The use of cerebral blood flow as an index of neuronal activity in functional neuroimaging: experimental and pathophysiological considerations
Introduction
Over the last two decades, the literal outburst of functional imaging techniques such as positron emission tomography (PET) or functional magnetic resonance imaging (fMRI) has allowed a remarkable improvement in the knowledge of brain physiology, and has opened important breakthroughs into pathophysiological studies. Major contributions in this domain have been made with activation paradigms in which changes of the level of synaptic transmission and therefore in neuronal activity are detected through the measurement of cerebral blood flow (CBF) variations. Such a contention on the use of CBF as an index of neuronal activity is based on the concept of a tight relationship, called coupling, existing between neuronal functioning and the local brain energy demand, and between local brain metabolic variations and CBF variations, since brain metabolic reserves are minimal. The term coupling is regularly used to qualify a linear relationship between cerebral metabolism and CBF that has been reported mainly at “rest” (i.e. without a stimulus-induced cerebral activation). Conversely, the idea of uncoupling refers to the perturbations of these relationships. The aim of this review is to focus on experimental, pharmacological and pathophysiological situations in which CBF and/or local brain metabolism might not represent a reliable index of neuronal activity. If such would be the case, activation studies, notably applied to the study and/or the diagnosis of neurodegenerative diseases, could be of limited use, since regulatory mechanisms of CBF and/or metabolism should be altered in a different manner.
Section snippets
Historical evolution of the concept of coupling: from Roy and Sherrington's theory to recent hypotheses
Arising from indirect quantifications, the concept of coupling between changes in neuronal activity and CBF was first evoked by Roy and Sherrington (1890). Since brain metabolic reserves are almost negligible, each variation of neuronal activity should lead to an increase of the local brain metabolic demand, that can be satisfied only through an increase in the energetic supply which, in turn, is dependent on local variations of blood perfusion. Thus, CBF is supposed to be dynamically and
Experimental and pharmacological demonstration of uncoupled situations: on the role of neurotransmitters and modulators
Based on the definition of coupling, an electrophysiological or metabolic variation should obligatory lead to a parallel CBF modification. This may not always the case. For example, it has been reported that electrical activation of the parallel fibers, in the cerebellum of the rat, while inhibiting the spiking activity of cerebellar target Purkinje cells, induces an increase in CBF in the same region (Mathiesen et al., 1998). In this case, the vascular response does not indicate an increase,
Pathological-induced alterations of cerebral blood flow and/or metabolism regulation
Based on the implication of neurotransmitters in the regulation of CBF and/or brain metabolism, and since alterations of neurotransmitter pathways, including ACh and NO, have been demonstrated in several neurodegenerative diseases, one can hypothesize important perturbations of the mechanisms that govern the coupling between local neuronal activity, metabolism and CBF. To illustrate the contention of selective uncoupled alterations in CBF or local metabolism induced by neurodegeneration, we
Why the comprehension of coupling and/or decoupling is necessary for a better interpretation of activation studies?
If the development of new non-invasive imaging techniques have contributed to the advance in the understanding of brain functioning, one should be careful in the interpretation of such data. Indeed, activation paradigms currently use CBF variations as a surrogate for neuronal activity changes based on the presupposed tight coupling between neuronal activity, metabolism and CBF. This review has however illustrated uncoupled situations that can be encountered under physiological conditions,
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