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

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  

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Composite ROI Inclusion ROI

ΔR

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Composite ROI Inclusion ROI

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Composite ROI Inclusion ROI

Field dependence of ΔR2*/R2*

Field dependence of fMRI responses

pcorr < 0.05 for motor task

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TE (ms)

7 T3 T1.5 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)

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

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

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)

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

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

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

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)

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2

salinemorphine

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salinemorphine

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hang

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% c

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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

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Cingulate cortex

Effects of morphine injection

MEG at the SPMMRC

w1

w2

w3

w275

m1

m2

m3

w1 m1 + w2 m2 + w3 m VE = 3+

m275

MEG beamformer

Vq=Σi=1..275wqimi

Σ

virtual electrode output

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)

MEG  responses  

0 500 1000 1500 2000 2500 3000 3500 4000 4500 50000.5

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Samples

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th Q

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Hilbert Transform of VE timecourse from peak of gamma 60-80Hz Subj2

•  Evoked response

•  Gamma band ERS

•  Beta band ERD and ERS

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)

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MEG Contrast Response Curves

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  

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 8s 2, 5 or 8 letters: 1 letter presented

every 1.4s

C

1.4s 2s

REL

AX

PRO

BE

N-BACK

STERNBERG TARGET

N-back and Sternberg paradigms

8

7

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itive

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Theta (4-8 Hz) activity during N-back (upper) and Sternberg (lower) paradigms. Group effect.

Gamma (20-40 Hz) activity during N-back (upper) and Sternberg (lower) paradigms Group effect

8

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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

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)

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 P e r i o d

Probe Stimulus

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

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 neuron Astrocyte

TCA Cycle

TCA Cycle

TCA Cycle

Brain Neurotransmission

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  

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•  Third level •  Fourth level •  Fifth level

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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)

7T 1H Spectrum

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The stimulus consists of radial white/black prisms covering the entire visual field and reversing at a frequency of 8Hz.

Visual Stimulus

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

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•  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

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