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 Functional MRI
Functional CNR
ΔS/N = SNR . ΔR2* / R2* 7T MPRAGE, 0.5mm isotropic resolution, SENSE factor 2, acquisition time 11 mins for
the whole head
ΔR2* maps as a func0on of strength 1.5T
5 s-1
3T
0.39 s-1
5 s-1
7T
0.39 s-1
5 s-1
0.39 s-1
Field dependence of ΔR2*/R2*
Composite ROI
0.1
ΔR2*/R2*
omposite 0.08
ROI
Inclusion ROI
Composite ROI
Inclusion ROI
Inclusion ROI
0.1
0.06 0.08
0.04 0.06
0.02 0.04
0 0.02
0 0
1
0
1
2
3
4
2
1
5
Field Strength (T)
6
3
4
5
6
7
Field
Strength
2
3
4
5(T) 6
7
Field 8Strength (T)
7
8
8
Field dependence of fMRI responses
pcorr < 0.05 for
motor task
0.14
7T
3T
1.5 T
0.12
0.1
ΔS/S
0.08
0.06
0.04
0.02
0
0
20
40
60
80
100
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.
TE (ms)
W. van der Zwaag, S. Francis, K. E. Head, A. Peters, P. Gowland, P. Morris and R. Bowtell, Neuroimage 47, 1425-1434 (2009)
High resolution somatosensory mapping at 7T
ventral
2
3
4
5
right
1
dorsal
anterior
posterior
1-thumb
2-index
3-middle
4-ring
5-little
Relating structure to function in the visual cortex at 7T
fMRI
lateral
medial
Rotating wedge
1.5 mm isotropic resolution
Structural
posterior
structural
Stria of
Gennari
seen as a
dark band
Resolution:0.35x0.35x1.5mm3
V1
functional
anterior
Resting state networks Correlation coefficients for sensorimotor and default mode resting
state networks
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
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)
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
Probe
Stimulus
P e r i o d
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)
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 Rat Model of Persistent
Nociception
Intraplantar injection of formalin into rat
hindpaw
Ascending and descending pain pathways
Formalin evoked increase in BOLD response
hl fl
Hindlimb area of
Somatosensory
cortex
vl
Thalamus
Amygdala
vpm
vpl
P<0.001
a
P<0.01
PAG
PAG
P<0.05
P.G. Morris, J. Psychopharm. 13 (4), 330-336 (1999)
% change in signal intensity
2
Periaqueductal
gray
1.5
1
morphine
saline
0.5
0
10
20
30
40
50
60
70
80
90
100
110
120
130
140
150
160
170
180
Time in minutes
-0.5
Cingulate cortex
2
1.5
1
morphine
saline
0.5
0
10
-0.5
20
30
40
50
60
70
80
90
100
110
120
Time in minutes
130
140
150
160
170
180
% change in signal intensity
% change in signal intensity
Effects of morphine injection
2
Thalamus
1.5
1
morphine
saline
0.5
0
10
-0.5
20
30
40
50
60
70
80
90
100
110
120
130
140
150
160
Time in minutes
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
170
180
MEG at the SPMMRC
MEG beamformer
w3
m3
w275
w2
m2
m275
m1
Vq=Σi=1..275wqimi
Σ
w1
virtual electrode output
VE = w1m1+ w2m2+ w3m3+
Retinotopic mapping using MEG
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
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)
MEG responses •  Evoked response
•  Gamma band ERS
•  Beta band ERD and ERS
Hilbert Transform of VE timecourse from peak of gamma 60-80Hz Subj2
3
Source Strength Q(nAm)
2.5
2
1.5
1
0.5
0
500
1000
1500
2000
2500 3000
Samples
3500
4000
4500
5000
Multimodal imaging: fMRI / MEG
MEG
fMRI
7T BOLD
T>6
3T BOLD
T>5.5
β-band ERS
(15-30Hz)
Ŧ>1.2
β-band ERD
(15-30Hz)
Ŧ>1.2
VEP
Ŧ>5
γ-band ERS
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)
(60-80Hz)
Ŧ>4
MEG Contrast Response Curves
1.1
1.1
Normalised Gamma Response
Normalised VEF Response
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
A
0
-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
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
-0.1
-0.1
B
Normalised Beta ERS Response
Normalised Beta ERD Response
0.1
0
-0.1
-0.2
-0.3
-0.4
-0.5
-0.6
-0.7
-0.8
-0.9
C
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
1.1
0.8
0.9
1
1.1
Michelson Contrast
1
0.2
-1
-0.1
0
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
Michelson Contrast
0.8
0.9
1
1.1
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
D
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
Michelson Contrast
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)
Working memory N-back and Sternberg paradigms
N-BACK
TARGETS
A… H S S G V D
P… X S S D V K
D… H Y R D V D
1-BACK
0-BACK
2-BACK
0
32
RELAX
96
64
126
Time (s)
STERNBERG
TARGET
RELAX
LETTER
PRESENTATION
1.4s
2, 5 or 8 letters: 1
letter presented
every 1.4s
MAINTENANCE
8s
PROBE
C
A D Y C Y M S P
2s
RELAX
8s
Time (s)
Number of
Subjects
Positive Change
Negative Change
8
7
Number of
Subjects
Positive Change
Negative Change
8
5
Theta (4-8 Hz) activity during N-back (upper) and Sternberg (lower)
paradigms. Group effect.
Number of
Subjects
Positive Change
Negative Change
8
7
Number of
Subjects
Positive Change
Negative Change
8
7
Gamma (20-40 Hz) activity during N-back (upper) and Sternberg (lower) paradigms
Group effect
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)
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)
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)
Resting state networks: MEG
Brookes et al. PNAS 108 (40): 16783-16788 (2011)
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
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
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
Probe
Stimulus
P e r i o d
Sternberg Working Memory Task
Primary visual areas
Medial Parietal cortex
Lateral visual areas
Bilateral TPJ
Bilateral Insula network
Right Motor Cortex
Fronto-parietal network
Left Motor Cortex
Time frequency plots for 8 networks associated with Sternberg paradigm
Brain Neurotransmission
Pathways of Glu/Gln and GABA/Glu/Gln Cycling"
Glutamatergic neuron
Astrocyte
GABAergic neuron
Glu
TCA
Cycle
Gln
Glu
Gln
Gln
Na+
GABAc
GAD65
GABA
TCA
Cycle
Glu
TCA
Cycle
GAD67
GABA
Na+
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 1H
MRS Repeatability: %CVs
Click to edit Master title style
•  Click to edit Master text styles
•  Second level
NAA
Glu
Gln
mI
GABA
Cr
Cho
•
Third
level
7T sh
3 (2)
4(2)
10(6)
9(3)
10(6)
3(2)
5(4)
3T sh
5(3)
8(6)•  Fourth
29(11)
8(4)
level21(14) 10(4) 16(16)
7T long
6(6)
10(6)
29(19)
19(10)
16(8)
7(6)
8(6)
Fifth 22(10)
level36(25) 22(13) 8(7)
3T long
6(6)
16(9) •  32(30)
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)
40
7T 1H Spectrum
Visual Stimulus
Click to edit Master title style
•  Click to edit Master text styles
•  Second level
•  Third level
•  Fourth level
•  Fifth level
The stimulus consists of radial white/black prisms covering the entire visual
field and reversing at a frequency of 8Hz.
42
SCmulaCon induced changes in metabolite levels determined by 1H MRS Lin et al., under revision for JCBFM
Time courses of
metabolite changes
during visual
stimulation
Lin et al., under revision for JCBFM
1H
MRS Changes due
ClickStimulation
to edit Master title style
to Visual
•  Significant decrease in Glc
–  Increased glucose consumption during stimulation
•
•
•
•  Click to edit Master text styles
Significant increase in
•  Lactate
Second level
–  Increased rates of glycolysis and TCA cycle
•  Third level
Suppression of second lactate response to stimulation
•  Fourth level
Significant increase in Glutamate,
decrease in Glutamine and trend
•
Fifth
level
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
45
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