review, we discuss conceptual basics of network theory and critically examine state-of-the-art recording techniques and analysis tools used to assess and characterize a time-evolving human epileptic brain network. We give an account on current shortcomings and highlight potential developments towards an improved clinical management of epilepsy.

The retina transforms light into electrical signals, which are sent to the brain via the optic nerve to form our visual perception. This complex signal processing is performed by the retinal neuron and requires a significant amount of energy. Since neurons are unable to store energy, they must obtain glucose and oxygen from the bloodstream to produce energy to match metabolic needs. This process is called neurovascular coupling (NVC), and it is based on a precise mechanism that is not totally understood. The discovery of fine tubular processes termed tunnelling nanotubes (TNTs) set a new type of cell-to-cell communication. TNTs are extensions of the cellular membrane that allow the transfer of material between connected cells. Recently, they have been reported in the brain and retina of living mice, where they connect pericytes, which are vascular mural cells that regulate vessel diameter. Accordingly, these TNTs were termed interpericyte tunnelling nanotubes (IPTNTs), which showed a vital role in blood delivery and NVC. In this chapter, we review the involvement of TNTs in NVC and discuss their implications in retinal neurodegeneration.

Göttingen Minipigs (GM) are used as an important preclinical model for cardiovascular safety pharmacology and for evaluation of cardiovascular drug targets. To improve the translational value of the GM model, the current study represents a basic characterization of vascular responses to endothelial regulators and sympathetic, parasympathetic, and sensory neurotransmitters in different anatomical origins. The aim of the current comparative and descriptive study is to use myography to characterize the vasomotor responses of coronary artery isolated from GM and compare the responses to those obtained from parallel studies using cerebral and mesenteric arteries. The selected agonists for sympathetic (norepinephrine), parasympathetic (carbachol), sensory (calcitonin gene-related peptide, CGRP), and endothelial pathways (endothelin-1, ET-1, and bradykinin) were used for comparison. Further, the robust nature of the vasomotor responses was evaluated after 24 h of cold storage of vascular tissue mimicking the situation under which human biopsies are often kept before experiments or grafting is feasible. Results show that bradykinin and CGRP consistently dilated, and endothelin consistently contracted artery segments from coronary, cerebral, and mesenteric origin. By comparison, norepinephrine and carbachol, had responses that varied with the anatomical source of the tissues. To support the basic characterization of GM vasomotor responses, we demonstrated the presence of mRNA encoding selected vascular receptors (CGRP- and ETA-receptors) in fresh artery segments. In conclusion, the vasomotor responses of isolated coronary, cerebral, and mesenteric arteries to selected agonists of endothelial, sympathetic, parasympathetic, and sensory pathways are different and the phenotypes are similar to sporadic human findings.

The neurovascular unit, comprised of vascular cell types that collectively regulate cerebral blood flow to meet the needs of coupled neurons, is paramount for the proper function of the central nervous system. The neurovascular unit gatekeeps blood-brain barrier properties, which experiences impairment in several central nervous system diseases associated with neuroinflammation and contributes to pathogenesis. To better understand function and dysfunction at the neurovascular unit and how it may confer inflammatory processes within the brain, isolation and characterization of the neurovascular unit is needed. Here, we describe a singular, standardized protocol to enrich and isolate microvessels from archived snap-frozen human and frozen mouse cerebral cortex using mechanical homogenization and centrifugation-separation that preserves the structural integrity and multicellular composition of microvessel fragments. For the first time, microvessels are isolated from postmortem ventromedial prefrontal cortex tissue and are comprehensively investigated as a structural unit using both RNA sequencing and Liquid Chromatography with tandem mass spectrometry (LC-MS/MS). Both the transcriptome and proteome are obtained and compared, demonstrating that the isolated brain microvessel is a robust model for the NVU and can be used to generate highly informative datasets in both physiological and disease contexts.

The benefits of long-term consumption of green tea on the brain are well known. However, among many ingredients of green tea, the acute effects of (-)-gallocatechin gallate-rich green tea extract (GCG-GTE), have received comparatively less attention. Herein, we investigated the acute effects of oral ingestion of green tea with GCG-GTE, which contains close replicas of the ingredients of hot green tea, on task-dependent hemodynamics in the prefrontal cortex of healthy adult human brains.

In this randomized, double-blind, placebo-controlled, parallel group trial, 35 healthy adults completed computerized cognitive tasks that demand activation of the prefrontal cortex at baseline and 1 h after consumption of placebo and 900 mg of GCG-GTE extract supplement. During cognitive testing, hemodynamic responses (change in HbO2 concentration) in the prefrontal cortex were assessed using functional near-infrared spectroscopy (fNIRS).

In fNIRS data, significant group x session interactions were found in the left (p = 0.035) and right (p = 0.036) dorsolateral prefrontal cortex (DLPFC). In behavioral data, despite the numerical increase in the GCG-GTE group and the numerical decrease in the Placebo group, no significant differences were observed in the cognitive performance measure between the groups.

The result suggests a single dose of orally administered GCG-GTE can reduce DLPFC activation in healthy humans even with increased task demand. GCG-GTE is a promising functional material that can affect neural efficiency to lower mental workload during cognitively demanding tasks. However, further studies are needed to verify this.

We describe a pericapillary organ in the rat forebrain and cerebellar cortex. It consists of a series of tripartite synapses with synaptic extensions enveloped by astrocytic endfeet that are linked to the capillary wall by synaptic extensions. Reciprocal specializations of the pericyte-capillary blood vessel (CBV) with such specialized synapses suggest a mechanoreceptor role. In Golgi-impregnated and 3D reconstructions of the cerebral cortex and thalamus, a series of TSs appear to be sequentially ordered in a common dendrite, paralleled by synaptic outgrowths termed golf club synaptic extensions (GCE) opposed to a longitudinal crest (LC) from the capillary basal lamina (BL). Our results show that, in the cerebellar cortex, afferent fibers and interneurons display microanatomical structures that strongly suggest an interaction with the capillary wall. Afferent mossy fiber (MF) rosettes and ascending granule cell axons and their dendrites define the pericapillary passage interactions that are entangled by endfeet. The presence of mRNA of the mechanosensitive channel Piezo1 in the MF rosettes, together with the surrounding end-feet and the capillary wall form mechanosensory units. The ubiquity of such units to modulate synaptic transmission is also supported by Piezo1 mRNA expressing pyramidal isocortical and thalamic neurons. This scenario suggests that ascending impulses to the cerebellar and cortical targets are presynaptically modulated by the reciprocal interaction with the mechanosensory pericapillary organ that ultimately modulates the vasomotor response.