1 / 43

BOLD imaging

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

payton
Download Presentation

BOLD imaging

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. Brain energy use, control of blood flow, and the basis of BOLD signalsDavid AttwellUniversity College London

  2. BOLD imaging Hariri et al. (2002) Science 297, 400

  3. 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

  4. stellate basket Purkinje granule Golgi input climbing fibre input mossy fibres output FLOW Hb HbO2 blood vessels O2

  5. stellate basket Purkinje granule Golgi input climbing fibre input mossy fibres output VOL FLOW Hb HbO2 blood vessels O2 ?

  6. 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?

  7. 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

  8. 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%)

  9. Energy use by neuronal microcircuits: the cerebellum as an example

  10. stellate basket Purkinje granule Golgi input climbing fibre input mossy fibres output

  11. stellate basket Purkinje granule Golgi input climbing fibre input mossy fibres output cerebral cortex cerebellar cortex

  12. 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)

  13. 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

  14. 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

  15. ATP Usage by Subcellular Task

  16. Effect of altering firing rate in a single cell type

  17. 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

  18. 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

  19. How is blood flow controlled? ML PC GL

  20. 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?

  21. stellate basket Purkinje granule Golgi input climbing fibre input mossy fibres output VOL FLOW Hb HbO2 blood vessels O2 energy lack?

  22. 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

  23. 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)?

  24. Feedforward vs feedback control of CBF Negative feedback Neuronal activity Energy falls Increase CBF - Feedforward Neuronal activity Energy supplied Increase CBF

  25. + + 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

  26. Glutamate is responsible for cerebellar CBF increase Purkinje cell spikes Parallel fibre stimulation CBF Climbing fibre stimulation CBF Matthiesen et al., 1998

  27. stellate basket Purkinje granule Golgi input climbing fibre input mossy fibres output VOL FLOW Hb HbO2 blood vessels O2 Glutamate (via neurons and glia)

  28. 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)

  29. 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

  30. 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

  31. 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

  32. 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

  33. 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

  34. 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

  35. Pericytes communicate with each other and could communicate from neurons near capillaries to precapillary arterioles

  36. 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

  37. 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

  38. BOLD imaging Hariri et al. (2002) Science 297, 400

  39. 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

  40. Collaborators Clare Howarth Claire Peppiatt Céline Auger Simon Laughlin

More Related