The neural basis of functional brain imaging signals

doi:10.1016/S0166-2236(02)02264-6

Trends in Neurosciences

Volume 25, Issue 12, 1 December 2002, Pages 621-625

https://doi.org/10.1016/S0166-2236(02)02264-6 Get rights and content

Abstract

The haemodynamic responses to neural activity that underlie the blood-oxygen-level-dependent (BOLD) signal used in functional magnetic resonance imaging (fMRI) of the brain are often assumed to be driven by energy use, particularly in presynaptic terminals or glia. However, recent work has suggested that most brain energy is used to power postsynaptic currents and action potentials rather than presynaptic or glial activity and, furthermore, that haemodynamic responses are driven by neurotransmitter-related signalling and not directly by the local energy needs of the brain. A firm understanding of the BOLD response will require investigation to be focussed on the neural signalling mechanisms controlling blood flow rather than on the locus of energy use.

Section snippets

Where is energy used in the brain?

If energy usage did control blood flow, then BOLD signals would reflect the activity of the cellular processes consuming most energy. Brain energy usage has been attributed mainly to activity in presynaptic terminals [15] or to the energy needed to take up the neurotransmitter glutamate and convert it to glutamine in astrocytes [17]. These ideas have been investigated by constructing an energy budget based on the measured properties of individual ion channels and synapses [18]. This analysis

Energy used on action potentials

The 10–47% of signalling energy predicted to be expended on action potentials [18] contrasts with a classic estimate by Creutzfeldt [20]. This estimate was based on heat generation by action potentials in peripheral nerves and suggested that only 0.3–3.0% of energy used in the brain was needed to support action potentials in human and cat cortex. However, Creutzfeldt's calculations employed a value of nerve heat production that was 6.6-fold lower than later measurements [21], he ignored the

Energy use does not directly increase blood flow

The preceding discussion suggests that, in primates, most of the increased energy use generated by neuronal activity is expended on reversing the ion movements that generate excitatory postsynaptic currents, with a smaller fraction being devoted to reversing the ion movements that generate action potentials. Does this energy usage directly control the blood flow to active regions of the brain and, hence, determine the functional imaging signal from those areas? Recent evidence suggests not.

Functional imaging of neuropsychiatric conditions

The findings that amines could be involved in CBF control and that CBF can be dissociated from energy utilization have important implications for the interpretation of functional magnetic resonance imaging (fMRI) data in disease states. Functional imaging is increasingly being used to investigate brain function in conditions with altered amine function, such as schizophrenia, Parkinson's disease, attention-deficit hyperactivity disorder or infusion of drugs affecting amine receptors or

Conclusions

The available evidence indicates that the haemodynamic response to neural activity is not initiated by signals arising from the energy deficit of the tissue but, rather, is driven locally by fast glutamate-mediated signalling processes, and more globally by amine- and ACh-mediated neural systems. Accordingly, the BOLD effect used in functional brain imaging should be interpreted as a reflection of neuronal signalling and not as a locus of increased energy utilization. BOLD signals could, as in

Acknowledgements

We thank Simon Laughlin for extended discussions on these issues, and Tony David and Chris Frith for comments on the manuscript. Supported by the Wellcome Trust and a Wolfson-Royal Society Award (DA) and the NIH (CI).

References (66)

M. Jueptner et al.
Does measurement of regional cerebral blood flow reflect synaptic activity? – Implications for PET and fMRI
Neuroimage
(1995)
M.T.T. Wong-Riley
Cytochrome oxidase: an endogenous metabolic marker for neuronal activity
Trends Neurosci.
(1989)
C.P. Chih
Do neurons really use lactate rather than glucose?
Trends Neurosci.
(2001)
G. Bonvento
Does glutamate image your thoughts?
Trends Neurosci.
(2002)
E. Pinard
Blood flow compensates oxygen demand in the vulnerable CA3 region of the hippocampus during kainate-induced seizures
Neuroscience
(1984)
J. Li et al.
Nitric oxide and adenosine mediate vasodilation during functional activation in cerebellar cortex
Neuropharmacology
(1994)
A. Fergus et al.
Regulation of cerebral microvessels by glutamatergic mechanisms
Brain Res.
(1997)
T. Lovick
Neurovascular relationships in hippocampal slices: physiological and anatomical studies of mechanisms underlying flow-metabolism coupling in intraparenchymal microvessels
Neuroscience
(1999)
C. Iadecola et al.
Focal elevations in neocortical interstitial K⁺ produced by stimulation of the fastigial nucleus in rat
Brain Res.
(1991)
E. Southam
Sources and targets of nitric oxide in rat cerebellum
Neurosci. Lett.
(1992)

Z. Cohen

Serotonin in the regulation of brain microcirculation

Prog. Neurobiol.

(1996)

A. Sato et al.

Regulation of regional cerebral blood flow by cholinergic fibers originating in the basal forebrain

Neurosci. Res.

(1992)

D.J. Reis et al.

Autonomic and vasomotor regulation

Int. Rev. Neurobiol.

(1997)

M. Hamann

Tonic and spillover inhibition of granule cells control information flow through cerebellar cortex

Neuron

(2002)

S. Ogawa

Brain magnetic resonance imaging with contrast dependent on blood oxygenation

Proc. Natl. Acad. Sci. U. S. A.

(1990)

P.T. Fox et al.

Focal physiological uncoupling of cerebral blood flow and oxidative metabolism during somatosensory stimulation in human subjects

Proc. Natl. Acad. Sci. U. S. A.

(1986)

D. Malonek

Vascular imprints of neuronal activity: relationships between the dynamics of cortical blood flow, oxygenation, and volume changes following sensory stimulation

Proc. Natl. Acad. Sci. U. S. A.

(1997)

Mosso, A. (1881) Ueber den Kreislauf des Blutes im menschlichen Gehirn, von Veit,...

C. Roy et al.

On the regulation of the blood supply of the brain

J. Physiol.

(1890)

Fulton, J.F. (1928) Observations upon the vascularity of the human occipital lobe during visual activity, Brain LI,...

C. Schmidt et al.

Action of chemical substances on cerebral blood vessels

Res. Publ. Assoc. Res. Nerv. Ment. Dis.

(1938)

M.E. Raichle

Behind the scenes of functional brain imaging: a historical and physiological perspective

Proc. Natl. Acad. Sci. U. S. A.

(1998)

R.D. Hoge

Linear coupling between cerebral blood flow and oxygen consumption in activated human cortex

Proc. Natl. Acad. Sci. U. S. A.

(1999)

J.B. Clark et al.

Circulation and energy metabolism of the brain

R.G. Shulman et al.

Interpreting functional imaging studies in terms of neurotransmitter cycling

Proc. Natl. Acad. Sci. U. S. A.

(1998)

P.J. Magistretti

Energy on demand

Science

(1999)

P.J. Magistretti et al.

Cellular mechanisms of brain energy metabolism and their relevance to functional brain imaging

Philos. Trans. R. Soc. London Ser. B

(1999)

C. Shin

Neurophysiologic basis of functional neuroimaging: animal studies

J. Clin. Neurophysiol.

(2000)

J.B. Mandeville

MRI measurement of the temporal evolution of relative CMRO₂ during rat forepaw stimulation

Magn. Reson. Med.

(1999)

N.R. Sibson

Stoichiometric coupling of brain glucose metabolism and glutamatergic neuronal activity

Proc. Natl. Acad. Sci. U. S. A.

(1998)

D. Attwell et al.

An energy budget for signalling in the grey matter of the brain

J. Cereb. Blood Flow Metab.

(2001)

O.D. Creutzfeldt

Neurophysiological correlates of different functional states of the brain

J.M. Ritchie

Energetic aspects of nerve conduction: the relationships between heat production, electrical activity and metabolism

Prog. Biophys. Mol. Biol.

(1973)

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Trends in Neurosciences

OpinionThe neural basis of functional brain imaging signals

Abstract

Section snippets

Where is energy used in the brain?

Energy used on action potentials

Energy use does not directly increase blood flow

Functional imaging of neuropsychiatric conditions

Conclusions

Acknowledgements

Neuroimage

Trends Neurosci.

Trends Neurosci.

Trends Neurosci.

Neuroscience

Neuropharmacology

Brain Res.

Neuroscience

Brain Res.

Neurosci. Lett.

Prog. Neurobiol.

Neurosci. Res.

Int. Rev. Neurobiol.

Neuron

Brain magnetic resonance imaging with contrast dependent on blood oxygenation

Proc. Natl. Acad. Sci. U. S. A.

Focal physiological uncoupling of cerebral blood flow and oxidative metabolism during somatosensory stimulation in human subjects

Proc. Natl. Acad. Sci. U. S. A.

Vascular imprints of neuronal activity: relationships between the dynamics of cortical blood flow, oxygenation, and volume changes following sensory stimulation

Proc. Natl. Acad. Sci. U. S. A.

On the regulation of the blood supply of the brain

J. Physiol.

Action of chemical substances on cerebral blood vessels

Res. Publ. Assoc. Res. Nerv. Ment. Dis.

Behind the scenes of functional brain imaging: a historical and physiological perspective

Proc. Natl. Acad. Sci. U. S. A.

Linear coupling between cerebral blood flow and oxygen consumption in activated human cortex

Proc. Natl. Acad. Sci. U. S. A.

Circulation and energy metabolism of the brain

Interpreting functional imaging studies in terms of neurotransmitter cycling

Proc. Natl. Acad. Sci. U. S. A.

Energy on demand

Science

Cellular mechanisms of brain energy metabolism and their relevance to functional brain imaging

Philos. Trans. R. Soc. London Ser. B

Neurophysiologic basis of functional neuroimaging: animal studies

J. Clin. Neurophysiol.

MRI measurement of the temporal evolution of relative CMRO2 during rat forepaw stimulation

Magn. Reson. Med.

Stoichiometric coupling of brain glucose metabolism and glutamatergic neuronal activity

Proc. Natl. Acad. Sci. U. S. A.

An energy budget for signalling in the grey matter of the brain

J. Cereb. Blood Flow Metab.

Neurophysiological correlates of different functional states of the brain

Energetic aspects of nerve conduction: the relationships between heat production, electrical activity and metabolism

Prog. Biophys. Mol. Biol.

Opinion
The neural basis of functional brain imaging signals

MRI measurement of the temporal evolution of relative CMRO₂ during rat forepaw stimulation