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Brain energy use, control of blood flow, and the basis of BOLD signals David Attwell University College London. BOLD imaging. Hariri et al. (2002) Science 297, 400. Overview. Brief review of BOLD imaging Coupling of neural activity to CBF, by (i) energy use or (ii) other signalling pathways

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slide1
Brain energy use, control of blood flow, and the basis of BOLD signalsDavid AttwellUniversity College London
bold imaging
BOLD imaging

Hariri et al. (2002) Science 297, 400

overview
Overview
  • Brief review of BOLD imaging
  • Coupling of neural activity to CBF, by (i) energy use or (ii) other signalling pathways
  • Energy budget for cerebral cortex
  • Energy use in neuronal microcircuits: cerebellum
  • Local regulation of CBF by glutamate
  • Global regulation of CBF by amines
  • Regulation of CBF by arterioles and capillaries
  • What does BOLD measure
slide4

stellate

basket

Purkinje

granule

Golgi

input

climbing fibre

input mossy fibres

output

FLOW

Hb

HbO2

blood vessels

O2

slide5

stellate

basket

Purkinje

granule

Golgi

input

climbing fibre

input mossy fibres

output

VOL

FLOW

Hb

HbO2

blood vessels

O2

?

signalling from neurons to blood vessels
Signalling from neurons to blood vessels
  • The neuron to CBF signal is often assumed to be energy usage or energy lack (assumes CBF increases to maintain glucose/O2 delivery to neurons)
  • So where does the brain use energy?
slide8

2K

3Na

2K

3Na

ATP

Pre-Synaptic

ATP

GLN

Neuron

ATP

GLU

+

3Na

GLUTAMATE

+

H

+

K

+

Na

2K

+

+

Ca

2

Na

3Na

ATP

Glial

Cell

Post-Synaptic

Neuron

primates vs rodents
Primates vs rodents
  • Primates: 3-10 times less cell density with same synapse density (so 3-10 times more synapses/cell)
  • Predicts a lower overall energy usage (54% for 10-fold - experimental value is 54%)
  • Increases fraction on glutamatergic signalling (from 34% to 74%)
slide13

stellate

basket

Purkinje

granule

Golgi

input

climbing fibre

input mossy fibres

output

slide14

stellate

basket

Purkinje

granule

Golgi

input

climbing fibre

input mossy fibres

output

cerebral cortex

cerebellar cortex

slide15

stellate

basket

Purkinje

granule

Golgi

input

climbing fibre

input mossy fibres

output

Predicted total ATP usage: 26.6 mmoles/g/min

Measured: 20 mmoles/g/min

(Sokoloff & Clarke in anaesthetized albino rats)

slide16

stellate

basket

Purkinje

granule

Golgi

input

climbing fibre

input mossy fibres

output

ATP/sec/cell

Purkinje

basket/stellate

Golgi

granule cell

climbing fibre

mossy fibre

Bergmann

astrocyte

slide17

stellate

basket

Purkinje

granule

Golgi

input

climbing fibre

input mossy fibres

output

ATP/sec/cell

ATP/sec/m2

granule cell

Purkinje

basket/stellate

Purkinje

Golgi

granule cell

mossy fibre

climbing fibre

climbing fibre

mossy fibre

Bergmann

Bergmann

astrocyte

bc/sc

astro

Golgi

slide20

Energy use by neuronal microcircuits: the cerebellum as an example

stellate

basket

Purkinje

granule

Golgi

input

climbing fibre

input mossy fibres

output

  • Most energy goes on granule cells re-mapping the sensory and motor command input arriving on the mossy fibres into a sparse coded representation used by the Purkinje cells to retrieve motor output patterns
slide21

Energy use by neuronal microcircuits: the cerebellum as an example

stellate

basket

Purkinje

granule

Golgi

input

climbing fibre

input mossy fibres

output

  • Most energy goes on granule cells re-mapping the sensory and motor command input arriving on the mossy fibres into a sparse coded representation used by the Purkinje cells to retrieve motor output patterns
  • 1011 ATP molecules are used per second to be able to retrieve 5kB of information from each Purkinje cell (which can store 40,000 input-output associations), or 2x1016 ATP/GB/s = (3.3x10-8moles/sec)x31kJ = 1mW/GB. Computer hard disks now use ~5mW/GB
does an energy lack signal increase blood flow
Does an energy-lack signal increase blood flow?
  • When [ATP] (or [O2] or [glucose]) falls, or [CO2] or [H+] or [lactate] rises, does that make blood flow increase?
  • In other words, do BOLD signals reflect the presence of a feedback system to conserve energy supply?
slide24

stellate

basket

Purkinje

granule

Golgi

input

climbing fibre

input mossy fibres

output

VOL

FLOW

Hb

HbO2

blood vessels

O2

energy lack?

what controls cerebral blood flow during brain activation
What controls cerebral blood flow during brain activation?
  • Not glucose lack (Powers et al., 1996)
  • Not oxygen lack (Mintun et al., 2001)
  • Not CO2 evoked pH change (pHo goes alkaline due to CBF increase removing CO2: Astrup et al., 1978; Pinard et al., 1984)
  • So CBF is not driven directly by energy lack maintaining O2/glucose delivery to neurons and keeping [ATP] high

Powers et al., 1996

what controls cerebral blood flow during brain activation1
What controls cerebral blood flow during brain activation?
  • CBF is not driven by energy lack
  • Not the spike rate of principal neurons (Mathiesen et al., 1998; Lauritzen 2001)
  • BOLD correlates (slightly!) better with synaptic field potentials than spike output (Logothetis et al., 2001)
  • So does synaptic signalling control CBF (i.e. is it a feedforward, rather than a feedback, system)?
feedforward vs feedback control of cbf
Feedforward vs feedback control of CBF

Negative feedback

Neuronal activity

Energy falls

Increase CBF

-

Feedforward

Neuronal activity

Energy supplied

Increase CBF

slide28

+

+

Ca

Ca

2

2

2K

3Na

2K

3Na

ATP

Pre-Synaptic

ATP

GLN

Neuron

ATP

GLU

+

3Na

GLUTAMATE

+

H

+

K

+

Na

2K

+

PLA2

Na

PLA2

3Na

ATP

Glial

NOS

Cell

Post-Synaptic

AA,PG

Neuron

NO

glutamate is responsible for cerebellar cbf increase
Glutamate is responsible for cerebellar CBF increase

Purkinje cell spikes

Parallel fibre

stimulation

CBF

Climbing fibre

stimulation

CBF

Matthiesen et al., 1998

slide30

stellate

basket

Purkinje

granule

Golgi

input

climbing fibre

input mossy fibres

output

VOL

FLOW

Hb

HbO2

blood vessels

O2

Glutamate (via

neurons and glia)

glutamate controls cbf and bold signals
Glutamate controls CBF and BOLD signals
  • Energy calculations implicate postsynaptic currents as the main energy consumer - so if energy use drove BOLD signals, BOLD would reflect the release of glutamate
  • In fact energy use does not drive CBF, but glutamate does - so BOLD is still likely to reflect glutamate release (via its postsynaptic actions)
what does bold measure
What does BOLD measure?
  • If BOLD signals largely reflect glutamate release:
  • (a) BOLD does not tell us about the spike output of an area, and will only reflect principal cell activity if most glutamate is released onto principal cells
  • (b) altered processing with no net change of glu release might produce no BOLD signal
  • (c) altered glu release with no change of the spike output of an area could produce a BOLD signal
slide33

VOL

FLOW

Hb

HbO2

blood vessels

O2

stellate

Glu

AMINES

NA, DA, 5-HT

basket

Purkinje

granule

Golgi

input

climbing fibre

input mossy fibres

output

control of cerebral blood flow by distributed systems using amines and ach
Control of cerebral blood flow by distributed systems using amines and ACh
  • Dopaminergic neurons (from VTA) innervate microvessels - DA constricts (Krimer et al., 1998): D1,2,4,5
  • Noradrenergic neurons (from locus coeruleus) also constrict microvessels (Raichle et al., 1975): a2
  • Serotoninergic neurons (from raphe) constrict cerebral arteries and microvessels (Cohen et al., 1996): 5-HT1,2
  • All are wide ranging systems - control CBF globally
slide35

Smooth Muscle vs Pericytes

pericytes

endothelial cells

smooth muscle

blood flow

capillary

10 µm

SM

s

p

s

5 µm

5 µm

p

10 µm

slide36

Smooth Muscle vs Pericytes

pericytes

65% of noradrenergic

innervation is of capillaries,

not arterioles

endothelial cells

smooth muscle

blood flow

capillary

10 µm

SM

s

p

s

5 µm

5 µm

p

10 µm

slide37

a

c

o

70s

185s

295s

390s

Noradrenaline constricts and glutamate dilates cerebellar capillaries

b

d

1mM

Glu

1mM NA

Peppiatt, Howarth, Auger & Attwell, unpublished

slide38

Pericytes communicate with each other

and could communicate from

neurons near capillaries

to precapillary arterioles

implications of control of cbf by amines for neuropsychiatric imaging
Implications of control of CBF by aminesfor neuropsychiatric imaging
  • Clinical disorders often involve disruption of amine function (schizophrenia, Parkinson’s, ADHD)
  • In imaging we would like a change in BOLD signals to imply an effect of the amine disorder on cortical processing
  • If amines control CBF, altered amine function may alter the relation between neural activity and BOLD signals (extreme example: amine depletion maximally dilates vessels, so no further dilation or BOLD signal possible)
  • Consequently altered BOLD signals may just reflect altered control of CBF, and provide no information on neural processing
slide40

VOL

FLOW

Hb

HbO2

blood vessels

O2

stellate

Glu

AMINES

NA, DA, 5-HT

basket

Purkinje

granule

Golgi

input

climbing fibre

input mossy fibres

output

bold imaging1
BOLD imaging

Hariri et al. (2002) Science 297, 400

conclusions
Conclusions
  • In primates, most of the brain’s energy goes on postsynaptic currents (and action potentials)
  • CBF changes and BOLD aren’t driven by O2/glucose lack nor by CO2 production, so are not driven by energy lack
  • CBF changes and BOLD don’t correlate well with spiking
  • Glutamate controls local CBF so BOLD signals will reflect glutamatergic signalling
  • Amines control CBF more globally - could confound studies on amine-related diseases
  • CONCLUSION: to interpret BOLD signals you need to consider the neural wiring of the area being studied
collaborators
Collaborators

Clare Howarth

Claire Peppiatt

Céline Auger

Simon Laughlin