Energetics and activation of the central nervous system by in vivo nuclear magnetic resonance

Stefano Pascarella, Mario Compiani, Staderin

Task-Related modulations of BOLD low-frequency fluctuations within the default mode Network

Spontaneous low-frequency Blood-Oxygenation Level-Dependent (BOLD) signals acquired during resting state are characterized by spatial patterns of synchronous fluctuations, ultimately leading to the identification of robust brain networks. The resting-state brain networks, including the Default Mode Network (DMN), are demonstrated to persist during sustained task execution, but the exact features of task-related changes of network properties are still not well characterized. In this work we sought to examine in a group of 20 healthy volunteers (age 33 ± 6 years, 8 F/12 M) the relationship between changes of spectral and spatiotemporal features of one prominent resting-state network, namely the DMN, during the continuous execution of a working memory n-back task. We found that task execution impacted on both functional connectivity and amplitude of BOLD fluctuations within large parts of the DMN, but these changes correlated between each other only in a small area of the posterior cingulate. We conclude that combined analysis of multiple parameters related to connectivity, and their changes during the transition from resting state to continuous task execution, can contribute to a better understanding of how brain networks rearrange themselves in response to a task

Computational Flux Balance Analysis Predicts that Stimulation of Energy Metabolism in Astrocytes and their Metabolic Interactions with Neurons Depend on Uptake of K(+) Rather than Glutamate

Brain activity involves essential functional and metabolic interactions between neurons and astrocytes. The importance of astrocytic functions to neuronal signaling is supported by many experiments reporting high rates of energy consumption and oxidative metabolism in these glial cells. In the brain, almost all energy is consumed by the Na(+)/K(+) ATPase, which hydrolyzes 1 ATP to move 3 Na(+) outside and 2 K(+) inside the cells. Astrocytes are commonly thought to be primarily involved in transmitter glutamate cycling, a mechanism that however only accounts for few % of brain energy utilization. In order to examine the participation of astrocytic energy metabolism in brain ion homeostasis, here we attempted to devise a simple stoichiometric relation linking glutamatergic neurotransmission to Na(+) and K(+) ionic currents. To this end, we took into account ion pumps and voltage/ligand-gated channels using the stoichiometry derived from available energy budget for neocortical signaling and incorporated this stoichiometric relation into a computational metabolic model of neuron-astrocyte interactions. We aimed at reproducing the experimental observations about rates of metabolic pathways obtained by (13)C-NMR spectroscopy in rodent brain. When simulated data matched experiments as well as biophysical calculations, the stoichiometry for voltage/ligand-gated Na(+) and K(+) fluxes generated by neuronal activity was close to a 1:1 relationship, and specifically 63/58 Na(+)/K(+) ions per glutamate released. We found that astrocytes are stimulated by the extracellular K(+) exiting neurons in excess of the 3/2 Na(+)/K(+) ratio underlying Na(+)/K(+) ATPase-catalyzed reaction. Analysis of correlations between neuronal and astrocytic processes indicated that astrocytic K(+) uptake, but not astrocytic Na(+)-coupled glutamate uptake, is instrumental for the establishment of neuron-astrocytic metabolic partnership. Our results emphasize the importance of K(+) in stimulating the activation of astrocytes, which is relevant to the understanding of brain activity and energy metabolism at the cellular level. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11064-016-2048-0) contains supplementary material, which is available to authorized users

Towards high-resolution quantitative assessment of vascular dysfunction

Neurovascular alterations are increasingly recognized as a key feature of many brain diseases. They can manifest as a reduction in resting cerebral blood flow or cerebrovascular reactivity (CVR) in the whole brain or in specific regions, depending on the underlying condition. Neurovascular impairment is observed in hypertension, Alzheimer’s disease, stroke, multiple sclerosis and cerebral small vessel disease. Magnetic resonance imaging (MRI)-derived CVR mapping is a reliable marker of vascular dysfunction and has been performed mainly at standard functional MRI (fMRI) resolutions of 2–3 mm using the blood oxygen level dependent (BOLD) contrast. However, vascular alterations may occur at a finer scale (i.e., in the capillary bed) which would be better characterized with smaller voxel sizes. Capillaries in gray matter deliver oxygen and glucose to neural tissue and are arranged in a mesh structure, with variable density across the cortical depth. Given that the human cortex is, on average, 2.5 mm thick, submillimetric voxel sizes are effective in increasing the spatial specificity of measurements of hemodynamic and metabolic changes. Novel MRI sequences offer the possibility to map physiological parameters at high resolution with relatively simple experimental setups. In particular, pairing the BOLD acquisition with a contrast sensitive to blood volume changes, while administering a mild hypercapnic challenge, allows for simultaneous mapping of CVR, cerebral metabolic rate of oxygen consumption and other relevant parameters at a high resolution and can be performed at the clinical field strength of 3 T. We propose that this approach will help provide crucial insights into vascular impairment

Simultaneous submicrometric 3D imaging of the micro-vascular network and the neuronal system in a mouse spinal cord

Defaults in vascular (VN) and neuronal networks of spinal cord are responsible for serious neurodegenerative pathologies. Because of inadequate investigation tools, the lacking knowledge of the complete fine structure of VN and neuronal systems is a crucial problem. Conventional 2D imaging yields incomplete spatial coverage leading to possible data misinterpretation, whereas standard 3D computed tomography imaging achieves insufficient resolution and contrast. We show that X-ray high-resolution phase-contrast tomography allows the simultaneous visualization of three-dimensional VN and neuronal systems of mouse spinal cord at scales spanning from millimeters to hundreds of nanometers, with neither contrast agent nor a destructive sample-preparation. We image both the 3D distribution of micro-capillary network and the micrometric nerve fibers, axon-bundles and neuron soma. Our approach is a crucial tool for pre-clinical investigation of neurodegenerative pathologies and spinal-cord-injuries. In particular, it should be an optimal tool to resolve the entangled relationship between VN and neuronal system.Comment: 15 pages, 6 figure

Scale-invariant rearrangement of resting state networks in the human brain under sustained stimulation

Brain activity at rest is characterized by widely distributed and spatially specific patterns of synchronized low-frequency blood-oxygenation level-dependent (BOLD) fluctuations, which correspond to physiologically relevant brain networks. This network behaviour is known to persist also during task execution, yet the details underlying task-associated modulations of within- and between-network connectivity are largely unknown. In this study we exploited a multi-parametric and multi-scale approach to investigate how low-frequency fluctuations adapt to a sustained n-back working memory task. We found that the transition from the resting state to the task state involves a behaviourally relevant and scale-invariant modulation of synchronization patterns within both task-positive and default mode networks. Specifically, decreases of connectivity within networks are accompanied by increases of connectivity between networks. In spite of large and widespread changes of connectivity strength, the overall topology of brain networks is remarkably preserved. We show that these findings are strongly influenced by connectivity at rest, suggesting that the absolute change of connectivity (i.e., disregarding the baseline) may not be the most suitable metric to study dynamic modulations of functional connectivity. Our results indicate that a task can evoke scale-invariant, distributed changes of BOLD fluctuations, further confirming that low frequency BOLD oscillations show a specialized response and are tightly bound to task-evoked activation