Brain, Vol. 125, No. 10, 2365-2367,
October 2002
© 2002 Oxford University Press
Book Review |
NEUROENERGETICS: RELEVANCE IN FUNCTIONAL BRAIN IMAGING
University Department of Clinical Neurology, The Radcliffe Infirmary, Oxford, UK
NEUROENERGETICS: RELEVANCE IN FUNCTIONAL BRAIN IMAGING
By R. S. J. Frackowiak, P. J. Magistretti, R. G. Shulman, J. S. Altman and M. Adams
2002. Strasbourg: Human Frontier Science Program Organization
ISBN 9291640107.
Perhaps the major goal for cognitive neuroscience is to define the ways in which the activity of aggregates of neurones create phenomena of mind. Brain functional imaging is proving to be one of the most versatile tools for working towards this goal. Two of the most powerful approaches have been positron emission tomography (PET) and, more recently, functional magnetic resonance imaging (fMRI). However, both provide only indirect measures of neuronal activity. Instead, they measure local changes in brain metabolism and physiology that are associated with neuronal activity. As interest has developed in applying these methods quantitatively, it has become critically important to understand the nature of the signals being measured and thus, the specific mechanisms coupling metabolic and physiological changes to changes in neuronal activity.
This slim volume leads the reader at an almost breathless pace from classical studies through to the most recent work concerning activity-coupled brain energy metabolism. As a report of a workshop held between a small group of research leaders in different areas with expertise converging on common problems, it manages to be more current than recent textbooks. It is also comprehensive, despite its brevity. It gives the reader a very clear sense of the way in which our understanding is changing and identifies areas of continued uncertainty. The editors and co-editors have done an excellent job in establishing a coherent style and in maintaining a consistent set of themes through the book.
It may be surprising to readers unfamiliar with the area, but fundamental issues of brain energy metabolism still are being reformulated. It has long been recognized that the brain, only representing 2% of the body weight, consumes an inordinately high 20% of the body’s energy. Yet the way in which this energy is used has been (curiously) uncertain. Classical studies by Creuzfeldt based on thermal measurements of the peripheral nerve lead to the widely accepted (but somewhat counter-intuitive) conclusion that the direct consequences of neuronal depolarization account for only a small proportion of energy consumption in the brain. If true, this conclusion certainly should raise questions about the interpretation of localization of neuronal activity (at least as related to electrophysiological studies) based on physiological or biochemical changes.
Frackowiak and Maguire open the book with a short and selective review of evidence that metabolic mapping can well localize neuronal activity, providing illustrative examples in which PET and fMRI studies show a close correspondence with evidence from both human psychophysical and animal studies. This theme is taken further in a report of very high magnetic field studies by Kamil Ugurbil and Seigi Ogawa who focus specifically on the blood oxygenation level-dependent (BOLD) fMRI signal. The very high field strengths allow both increased sensitivity and spatial localization and Ugurbil and Ogawa demonstrate that localization of activation-related BOLD signal changes is not only entirely consistent with electrophysiological measurements, but also that the time course of changes is just as predicted by direct observation of local haemoglobin oxygenation changes by optical imaging studies.
The brain is a highly oxidative organ. Neurones have a high oxidative capacity and the brain has only a limited capacity for anaerobic metabolism. However, PET studies from Marcus Raichle’s laboratory in St Louis in the mid-1980s provided a challenge to this notion that has yet to be fully resolved. In careful experiments measuring the local changes in cerebral blood flow, cerebral oxygen and glucose consumption, Raichle and his colleagues noted a curious discrepancy. While blood flow increases are large in regions local to neuronal activation and are associated with proportional increases in glucose consumption, increases in oxygen consumption are much more limited, suggesting a local ‘uncoupling’ of oxygen and glucose utilization. This observation suggests that the brain metabolises glucose anaerobically (at least to an extent) during the activation response.
Different contributors to the book approach this central problem in distinct ways. Pierre Magistretti and Luc Pellerin have set out a very specific hypothesis regarding the nature of the uncoupling which has driven the field forward substantially by providing clearly testable ideas. Starting from the observation that astrocytes have relatively high concentrations of glycolytic enzymes and glycogen, while mitochondria are more abundant in neurones, Magistretti and his colleagues argue that there may be a specialized form of metabolic coupling between the two different cell types. Astrocyte processes are found in close relationship to the synapse. According to the Magistrettti–Pellerin hypothesis, glucose uptake in the relatively glycolytic astrocytes may be preferentially used for lactate production, which, when released, can then be utilized by nearby neurones to fuel oxidative metabolism. Given that glutamate transport into astrocytes is linked to increased glucose utilization and lactate production, the glutamate release from excitatory synapses could directly coordinate this local metabolic cycle by linking to glucose utilization in astrocytes.
The elegant animal studies of Doug Rothman, Bob Shulman and their colleagues at Yale is presented to complement this work in vitro. The Yale group has pioneered applications of magnetic resonance spectroscopy to functional imaging and demonstrated the predicted coupling between glutamate–glutamine cycling and glucose utilization. With a two-compartment model such as that used by these workers, transient uncoupling of glucose and oxygen utilization can be modelled directly.
However, Gjedde provides a challenging argument that such a specific, tight neural–glial metabolic substrate coupling at the synapse is not necessary to explain the observations. While accepting that both neuronal depolarization and astrocytic glutamate re-uptake contribute to post-synaptic energy utilisation, Gjedde’s interpretation proposes that both neurones and astrocytes metabolise glucose, although the extent to which this occurs may vary between different brain regions and over time. In a useful series of calculations, he thus suggests the need to consider the dynamics of local energy processes, as much as their steady state changes. This idea is made more compelling by elegant empirical data from the Oxford laboratory of Fillenz. In studies of the stimulated striate cortex using local measures of oxygen, glucose and lactate, she demonstrates that the local metabolic changes are indeed time-dependent and, more intriguingly, that glucose concentrations around active synapses actually increase immediately following periods of stimulation. Clearly, this does not conform to a simple diffusion limited model of glucose transport and suggests a more active process is occurring, perhaps with astrocytes mediating transfer of glucose from the vascular compartment to the immediate extra-neuronal space. Returning from the biochemistry to the local cytoarchitecture, Fillenz reminds the reader of the close juxtaposition of the foot processes of astrocytes on capillaries. Glucose transporters are found on these processes and tight junctions should limit any passive flow of glucose from the capillary into the extra-cellular space elsewhere. This structural organization suggests that the astrocyte might provide the key conduit for glucose from the blood to the neurone. Local glucose concentrations then could be coupled via sensitivity to glutamate release to increased metabolic needs for synaptic activity.
Such a mechanism puts the question of substrate provision central to understanding brain activity. Not only could the astrocytes act to facilitate glucose transport, they also may act as local stores of glucose equivalents that can be mobilised for rapid increases in energy consumption with neuronal activation. This could be determined by local neurotransmitter release. Astrocytic glycogenolysis (hydrolysing glycogen to glucose) is stimulated by increases in cAMP, which can be driven, for example, by neuroadrenergic stimulation or release of vasoactive intestinal peptide (VIP). Neuro adrenergic stimulation is a known diffuse modulator of neuronal function. VIP release occurs via more specific mechanisms, consistent with functions as a local modulator of neuronal activity. Both neurotransmitters potentially could ‘facilitate’ neuronal activity by the common metabolic effects of promoting glycogenolysis from astrocytes. Given that each astrocyte contacts 30 000–40 000 synapses (about the number on approximately eight pyramidal neurones) such a mechanism would provide an additional way of coordinating activity in larger neuronal aggregates.
The theme of linked activity between astrocytic glial cells and neurones is one that runs across most of the reports in this book. It appears integral to a question key to understanding the coupling between neuronal activity and the fMRI BOLD response: the nature of local control of the haemodynamic response to neuronal activity. There is considerable evidence that neurovascular coupling is at least in part a response to local release of nitric oxide (NO). Increased neuronal calcium concentrations post-synaptically with NMDA receptor activation stimulates neuronal nitric oxide synthase (nNOS). This releases NO, which also then can interact with thiols to give highly vasodilatory nitrothiol compounds. However, the substrate for NOS in the neurone is arginine, which is synthesized from citrulline in astrocytes. Thus, an arginine–citrulline cycle between neurones and astrocytes appears important for controlling local coupling of increased blood flow to neuronal activity.
Understanding the physiological mechanisms underlying fMRI and forms of PET activation imaging thus involves understanding metabolic relationships between neurones and the surrounding astrocytes. It is remarkable to consider that interactions between these cell types underly mechanisms of substrate delivery (by mobilisation of glucose or lactate), neurotransmitter release and re-uptake (via calcium-stimulated glutamate release from astrocytes and re-uptake by the excitatory amino acid transporter), and local stimulation of increased blood flow (by NO released with greater activity of the arginine–citrulline cycle). It therefore follows that relating quantitative measurements of physiological parameters to underlying neuronal activity demands not only an appreciation for the potential variability in the neuronal responsiveness, but also activity in glial populations and their potentially variable relationships to neurones. It is interesting to speculate that glia may help to organise neuronal responses. Astrocytes are coupled by tight junctions. Waves of calcium-induced activity can be transmitted over large astrocytic fields crossing at least millimetres, providing a mechanism for electrical coupling of neuronal responses complementary to those of neurones themselves.
The neuronal responses, however, may be highly variable. Lauritzen reviewed the elegant work that he and his colleagues (including Claus Mathieson) have been performing in Copenhagen. They have studied isolated cerebellar slices, using laser Doppler methods to study blood flow with selective stimulation of either the monosynaptic climbing fibre or parallel fibre excitatory pathways or the disynaptic inhibitory parallel fibre pathway projecting onto single Purkinje cells. With this elegant approach, the relationship between extracellular field potential, Purkinje cell firing and blood flow can be measured. Similar to the more recent results presented by Nikos Logothetis for the monkey visual cortex in vivo, Lauritzen demonstrates that there is a proportional relationship between the extracellular field potential and local blood flow response with excitatory stimulation of the Purkinje cell by climbing fibres. This relationship is dependent on post-synaptic excitatory neurotransmitter receptor occupation, consistent with the notion that it is driven by demands related to needs for local energy production consequent upon excitatory neurotransmitter interactions. However, the situation is not so simple with parallel fibre stimulation, where a more complex, S-shaped response results that is only in part altered by excitatory neurotransmitter receptor blockade.
Ultimately, the focus of this workshop was very much directed towards the pragmatic question of understanding the BOLD fMRI signal. It is accepted generally that there should be a close relationship between the BOLD signal activation and underlying neuronal activity, but there are a number of central questions that have been answered only partially. First is the question of the precise localization signal relative to neuronal activity. The elegant experiments reviewed by Ugurbil argue that ‘the initial dip’ (a small, transient decrease in BOLD signal 1–2 s after stimulus that precedes a larger positive BOLD response) theoretically provides more accurate localization, something elegantly shown by the beautiful orientation column mapping performed by Ugurbil’s colleagues, Dong and Kim. However, it is pointed out that analysis of the early dip is not practical in most settings because of its very small magnitude. It also may vary significantly between the species or areas of brain depending on the relative rates of increase in local blood flow and local blood volume.
The second question concerns defining the mechanisms that drive the BOLD response so that an unequivocal interpretation of signal changes can be made. At this point, it appears as though inhibitory input gives rise to little or no BOLD response. However, a theoretical argument is that inhibitory modulation, by increasing the excitatory current necessary to achieve threshold depolarisation, should alter the local energy requirements for neuronal firing. Thus, altered inhibitory input might be reflected in changes in the magnitude of the BOLD response, were it to remain proportional to excitatory neurotransmitter induced current changes. However, there is no clear guarantee that a quantitatively invariant coupling would be found. The theoretical arguments of Gjedde and the empirical evidence of Fillenz demonstrate very nicely that the relationship between blood flow and metabolic changes may vary over time so that brief neuronal activation and steady-state neuronal changes give rise to quite distinct patterns of metabolic change. Clearly also, the quantitative correlation of BOLD changes between different regions of the brain must be done with great caution. Based on the metabolic arguments outlined in this workshop and anatomical differences in capillaries and neurones defined between brain areas, quantitative relations could vary dramatically. Interpretations could become even more problematic with pathology. These ideas even raise the intriguing question of whether pathology affecting glial cells primarily may give rise to early derangements of brain activity via their effects on the integrated neurone–astrocyte coupling.
This book provides the background to understanding a number of questions fundamental to the interpretation of functional imaging data and particularly fMRI. Despite their complexity, the book gives some confidence that a detailed understanding of the nature of the functional imaging signal is achievable in the relatively near future. Thus, there is a potential for using a variety of imaging parameters to characterize different aspects of this complex process in order to provide more specific probes of normal and diseased brain function. Because of this, the book deserves to be read widely by those interested in applications of neuroimaging to either basic or clinical neuroscience.
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