1. Sir
Peter
Mansfield
Magne0c
Resonance
Centre
University
of
No:ngham,
UK
FP7
Neurophysics
Workshop
Pharmacological
fMRI
Warwick
Conference
Centre,
23
January
2012
Mul0modal
approaches
to
func0onal
neuroimaging
Peter
Morris

2. Functional MRI

3. Functional CNR
ΔS/N
=
SNR
.
ΔR2*
/
R2*

4. 7T MPRAGE, 0.5mm isotropic resolution, SENSE factor 2, acquisition time 11 mins for
the whole head

5. 1.5T
3T
7T
5 s-1
0.39 s-1
5 s-1
5 s-1
0.39 s-1
0.39 s-1
ΔR2*
maps
as
a
func0on
of
strength

6. 0
0.02
0.04
0.06
0.08
0.1
0 1 2 3 4 5 6 7 8
Field Strength (T)
Composite ROI Inclusion ROI
ΔR2
*/R2
*
0
0.02
0.04
0.06
0.08
0.1
0 1 2 3 4 5 6 7 8
Field Strength (T)
Composite ROI Inclusion ROI
1 2 3 4 5 6 7 8
Field Strength (T)
omposite ROI Inclusion ROI
Field dependence of ΔR2*/R2*

7. Field dependence of fMRI responses
pcorr < 0.05 for
motor task
0
0.02
0.04
0.06
0.08
0.1
0.12
0.14
0 20 40 60 80 100
TE (ms)
7 T
3 T
1.5 T
ΔS/S
Motor task (8 s ON; 20 s off; 5
cycles)
Same 6 subjects scanned at
1.5, 3 & 7 T
Data co-registered across fields
and echo times.
W. van der Zwaag, S. Francis, K. E. Head, A. Peters, P. Gowland, P. Morris and R. Bowtell, Neuroimage 47, 1425-1434 (2009)

8. anterior
posterior
1-thumb 2-index 3-middle 4-ring 5-little
ventral
dorsal
right
High resolution somatosensory mapping at 7T
2
1
4
3
5

9. Relating structure to function in the visual cortex at 7T
medial
lateral
fMRI
Structural
Rotating wedge
V1
posterior anterior
structural
functional
1.5 mm isotropic resolution
Resolution:0.35x0.35x1.5mm3
Stria of
Gennari
seen as a
dark band

10. Resting state networks

11. J.R. Hale, M.J. Brookes, E.L. Hall, J.M. Zummer, C.M. Stevenson, S.T. Francis and P.G. Morris, Magn. Reson.
Mater. Phy. 23, 339-349 (2010)
Correlation coefficients for sensorimotor and default mode resting
state networks

12. J.R. Hale, M.J. Brookes, E.L. Hall, J.M. Zummer, C.M. Stevenson, S.T. Francis and P.G. Morris, Magn. Reson.
Mater. Phy. 23, 339-349 (2010)
Default mode network

13. Sternberg Working Memory Task
Paradigm:
Two visual stimuli presented in quick succession
Following a maintenance period of 8s, a third “probe” stimulus presented
Subject responds if the the probe is the same as either of the two initial stimuli
Visual
Stimulus 1
Visual
Stimulus 2
M a i n t e n a n c e P e r i o d
Probe
Stimulus

14. Working
Memory
(Sternberg)
Paradigm
S. Clare, M. Humberstone, J.L. Hykin, L.D. Blumhardt, R. Bowtell and P.G. Morris,
Magn Reson Med 42, 1117-1122 (1999)

15. Challenges
of
pharmacological
MRI
• Direct
affect
(BOLD
response)
of
agent
– DifferenCaCon
between
direct
and
acCvity
mediated
effects
on
haemodynamic
response
– Pharmacodynamics
• Modulatory
effect
of
agent
– Pharmacodynamics

16. Rat Model of Persistent
Nociception
Intraplantar injection of formalin into rat
hindpaw

17. Ascending and descending pain pathways

18. hl fl
a
vpm
vpl
vl
PAG
Thalamus
Formalin evoked increase in BOLD response
P<0.05
P<0.01
P<0.001
Hindlimb area of
Somatosensory
cortex
Thalamus
Amygdala
PAG
P.G. Morris, J. Psychopharm. 13 (4), 330-336 (1999)

19. -0.5
0
0.5
1
1.5
2
saline
morphine
10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180
-0.5
0
0.5
1
1.5
2
saline
morphine
10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180
Time in minutes Time in minutes
%changeinsignalintensity
%changeinsignalintensity
Periaqueductal
gray
Thalamus
An acute high dose of
morphine (5mg/kg, IP
cannula) evoked significant
increases (p<0.002) in
BOLD response in the PAG,
thalamus and cingulate
cortex-0.5
0
0.5
1
1.5
2
saline
morphine
10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180
Time in minutes
%changeinsignalintensity
Cingulate cortex
Effects of morphine injection

20. MEG at the SPMMRC

21. w1
w2
w3
w275
m1
m2
m3
w1m1+w2m2+w3mVE = 3+
m275
MEG beamformer
Vq=Σi=1..275wqimi
Σ
virtual electrode output

22. Stimulus was a rotating
wedge containing a 10Hz
flashing checkerboard.
Wedge rotated through 360
degrees smoothly once
every 25 seconds.
Functional images created
using adaptive beamformer
using short covariance
windows
Functional images show the
location of the 10Hz driven
neuromagnetic response
Response is mapped
retinotopically onto the
occipital cortex
Retinotopic mapping using MEG
M. J. Brookes, J. M. Zumer, C. M. Stevenson, J. R. Hale, G. R. Barnes, J. Vrba, and P. G. Morris, Neuroimage 49(1), 525-538 (2010)

23. MEG
responses
0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000
0.5
1
1.5
2
2.5
3
Samples
SourceStrengthQ(nAm)
Hilbert Transform of VE timecourse from peak of gamma 60-80Hz Subj2
• Evoked response
• Gamma band ERS
• Beta band ERD and ERS

24. Multimodal imaging: fMRI / MEG
7T BOLD
T>6
fMRI
3T BOLD
T>5.5
MEG
β-band ERS
(15-30Hz)
Ŧ>1.2
VEP
Ŧ>5
γ-band ERS
(60-80Hz)
Ŧ>4
β-band ERD
(15-30Hz)
Ŧ>1.2
M.J. Brookes, A.M. Gibson, S.D. Hall, P.L. Furlong, G.R.
Barnes, A. Hillebrand, K.D. Singh, I.E. Holliday, S.T.
Francis, P.G. Morris, Neuroimage 26 (1), 302-308 (2005)

25. 0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
1.1
-0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1.1
Michelson Contrast
NormalisedVEFResponse
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
1.1
-0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1.1
Michelson Contrast
NormalisedVEFResponse
-0.1
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
1.1
-0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1.1
Michelson Contrast
NormalisedGammaResponse
-1
-0.9
-0.8
-0.7
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
0
0.1
0.2
-0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1.1
Michelson Contrast
NormalisedBetaERDResponse
-0.2
-0.1
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
-0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1.1
Michelson Contrast
NormalisedBetaERSResponse
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
1.1
-0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1.1
Michelson Contrast
NormalisedVEFResponse
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
1.1
-0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1.1
Michelson Contrast
NormalisedVEFResponse
-0.1
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
1.1
-0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1.1
Michelson Contrast
NormalisedGammaResponse
-1
-0.9
-0.8
-0.7
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
0
0.1
0.2
-0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1.1
Michelson Contrast
NormalisedBetaERDResponse
-0.2
-0.1
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
-0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1.1
Michelson Contrast
NormalisedBetaERSResponse
A B
C D
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
1.1
-0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1.1
Michelson Contrast
NormalisedVEFResponse
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
1.1
-0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1.1
Michelson Contrast
NormalisedVEFResponse
-0.1
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
1.1
-0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1.1
Michelson Contrast
NormalisedGammaResponse
-1
-0.9
-0.8
-0.7
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
0
0.1
0.2
-0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1.1
Michelson Contrast
NormalisedBetaERDResponse
-0.2
-0.1
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
-0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1.1
Michelson Contrast
NormalisedBetaERSResponse
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
1.1
-0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1.1
Michelson Contrast
NormalisedVEFResponse
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
1.1
-0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1.1
Michelson Contrast
NormalisedVEFResponse
-0.1
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
1.1
-0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1.1
Michelson Contrast
NormalisedGammaResponse
-1
-0.9
-0.8
-0.7
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
0
0.1
0.2
-0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1.1
Michelson Contrast
NormalisedBetaERDResponse
-0.2
-0.1
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
-0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1.1
Michelson Contrast
NormalisedBetaERSResponse
A B
C D
MEG Contrast Response Curves

26. Correlation of fMRI BOLD with neural oscillations
J.M. Zumer, M.J. Brookes, C.M. Stevenson, S.T. Francis and P. G. Morris, Neuroimage 49(2) 1479-1489 (2010)

27. Working
memory

28. 1-BACK 0-BACK 2-BACK RELAX
A… H S S G V D P… X S S D V K D… H Y R D V D
TARGETS
Time (s)0 32 64 96 126
Time (s)
LETTER
PRESENTATION
MAINTENANCE RELAX
A D Y C Y M S P
8s 8s2, 5 or 8 letters: 1
letter presented
every 1.4s
C
1.4s 2s
RELAX
PROBE
N-BACK
STERNBERG
TARGET
N-back and Sternberg paradigms

29. 8
7
Number of
Subjects
NegativeChange
PositiveChange
8
5
Number of
Subjects
NegativeChange
PositiveChange
Theta (4-8 Hz) activity during N-back (upper) and Sternberg (lower)
paradigms. Group effect.

30. Gamma (20-40 Hz) activity during N-back (upper) and Sternberg (lower) paradigms
Group effect
8
7
Number of
Subjects
NegativeChange
PositiveChange
8
7
Number of
Subjects
NegativeChange
PositiveChange

31. Spectral changes in oscillatory
power in medial frontal lobe:
N-back
Spectral changes in oscillatory
power in medial frontal lobe:
Sternberg
M.J. Brookes, J.R. Wood, C.M. Stevenson,
J.M. Zumer, T.P. White, P.F. Liddle and P.G.
Morris, Neuroimage 55, 1804-1815 (2011)

32. ICA analysis of resting state data
M.Brookes, M. Woolrich, H. Luckoo, D. Price, J.R. Hale, M.C. Stephenson, G.R. Barnes,
S.M. Smith and P.G. Morris, PNAS 108 (40), 16783-16788 (2011)

33. ICA analysis of resting state data
M.Brookes, M. Woolrich, H. Luckoo, D. Price, J.R. Hale, M.C. Stephenson, G.R. Barnes,
S.M. Smith and P.G. Morris, PNAS 108 (40), 16783-16788 (2011)

34. Resting state networks: MEG
Resting state brain networks observable using both fMRI and MEG in the “resting state”
Shows that the haemodynamic networks in fMRI have an electrophysiological basis
MEG also shows that neural oscillatory processes underlies haemodynamic connectivity
Agrees with invasive measurements made in patients
Brookes et al. PNAS 108 (40): 16783-16788 (2011)

35. Networks associated with working memory tasks
A: Visual, B: Fronto-Parietal, C: L/R Insula, D L/R TPJ, E: R Motor, F: L Motor, G Lateral
Visual, H: Medial Parietal

36. Sternberg Working Memory Task
Paradigm:
Two visual stimuli presented in quick succession
Following a maintenance period of 8s, a third “probe” stimulus presented
Subject responds if the the probe is the same as either of the two initial stimuli
Visual
Stimulus 1
Visual
Stimulus 2
M a i n t e n a n c e P e r i o d
Probe
Stimulus

37. Sternberg Working Memory Task
Primary visual areas
Lateral visual areas
Bilateral Insula network
Fronto-parietal network
Medial Parietal cortex
Bilateral TPJ
Right Motor Cortex
Left Motor Cortex
Time frequency plots for 8 networks associated with Sternberg paradigm

38. Pathways of Glu/Gln and GABA/Glu/Gln Cycling"
Gln
Glu
Gln
Glu
Glu
GABA
Gln GABAc
GAD67
GAD65
Na+ Na+
GABA
Glutamatergic neuron GABAergic neuronAstrocyte
TCA
Cycle
TCA
Cycle
TCA
Cycle
Brain Neurotransmission

39. Advantages
of
high
field
for
MRS
• Increased
SNR
(~
B0)
– improved
spa0al
resolu0on
– shorter
scan
0mes
• Increased
spectral
resolu0on
• Simpler
spin
coupling
paVerns
– weak
rather
than
strong
coupling

40. Click to edit Master title style
• Click to edit Master text styles
• Second level
• Third level
• Fourth level
• Fifth level
40
1H MRS Repeatability: %CVs
NAA Glu Gln mI GABA Cr Cho
7T sh 3 (2) 4(2) 10(6) 9(3) 10(6) 3(2) 5(4)
3T sh 5(3) 8(6) 29(11) 8(4) 21(14) 10(4) 16(16)
7T long 6(6) 10(6) 29(19) 19(10) 16(8) 7(6) 8(6)
3T long 6(6) 16(9) 32(30) 22(10) 36(25) 22(13) 8(7)
Values are mean (± SD)
M. C. Stephenson, F. Gunner, A. Napolitano, P. L. Greenhaff, I. A .MacDonald, N. Saeed,
W. Vennart, S. T. Francis and P. G. Morris, World J. Radiol. 3(4), 105-113 (2011)

41. 7T 1H Spectrum

42. Click to edit Master title style
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• Second level
• Third level
• Fourth level
• Fifth level
42
The stimulus consists of radial white/black prisms covering the entire visual
field and reversing at a frequency of 8Hz.
Visual Stimulus

43. SCmulaCon
induced
changes
in
metabolite
levels
determined
by
1H
MRS
Lin et al., under revision for JCBFM

44. Time courses of
metabolite changes
during visual
stimulation
Lin et al., under revision for JCBFM

45. Click to edit Master title style
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• Second level
• Third level
• Fourth level
• Fifth level
45
• Significant decrease in Glc
– Increased glucose consumption during stimulation
• Significant increase in Lactate
– Increased rates of glycolysis and TCA cycle
• Suppression of second lactate response to stimulation
• Significant increase in Glutamate, decrease in Glutamine and trend
to increase in GABA
- Changes in the neurotransmitter levels due to increased turnover
• Significant Increase in Glutathione
– Possibly related to oxidative stress or a ‘buffer’ of excess
synaptic glutamate
1H MRS Changes due
to Visual Stimulation

46. Acknowledgements
• All
my
colleagues
at
the
Sir
Peter
Mansfield
Magne0c
Resonance
Centre,
and
especially
Sir
Peter
• Wellcome
Trust,
MRC,
EPSRC,
MS
Society
&
others
for
grant
support