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Processing of incoming sensory stimulation triggers an increase of cerebral perfusion and blood oxygenation (neurovascular response) as well as an alteration of the metabolic neurochemical profile (neurometabolic response). Here we show that perceived and unperceived isoluminant chromatic flickering stimuli designed to have similar neurovascular responses as measured by blood oxygenation level dependent functional MRI (BOLD-fMRI) in primary visual cortex (V1) have markedly different neurometabolic responses as measured by functional MRS. In particular, a significant regional buildup of lactate, an index of aerobic glycolysis, and glutamate, an index of malate-aspartate shuttle, occurred in V1 only when the flickering is perceived, without any relation with behavioral or physiological variables. Wheras the BOLD-fMRI signal in V1, a proxy for input to V1, was insensitive to flickering perception by design, the BOLD-fMRI signal in secondary visual areas was larger during perceived than unperceived flickering indicating increased output from V1. These results indicate that the upregulation of energy metabolism induced by visual stimulation depends on the type of information processing taking place in V1, and that 1H-fMRS provides unique information about local input/output balance that is not measured by BOLD-fMRI.Significance statementVisual perception has a measurable metabolic effect in the primary visual cortex (V1). Here we show that the upregulation of energy metabolism induced by isoluminant chromatic flickering depends on subjective visual perception. Within V1, perceived and unperceived stimuli that are contrast-matched to elicit similar blood-oxygenation level-dependent fMRI response are associated with clearly distinct neurochemical profiles. Specifically, regional accumulations of lactate (an index of aerobic glycolysis) and glutamate (an index of malate-aspartate shuttle) only develop during perceived stimuli, together with a larger activation of secondary visual areas. Our results imply a dissociation between metabolic and functional response, and indicate that that the upregulation of energy metabolism induced by visual stimulation depends on the type of information processing taking place in V1.

Spontaneous oscillations of the blood oxygenation level-dependent (BOLD) signal are spatially synchronized within specific brain networks and are thought to reflect synchronized brain activity. Networks are modulated by the performance of a task, even if the exact features and degree of such modulations are still elusive. The presence of networks showing anticorrelated fluctuations lend initially to suppose that a competitive relationship between the default mode network (DMN) and task positive networks (TPNs) supports the efficiency of brain processing. However, more recent results indicate that cooperative and competitive dynamics between networks coexist during task performance. In this study, we used graph analysis to assess the functional relevance of the topological reorganization of brain networks ensuing the execution of a steady state working-memory (WM) task. Our results indicate that the performance of an auditory WM task is associated with a switching between different topological configurations of several regions of specific networks, including frontoparietal, ventral attention, and dorsal attention areas, suggesting segregation of ventral attention regions in the presence of increased overall integration. However, the correct execution of the task requires integration between components belonging to all the involved networks.

Subtle semantic deficits can be observed in Alzheimer's disease (AD) patients even in the early stages of the illness. In this work, we tested the hypothesis that the semantic control network is deregulated in mild AD patients. We assessed the integrity of the semantic control system using resting-state functional magnetic resonance imaging in a cohort of patients with mild AD (n = 38; mean mini-mental state examination = 20.5) and in a group of age-matched healthy controls (n = 19). Voxel-wise analysis spatially constrained in the left fronto-temporal semantic control network identified two regions with altered functional connectivity (FC) in AD patients, specifically in the pars opercularis (POp, BA44) and in the posterior middle temporal gyrus (pMTG, BA21). Using whole-brain seed-based analysis, we demonstrated that these two regions have altered FC even beyond the semantic control network. In particular, the pMTG displayed a wide-distributed pattern of lower connectivity to several brain regions involved in language-semantic processing, along with a possibly compensatory higher connectivity to the Wernicke's area. We conclude that in mild AD brain regions belonging to the semantic control network are abnormally connected not only within the network, but also to other areas known to be critical for language processing.

In the present study, we aimed at determining the metabolic responses of the human visual cortex during the presentation of chromatic and achromatic stimuli, known to preferentially activate two separate clusters of neuronal populations (called “blobs” and “interblobs”) with distinct sensitivity to color or luminance features. Since blobs and interblobs have different cytochrome-oxidase (COX) content and micro-vascularization level (i.e., different capacities for glucose oxidation), different functional metabolic responses during chromatic vs. achromatic stimuli may be expected. The stimuli were optimized to evoke a similar load of neuronal activation as measured by the bold oxygenation level dependent (BOLD) contrast. Metabolic responses were assessed using functional 1H MRS at 7 T in 12 subjects. During both chromatic and achromatic stimuli, we observed the typical increases in glutamate and lactate concentration, and decreases in aspartate and glucose concentration, that are indicative of increased glucose oxidation. However, within the detection sensitivity limits, we did not observe any difference between metabolic responses elicited by chromatic and achromatic stimuli. We conclude that the higher energy demands of activated blobs and interblobs are supported by similar increases in oxidative metabolism despite the different capacities of these neuronal populations.

Phasic changes in eye's pupil diameter have been repeatedly observed during cognitive, emotional and behavioral activity in mammals. Although pupil diameter is known to be associated with noradrenergic firing in the pontine Locus Coeruleus (LC), thus far the causal chain coupling spontaneous pupil dynamics to specific cortical brain networks remains unknown. In the present study, we acquired steady-state blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) data combined with eye-tracking pupillometry from fifteen healthy subjects that were trained to maintain a constant attentional load. Regression analysis revealed widespread visual and sensorimotor BOLD-fMRI deactivations correlated with pupil diameter. Furthermore, we found BOLD-fMRI activations correlated with pupil diameter change rate within a set of brain regions known to be implicated in selective attention, salience, error-detection and decision-making. These regions included LC, thalamus, posterior cingulate cortex (PCC), dorsal anterior cingulate and paracingulate cortex (dACC/PaCC), orbitofrontal cortex (OFC), and right anterior insular cortex (rAIC). Granger-causality analysis performed on these regions yielded a complex pattern of interdependence, wherein LC and pupil dynamics were far apart in the network and separated by several cortical stages. Functional connectivity (FC) analysis revealed the ubiquitous presence of the superior frontal gyrus (SFG) in the networks identified by the brain regions correlated to the pupil diameter change rate. No significant correlations were observed between pupil dynamics, regional activation and behavioral performance. Based on the involved brain regions, we speculate that pupil dynamics reflects brain processing implicated in changes between self- and environment-directed awareness.

Idiopathic rapid eye movement sleep behavior disorder (iRBD) is a condition that often evolves into Parkinson's disease (PD). Therefore, by monitoring iRBD it is possible to track the neurodegeneration of individuals who may progress to PD. Here we aimed at piloting the characterization of brain tissue properties in mid-brain subcortical regions of 10 healthy subjects, 8 iRBD, and 9 early-diagnosed PD. We used a battery of magnetic resonance imaging (MRI) contrasts at 3 T, including adiabatic and non-adiabatic rotating frame techniques developed by our group, along with diffusion tensor imaging (DTI) and resting-state fMRI. Adiabatic T1ρ and T2ρ, and non-adiabatic RAFF4 (Relaxation Along a Fictitious Field in the rotating frame of rank 4) were found to have lower coefficient of variations and higher sensitivity to detect group differences as compared to DTI parameters such as fractional anisotropy and mean diffusivity. Significantly longer T1ρ were observed in the amygdala of PD subjects vs. controls, along with a trend of lower functional connectivity as measured by regional homogeneity, thereby supporting the notion that amygdalar dysfunction occurs in PD. Significant abnormalities in reward networks occurred in iRBD subjects, who manifested lower network strength of the accumbens. In agreement with previous studies, significantly longer T1ρ occurred in the substantia nigra compacta of PD vs. controls, indicative of neuronal degeneration, while regional homogeneity was lower in the substantia nigra reticulata. Finally, other trend-level findings were observed, i.e., lower RAFF4 and T2ρ in the midbrain of iRBD subjects vs. controls, possibly indicating changes in non-motor features as opposed to motor function in the iRBD group. We conclude that rotating frame relaxation methods along with functional connectivity measures are valuable to characterize iRBD and PD subjects, and with proper validation in larger cohorts may provide pathological signatures of iRBD and PD.

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 be not 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. The human brain is organized in functional networks, characterized by long range functional connections between brain areas. This network behavior is modulated by the execution of tasks. In our work, we show that modulations associated to a task are massive and widespread, but changes are scale invariant and the overall topology of the networks is well preserved under stimulation, confirming that the functional networks are intrinsic features of the human brain function. We found also that the amplitude of the massive change we observed is heavily influenced by the degree of connectivity at rest, indicating that the magnitude of connectivity change is not an independent metric for the assessment of functional network dynamics.

Idiopathic rapid eye movement sleep behavior disorder (iRBD) is a condition that often evolves into Parkinson’s disease (PD). Therefore, by monitoring iRBD it is possible to track the neurodegeneration of individuals who may progress to PD. Here we aimed at piloting the characterization of brain tissue properties in mid-brain subcortical regions of 10 healthy subjects, 8 iRBD, and 9 early-diagnosed PD. We used a battery of magnetic resonance imaging (MRI) contrasts at 3 T, including adiabatic and non-adiabatic rotating frame techniques developed by our group, along with diffusion tensor imaging and resting-state fMRI. Adiabatic T1 and T2, and non-adiabatic RAFF4 (Relaxation Along a Fictitious Field in the rotating frame of rank 4) were found to have lower coefficient of variations and higher sensitivity to detect group differences as compared to DTI parameters such as fractional anisotropy and mean diffusivity. Significantly longer T1 were observed in the amygdala of PD subjects versus controls, along with a trend of lower functional connectivity as measured by network regional homogeneity, thereby supporting the notion that amygdalar dysfunction occurs in PD. Significant abnormalities in reward networks occurred in iRBD subjects, who manifested lower network strength of the accumbens. In agreement with previous studies, significantly longer T1 occurred in the substantia nigra compacta of PD versus controls, indicative of neuronal degeneration, while regional homogeneity was lower in the network of the substantia nigra reticulata. Finally, other trend-level findings were observed, i.e., lower RAFF4 and T2 in the midbrain of iRBD subjects vs controls, possibly indicating changes in non-motor features as opposed to motor function in the iRBD group. We conclude that rotating frame relaxation methods along with functional connectivity measures are valuable to characterize iRBD and PD subjects, and with proper validation in larger cohorts may provide pathological signatures of iRBD and PD.

Time-domain analysis of blood-oxygenation level-dependent (BOLD) signals allows the identification of clusters of voxels responding to photic stimulation in primary visual cortex (V1). However, the characterization of information encoding into temporal properties of the BOLD signals of an activated cluster is poorly investigated. Here, we used Shannon entropy to determine spatial and temporal information encoding in the BOLD signal within the most strongly activated area of the human visual cortex during a hemifield photic stimulation. We determined the distribution profile of BOLD signals during epochs at rest and under stimulation within small (19-121 voxels) clusters designed to include only voxels driven by the stimulus as highly and uniformly as possible. We found consistent and significant increases (2-4% on average) in temporal information entropy during activation in contralateral but not ipsilateral V1, which was mirrored by an expected loss of spatial information entropy. These opposite changes coexisted with increases in both spatial and temporal mutual information (i.e., dependence) in contralateral V1. Thus, we showed that the first cortical stage of visual processing is characterized by a specific spatiotemporal rearrangement of intracluster BOLD responses. Our results indicate that while in the space domain BOLD maps may be incapable of capturing the functional specialization of small neuronal populations due to relatively low spatial resolution, some information encoding may still be revealed in the temporal domain by an increase of temporal information entropy.

The investigation of the neuronal network in mouse spinal cord models represents the basis for the research on neurodegenerative diseases. In this framework, the quantitative analysis of the single elements in different districts is a crucial task. However, conventional 3D imaging techniques do not have enough spatial resolution and contrast to allow for a quantitative investigation of the neuronal network. Exploiting the high coherence and the high flux of synchrotron sources, X-ray Phase-Contrast multiscale-Tomography allows for the 3D investigation of the neuronal microanatomy without any aggressive sample preparation or sectioning. We investigated healthy-mouse neuronal architecture by imaging the 3D distribution of the neuronal-network with a spatial resolution of 640 nm. The high quality of the obtained images enables a quantitative study of the neuronal structure on a subject-by-subject basis. We developed and applied a spatial statistical analysis on the motor neurons to obtain quantitative information on their 3D arrangement in the healthy-mice spinal cord. Then, we compared the obtained results with a mouse model of multiple sclerosis. Our approach paves the way to the creation of a “database” for the characterization of the neuronal network main features for a comparative investigation of neurodegenerative diseases and therapies.

Epilepsy is a heterogeneous family of neurological disorders that manifest as seizures, i.e. the hypersynchronous activity of large population of neurons. About 30% of epileptic patients do not respond to currently available antiepileptic drugs. Decades of intense research have elucidated the involvement of a number of possible signaling pathways, however, at present we do not have a fundamental understanding of epileptogenesis. In this paper, we review the literature on epilepsy under a wide-angle perspective, a mandatory choice that responds to the recurrent and unanswered question about what is epiphenomenal and what is causal to the disease. While focusing on the involvement of K+ and glutamate/GABA in determining neuronal hyperexcitability, emphasis is given to astrocytic contribution to epileptogenesis, and especially to loss-of-function of astrocytic glutamine synthetase following reactive astrogliosis, a hallmark of epileptic syndromes. We finally introduce the potential involvement of abnormal glycogen synthesis induced by excess glutamate in increasing susceptibility to seizures.

Epilepsy is a family of brain disorders with a largely unknown etiology and high percentage of pharmacoresistance. The clinical manifestations of epilepsy are seizures, which originate from aberrant neuronal synchronization and hyperexcitability. Reactive astrocytosis, a hallmark of the epileptic tissue, develops into loss-of-function of glutamine synthetase, impairment of glutamate-glutamine cycle and increase in extracellular and astrocytic glutamate concentration. Here, we argue that chronically elevated intracellular glutamate level in astrocytes is instrumental to alterations in the metabolism of glycogen and leads to the synthesis of polyglucosans. Unaccessibility of glycogen-degrading enzymes to these insoluble molecules compromises the glycogenolysis-dependent reuptake of extracellular K(+) by astrocytes, thereby leading to increased extracellular K(+) and associated membrane depolarization. Based on current knowledge, we propose that the deterioration in structural homogeneity of glycogen particles is relevant to disruption of brain K(+) homeostasis and increased susceptibility to seizures in epilepsy.

Functional magnetic resonance imaging (fMRI) techniques are widely exploited for the study of brain activation. In recent years, similar approaches have been attempted for the study of spinal cord function; however, obtaining good functional images of spinal cord still represents a technical and scientific challenge. Some of the main limiting factors can be classified under the broad category of "physiological noise," and are related to 1) the cerebrospinal fluid (CSF) flux in the subarachnoid space surrounding the spinal cord; 2) the cord motion itself; and 3) the small area of the cord, which makes it critical to have a high image resolution. In addition, the different magnetic susceptibility properties of tissues surrounding the spinal cord reduce the local homogeneity of the static magnetic field, causing image distortion, reduction of the effective resolution, and signal loss, all effects that are modulated by motion. For these reasons, a number of methods have been developed for the purpose of denoising spinal cord fMRI time series. In this work, after a short introduction on the relevant features of the spinal cord anatomy, we review the main sources of physiological noise in spinal cord fMRI and discuss the main approaches useful for its mitigation.

The available estimate of the energy expended for signaling in rat neocortex is refined to examine the separate contribution of spiking and synaptic activity as a function of average neuronal firing rate. By taking into account a phenomenological model of short-term synaptic plasticity, we show that the transition from low to high cortical activity is accompanied by a substantial increase in relative energy consumed by action potentials vs. synaptic potentials. This consideration might be important for a deeper understanding of how information is represented in the cortex and which metabolic pathways are upregulated to sustain cortical activity.

For many years, a tenet of cerebral metabolism held that glucose was the obligate energy substrate of the mammalian brain and that neuronal oxidative metabolism represented the majority of this glucose utilization. In 1994, Pellerin and Magistretti formulated the astrocyte-neuron lactate shuttle (ANLS) hypothesis, in which astrocytes, not neurons, metabolized glucose, with subsequent transport of the glycolytically derived lactate to fuel the energy needs of the neuron during neurotransmission. By considering the concentrations and kinetic characteristics of the nutrient transporter proteins, Simpson et al later supported the opposite view, in which lactate flows from neurons to astrocytes, thus leading to the neuron-astrocyte lactate shuttle (NALS). Most recently, a commentary was published in this journal attempting to discredit the NALS. This challenge has stimulated the present response in which we detail the inaccuracies of the commentary and further model several different possibilities. Although our simulations continue to support the predominance of neuronal glucose utilization during activation and neuronal to astrocytic lactate flow, the most important result is that, regardless of the direction of the flow, the overall contribution of lactate to cerebral glucose metabolism is found to be so small as to make this ongoing debate ‘much ado about nothing'.

Functional Magnetic Resonance Imaging (fMRI) based on Blood Oxygenation Level Dependent (BOLD) contrast has become one of the most powerful tools in neuroscience research. On the other hand, fMRI approaches have seen limited use in the study of spinal cord and subcortical brain regions (such as the brainstem and portions of the diencephalon). Indeed obtaining good BOLD signal in these areas still represents a technical and scientific challenge, due to poor control of physiological noise and to a limited overall quality of the functional series. A solution can be found in the combination of optimized experimental procedures at acquisition stage, and well-adapted artifact mitigation procedures in the data processing. In this framework, we studied two different data processing strategies to reduce physiological noise in cortical and subcortical brain regions and in the spinal cord, based on the aCompCor and RETROICOR denoising tools respectively. The study, performed in healthy subjects, was carried out using an ad hoc isometric motor task. We observed an increased signal to noise ratio in the denoised functional time series in the spinal cord and in the subcortical brain region.

Faults 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 system represents 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 ex-vivo mouse spinal cord at scales spanning from millimeters to hundreds of nanometers, with nor contrast agent nor sectioning and neither 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 very suitable for pre-clinical investigation of neurodegenerative pathologies and spinal-cord-injuries, in particular to resolve the entangled relationship between VN and neuronal system.

Brainstem nuclei are the principal sites of monoamine (MA) innervation to major forebrain structures. In the cortical grey matter, increased secretion of MA neuromodulators occurs in response to a wealth of environmental and homeostatic challenges, whose onset is associated with rapid, preparatory changes in neural activity as well as with increases in energy metabolism. Blood-borne glucose is the main substrate for energy production in the brain. Once entered the tissue, interstitial glucose is equally accessible to neurons and astrocytes, the two cell types accounting for most of cellular volume and energy metabolism in neocortex and hippocampus. Astrocytes also store substantial amounts of glycogen, but non-stimulated glycogen turnover is very small. The rate of cellular glucose utilization in the brain is largely determined by hexokinase, which under basal conditions is more than 90 % inhibited by its product glucose-6-phosphate (Glc-6-P). During rapid increases in energy demand, glycogen is a primary candidate in modulating the intracellular level of Glc-6-P, which can occur only in astrocytes. Glycogenolysis can produce Glc-6-P at a rate higher than uptake and phosphorylation of glucose. MA neurotransmitter are released extrasinaptically by brainstem neurons projecting to neocortex and hippocampus, thus activating MA receptors located on both neuronal and astrocytic plasma membrane. Importantly, MAs are glycogenolytic agents and thus they are exquisitely suitable for regulation of astrocytic Glc-6-P concentration, upstream substrate flow through hexokinase and hence cellular glucose uptake. Conforming to such mechanism, Gerald A. Dienel and Nancy F. Cruz recently suggested that activation of noradrenergic locus coeruleus might reversibly block astrocytic glucose uptake by stimulating glycogenolysis in these cells, thereby anticipating the rise in glucose need by active neurons. In this paper, we further develop the idea that the whole monoaminergic system modulates both function and metabolism of forebrain regions in a manner mediated by glycogen mobilization in astrocytes.

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 figures

Several laboratories have consistently reported small concentration changes in lactate, glutamate, aspartate, and glucose in the human cortex during prolonged stimuli. However, whether such changes correlate with blood oxygenation level-dependent functional magnetic resonance imaging (BOLD-fMRI) signals have not been determined. The present study aimed at characterizing the relationship between metabolite concentrations and BOLD-fMRI signals during a block-designed paradigm of visual stimulation. Functional magnetic resonance spectroscopy (fMRS) and fMRI data were acquired from 12 volunteers. A short echo-time semi-LASER localization sequence optimized for 7 Tesla was used to achieve full signal-intensity MRS data. The group analysis confirmed that during stimulation lactate and glutamate increased by 0.26±0.06 μmol/g (~30%) and 0.28±0.03 μmol/g (~3%), respectively, while aspartate and glucose decreased by 0.20±0.04 μmol/g (~5%) and 0.19±0.03 μmol/g (~16%), respectively. The single-subject analysis revealed that BOLD-fMRI signals were positively correlated with glutamate and lactate concentration changes. The results show a linear relationship between metabolic and BOLD responses in the presence of strong excitatory sensory inputs, and support the notion that increased functional energy demands are sustained by oxidative metabolism. In addition, BOLD signals were inversely correlated with baseline ã-aminobutyric acid concentration. Finally, we discussed the critical importance of taking into account linewidth effects on metabolite quantification in fMRS paradigms.Journal of Cerebral Blood Flow and Metabolism advance online publication, 7 January 2015; doi:10.1038/jcbfm.2014.233.

Noninvasive functional studies on human spinal cord by means of magnetic resonance imaging (MRI) are gaining attention because of the promising applications in the study of healthy and injured central nervous system. The findings obtained are generally consistent with the anatomic knowledge based on invasive methods, but the origin and specificity of functional contrast is still debated. In this paper, a review of current knowledge and major issues about functional MRI (fMRI) in the human spinal cord is presented, with emphasis on the main methodological and technical problems and on forthcoming applications as clinical tool.

In the present work, an arteriovenous malformation was taken as a pathological model for studying task-related flow decreases during a motor task. Combined Blood Oxygen Level Dependent (BOLD)-perfusion experiments were applied in order to evaluate the relative sensitivity of these techniques to task-related reductions in cerebral blood flow (CBF). Results shows that, by matching the sensitivity of the methods (which exhibit a different contrast-to-noise ratio) in the primary motor cortex, the spatial extent of the regions of decreased perfusion signal is larger than those of the BOLD signal reduction. The above finding suggests that perfusion imaging, that already represents a gold standard method in the detection of vascular phenomena, may estimate task-related flow decreases in a functional time-series better than BOLD.

The results of the study of Xu and colleagues in this issue constitute a critical new piece of information on the functional specialization of astrocytes for K(+) homeostasis in the brain. The relationship between astrocytes and potassium has been long recognized in half a century of research. Now this relation appears to have found its metabolic correlate in astrocytic glycogen. Xu et al. showed that glycogen is committed to fuel astrocytic K(+) uptake, as this process is abolished when glycogenolysis is inhibited even in the presence of glucose. They went further by showing that the cellular mechanisms which selectively mobilize glycogen involve the participation of several intracellular signaling cascades. As with all good science, these findings generate a number of fundamental questions that are open for experimental research.

Several brain regions exhibit a sustained negative BOLD response (NBR) during specific tasks, as assessed with functional magnetic resonance imaging. The origin of the NBR and the relationships between the vascular/metabolic dynamics and the underlying neural activity are highly debated. Converging evidence indicates that NBR, in human and non-human primates, can be interpreted in terms of decrease in neuronal activity under its basal level, rather than a purely vascular phenomenon. However, the scarcity of direct experimental evidence suggests caution and encourages the ongoing utilization of multimodal approaches in the investigation of this effect.

Energy homeostasis in the brain is maintained by oxidative metabolism of glucose, primarily to fulfil the energy demand associated with ionic movements in neurons and astrocytes. In this contribution we review the experimental evidence that grounds a specific role of glycogen metabolism in supporting the functional energetic needs of astrocytes during the removal of extracellular potassium. Based on theoretical considerations, we further discuss the hypothesis that the mobilization of glycogen in astrocytes serves the purpose to enhance the availability of glucose for neuronal glycolytic and oxidative metabolism at the onset of stimulation. Finally, we provide an evolutionary perspective for explaining the selection of glycogen as carbohydrate reserve in the energy-sensing machinery of cell metabolism.

Glutamate is one of the most versatile molecules present in the human brain, involved in protein synthesis, energy production, ammonia detoxification, and transport of reducing equivalents. Aside from these critical metabolic roles, glutamate plays a major part in brain function, being not only the most abundant excitatory neurotransmitter, but also the precursor for γ-aminobutyric acid (GABA), the predominant inhibitory neurotransmitter. Regulation of glutamate levels is pivotal for normal brain function, as abnormal extracellular concentration of glutamate can lead to impaired neurotransmission, neurodegeneration and even neuronal death. Understanding how the neuron-astrocyte functional and metabolic interactions modulate glutamate concentration during different activation status and under physiological and pathological conditions is a challenging task, and can only be tentatively estimated from current literature. In this paper, we focus on describing the various metabolic pathways which potentially affect glutamate concentration in the brain, and emphasize which ones are likely to produce the variations in glutamate concentration observed during enhanced neuronal activity in human studies.

A consistent and prominent feature of brain functional magnetic resonance imaging (fMRI) data is the presence of low-frequency (2+ signaling. Specifically, neurotransmission induces pulses of Ca2+ concentration in astrocytes, resulting in increased cerebral perfusion and neuroactive transmitter release by these cells (i.e., gliotransmission), which in turn stimulates neuronal activity. Noticeably, the level of neuron-astrocyte cross talk regulates the periodic behavior of the Ca2+ wave-induced BOLD fluctuations. Our results suggest that the spontaneous ongoing activity of neuroglial networks is a potential source of the observed slow fMRI signal oscillations.

In this study, we assess white matter microstructural deficit correlates of apathy level in 20 patients with amnestic mild cognitive impairment by means of diffusion tensor imaging. Mean diffusivity correlated positively with apathy level in the right temporal portion of the uncinate, middle longitudinal and inferior longitudinal fasciculi and in the parathalamic white matter, the fornix and the posterior cingulum of the right hemisphere. Fractional anisotropy results confirmed evidence of disconnection associated with apathy in all white matter areas except the middle longitudinal fasciculus. These results support the view that alterations in the neural mechanisms underlying apathy level occur in the early phase of degenerative dementias.

The correlation and the interactions between neuronal activity and underlying metabolic dynamics are still a matter of debate, especially in pathological conditions. This study reports findings obtained on a subject suffering from fixation-off sensitivity (FOS) epilepsy, exploited as a model system of triggerable anomalous electrical activity. Functional Magnetic Resonance Spectroscopy was used to investigate the metabolic response to visual spike-inducing stimuli in a single voxel placed in the temporo-occipital lobe of a FOS epilepsy patient. MRS measurements were additionally performed on a control group of five healthy volunteers. The FOS patient also underwent an EEG session with the same stimulus paradigm. Uniquely in the FOS patient, glutamate and glutamine concentration increased during the first 10 min of stimulation and then returned to baseline. On the other hand, FOS-induced epileptic activity (spiking) endured throughout all the stimulation epoch. The observed metabolic dynamics may be likely linked to a complex interplay between alterations of the metabolic pathways of glutamate and modulation of the neuronal activity.

Objective To assess the contribution of regional grey matter (GM) atrophy and functional disconnection in determining the level of cognitive decline in patients with Alzheimer9s disease (AD) at different clinical stages. Methods Ten patients with amnesic mild cognitive impairment (a-MCI), 11 patients with probable AD and 10 healthy controls were recruited. T1 volumes were obtained from each subject and postprocessed according to an optimised voxel based morphometry protocol. Resting state functional MRI data were also collected from the same individuals and analysed to produce connectivity maps after identification of the default mode network (DMN) by independent component analysis. Results Compared with healthy controls, both AD and a-MCI patients showed a similar regional pattern of brain disconnection between the posterior cingulate cortex (PCC) and the medial prefrontal cortex and the rest of the brain. Conversely, the distribution of GM atrophy was significantly more restricted in a-MCI than in AD patients. Interestingly, the PCC showed reduced connectivity in a-MCI patients in the absence of GM atrophy, which was, in contrast, detectable at the stage of fully developed AD. Conclusions This study indicates that disconnection precedes GM atrophy in the PCC, which is a critical area of the DMN, and supports the hypothesis that GM atrophy in specific regions of AD brains likely reflects a long term effect of brain disconnection. In this context, our study indicates that GM atrophy in PCC accompanies the conversion from MCI to AD.

In this article, we examined theoretically the role of human cerebral glycogen in buffering the metabolic requirement of a 360-second brain stimulation, expanding our previous modeling study of neurometabolic coupling. We found that glycogen synthesis and degradation affects the relative amount of glucose taken up by neurons versus astrocytes. Under conditions of 175:115 mmol/L (∼1.5:1) neuronal versus astrocytic activation-induced Na+ influx ratio, ∼12% of astrocytic glycogen is mobilized. This results in the rapid increase of intracellular glucose-6-phosphate level on stimulation and nearly 40% mean decrease of glucose flow through hexokinase (HK) in astrocytes via product inhibition. The suppression of astrocytic glucose phosphorylation, in turn, favors the channeling of glucose from interstitium to nearby activated neurons, without a critical effect on the concurrent intercellular lactate trafficking. Under conditions of increased neuronal versus astrocytic activation-induced Na+ influx ratio to 190:65 mmol/L (∼3:1), glycogen is not significantly degraded and blood glucose is primarily taken up by neurons. These results support a role for astrocytic glycogen in preserving extracellular glucose for neuronal utilization, rather than providing lactate to neurons as is commonly accepted by the current ‘thinking paradigm’. This might be critical in subcellular domains during functional conditions associated with fast energetic demands.

Parkinson's disease is a neurological disorder associated with the disfunction of dopaminergic pathways of the basal ganglia, mainly resulting in a progressive alteration in the execution of voluntary movements. We present a functional magnetic resonance imaging (fMRI) study on cortical activations during simple motor task performance, in six early–stage hemiparkinsonian patients and seven healthy volunteers. We acquired data in three sessions, during which subjects performed the task with right or left hand, or bimanually. We observed consistent bilateral activations in cingulate cortex and dorsolateral prefrontal cortex of Parkinsonian subjects during the execution of the task with the affected hand. In addition, patients showed both larger and stronger activations in motor cortex of the affected hemisphere with respect to the healthy hemisphere. Compared with the control group, patients showed a hyperactivation of the dorsolateral prefrontal cortex of the affected hemisphere. We concluded that a presymptomatic reorganization of the motor system is likely to occur in Parkinson's disease at earlier stages than previously hypothesized. Moreover, our results support fMRI as a sensitive technique for revealing the initial involvement of motor cortex areas at the debut of this degenerative disorder.

Unraveling the energy metabolism and the hemodynamic outcomes of excitatory and inhibitory neuronal activity is critical not only for our basic understanding of overall brain function, but also for the understanding of many brain disorders. Methodologies of magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) are powerful tools for the noninvasive investigation of brain metabolism and physiology. However, the temporal and spatial resolution of in vivo MRS and MRI is not suitable to provide direct evidence for hypotheses that involve metabolic compartmentalization between different cell types, or to untangle the complex neuronal microcircuitry, which results in changes of electrical activity. This review aims at describing how the current models of brain metabolism, mainly built on the basis of in vitro evidence, relate to experimental findings recently obtained in vivo by 1H MRS, 13C MRS, and MRI. The hypotheses related to the role of different metabolic substrates, the metabolic neuron—glia interactions, along with the available theoretical predictions of the energy budget of neurotransmission will be discussed. In addition, the cellular and network mechanisms that characterize different types of increased and suppressed neuronal activity will be considered within the sensitivity-constraints of MRS and MRI.

Functional magnetic resonance imaging (fMRI) has emerged during the last decade as the main non-invasive technique for the investigation of human brain function. More recently, fMRI was also proposed for functional studies of the human spinal cord, but with controversial results. In fact, the functional contrast is not well-characterized, and even its origin has been challenged. In the present work, we characterized the temporal features of the functional signal evoked in the human spinal cord by a motor task, studied with an approach based on time-locked averaging of functional time series of different durations. Based on the results here reported, we defined an impulse-response function (irf) able to explain the functional response for motor tasks in the interval of 15-42 s of duration, thus suggesting the linearity of the phenomenon in this interval. Conversely, with stimulation durations ranging between 3 and 9 s, the functional signal was not detectable, and was under the level predicted by a linear behavior, suggesting deviation from linearity during short stimulations. The impulse-response function appeared slower than in the brain, peaking at about 9 s after its beginning. The observed contrast was generally larger than in the brain, on the order of about 5.4% of baseline signal at 1.5 T. The findings further suggested that the physiological origin of T(2) weighted functional imaging is similar in the spinal cord and in the brain.

Low frequency fluctuations (LFFs) of the BOLD signal are a major discovery in the study of the resting brain with functional magnetic resonance imaging (fMRI). Two fMRI-based measures, functional connectivity (FC), a measure of signal synchronicity, and the amplitude of LFFs (ALFF), a measure of signal periodicity, have been proved to be sensitive to changes induced by several neurological diseases, including degenerative dementia. In spite of the increasing use of these measures, whether and how they are related to each other remains to be elucidated. In this work we used voxel-wise FC and ALFF computed in different frequency bands (slow-5: 0.01-0.027 Hz; slow-4: 0.027-0.073 Hz; and full-band: 0.01-0.073 Hz), in order to assess their relationship in healthy elderly as well as the relevant changes induced by Alzheimer's Disease (AD) and Mild Cognitive Impairment (MCI). We found that in healthy elderly subjects FC and ALFF are positively correlated in anterior and posterior cingulate cortex (full-band, slow-4 and slow-5), temporal cortex (full-band and slow-5), and in a set of subcortical regions (full-band and slow-4). These correlation patterns between FC and ALFF were absent in either AD or MCI patients. Notably, the loss of correlation between FC and ALFF in the AD group was primarily due to changes in FC rather than in ALFF. Our results indicate that degenerative dementia is characterized by a loss of global connection rather than by a decrease of fluctuation amplitude.

The metabolic events underlying neuronal activity still remain the object of intense debate, in spite of the considerable amount of information provided from different experimental techniques. Indeed, several attempts at linking the cellular metabolic phenomena with the macroscopic physiological changes have not yet attained foolproof conclusions. The difficulties in drawing definitive conclusions are due primarily to the heterogeneity of the experimental procedures used in different laboratories, and also given the impossibility of extrapolating the findings obtained under stationary conditions (prolonged stimulation) to dynamic and transient phenomena. Recently, lactate has received much attention, following its proposal by Pellerin and Magistretti (1994; Proc. Natl. Acad. Sci. USA 91:10625-10629), instead of glucose, as the main substrate for neurons during activity. Several challenging aspects suggest the return to a more conventional view of neuronal metabolism, in which neurons are able to metabolize ambient glucose directly as their major substrate, also during activation.

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, 8F/12M) the relationship between changes of spectral and spatiotemporal features of one prominent resting-state network, namely the DMN, during the steady-state execution of a sustained working memory n-back task. We found that the steady state execution of such a task 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 steady-state task execution, can contribute to a better understanding of how brain networks rearrange themselves in response of a task.