Multimodal Approaches to Functional Neuroimaging

Sir Peter Mansﬁeld Magnec Resonance Centre

University of Nongham, UK

FP7 Neurophysics Workshop Pharmacological fMRI Warwick Conference Centre, 23 January 2012

Mulmodal approaches to funconal 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 funcon of strength

-1 1.5T 5 s

0.39 s-1 3T 5 s-1

0.39 s-1 7T 5 s-1

0.39 s-1 Field dependence of ΔR2*/R2* Composite ROI Inclusion ROI

0.1 Composite ROI Inclusion ROI Composite 0.08ROI Inclusion ROI 0.1

0.1 *

2 0.06 0.08 /R * 0.08 2 R 0.04 0.06 Δ 0.06 0.02 0.04 0.04 0 0.02 0.02 0 0 1 2 3 4 5 6 7 8 0 0 1 Field2 3Strength4 5(T) 6 7 8 0 1 2 3 4 5 6 7Field 8Strength (T) Field Strength (T) Field dependence of fMRI responses

pcorr < 0.05 for motor task

0.14 7 T 3 T 0.12 1.5 T Motor task (8 s ON; 20 s off; 5 0.1 cycles) 0.08 Same 6 subjects scanned at 0.06 S/S Δ 0.04 1.5, 3 & 7 T 0.02 Data co-registered across fields 0 and echo times. 0 20 40 60 80 100 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

3 2 4 5 1 right

dorsal

little anterior 1-thumb 2-index 3-middle 4-ring 5-

posterior Relating structure to function in the visual cortex at 7T

lateral fMRI medial

Rotating wedge 1.5 mm isotropic resolution

Structural posterior anterior structural

Stria of Gennari seen as a dark band V1

functional Resolution:0.35x0.35x1.5mm3 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 Visual Probe Stimulus 1 Stimulus 2 Stimulus

M a i n t e n a n c e 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 – Differenaon between direct and acvity 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 vpm ThalamusThalamus vpl

P<0.001 a Amygdala

P<0.01

PAGPAG

P<0.05

P.G. Morris, J. Psychopharm. 13 (4), 330-336 (1999) Effects of morphine injection

2 2 Periaqueductal Thalamus 1.5 gray 1.5

1 morphine 1 saline morphine saline

0.5 0.5

0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 Time in minutes

% change in signal intensity -0.5 -0.5

% change in signal intensity signal in change % Time in minutes

2 Cingulate cortex An acute high dose of

1.5 morphine (5mg/kg, IP cannula) evoked significant 1 morphine saline increases (p<0.002) in 0.5 BOLD response in the PAG,

0 thalamus and cingulate 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 cortex -0.5

% change in signal intensity intensity signal in change % Time in minutes MEG at the SPMMRC MEG beamformer

m3 w 2 Σ w275 m2

m275 w1 m1

V = w m q Σi=1..275 qi i virtual electrode output w m VE = 1 1+ w2m 2+ w3m 3 + 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

2.5

1.5 Source Strength Q(nAm) Strength Source

0.5 0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 Samples Multimodal imaging: fMRI / MEG fMRI MEG

β-band ERS (15-30Hz) 7T BOLD Ŧ>1.2 T>6 β-band ERD (15-30Hz) Ŧ>1.2

3T BOLD VEP Ŧ>5 T>5.5 γ-band ERS (60-80Hz) M.J. Brookes, A.M. Gibson, S.D. Hall, P.L. Furlong, G.R. Ŧ>4 Barnes, A. Hillebrand, K.D. Singh, I.E. Holliday, S.T. Francis, P.G. Morris, Neuroimage 26 (1), 302-308 (2005) MEG Contrast Response Curves

1.1 1.1 1 1 0.9 0.9 0.8 0.8 0.7 0.7 0.6 0.6 0.5 0.5 0.4 0.4 0.3 0.3 0.2 0.2

Normalised VEF Response Normalised 0.1

0.1 Gamma Response Normalised 0 0 -0.1 -0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1.1 -0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1.1 A Michelson Contrast B Michelson Contrast

0.2 1 0.1 0.9 0 0.8 -0.1 0.7 -0.2 0.6 -0.3 0.5 -0.4 0.4 -0.5 0.3 -0.6 0.2 -0.7 0.1 -0.8 0 Normalised Beta ERS Response Beta Normalised

Normalised Beta ERD Response Beta Normalised -0.9 -0.1 -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 -0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1.1 C Michelson Contrast D 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 RELAX

0 32 64 96 126 Time (s) STERNBERG TARGET

A D Y C Y M S P C

LETTER MAINTENANCE RELAX RELAX RELAX

PRESENTATION PROBE

2, 5 or 8 letters: 1 8s 8s Time (s) 1.4s letter presented 2s every 1.4s Number of Subjects 8

PositiveChange Negative Change NegativeChange 7

Number of Subjects 8

PositiveChange Negative Change NegativeChange 5

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

Number of Subjects

Positive Change PositiveChange NegativeChange 7

Number of Subjects

Positive Change PositiveChange NegativeChange 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

Visual Visual Probe Stimulus 1 Stimulus 2 Stimulus

M a i n t e n a n c e 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 GAD67

TCA GABAc TCA Gln Gln Gln Cycle GAD65 Cycle TCA Cycle GABA Glu Glu GABA Na+ Na+ Advantages of high ﬁeld for MRS

• Increased SNR (~ B0) – improved spaal resoluon – shorter scan mes • Increased spectral resoluon • Simpler spin coupling paerns – 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 • ThirdGln levelmI 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) • Fourth29(11) 8(4) level 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)Fifth 22(10)level 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) 40 7T 1H Spectrum ClickVisual to Stimulus 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

Smulaon 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 to VisualClick Stimulation to edit Master title style • Significant decrease in Glc – Increased• Click glucose to consumptionedit Master during text stimulation styles

• Significant increase in• LactateSecond level – Increased rates of glycolysis and TCA cycle • Third level • Suppression of second• lactateFourth response level to stimulation

• Significant increase in Glutamate,• Fifth leveldecrease 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 45 Acknowledgements

• All my colleagues at the Sir Peter Mansﬁeld Magnec Resonance Centre, and especially Sir Peter

• Wellcome Trust, MRC, EPSRC, MS Society & others for grant support