Multimodal Neuroimaging Course Overview

2012.10.30.

Multimodal Imaging in Neurosciences Course
COURSE FAQ

Forthcoming lectures:
16. October – „IGT lecture”
23. October – NO LECTURE, holiday
30. October – MR Spectroscopy
6. November – PET + Final Test

Test:
- Basic imaging techniques, what are they
- 5-10 easy, simple choice questions
Image guided therapies in - If November 6. is not good for everyone, I will organize extra
neurological sciences and VR time for getting the short test done

Dr. András Jakab, MD, PhD
Study material:
Lecture material will be distributed in PDF 2 wks before the
test.

Diagnostic neuroimaging modalities What is multimodality?
CT – Computed Tomography Structural MRI
Combining images and information from multiple
Brain anatomy Fine brain anatomy imaging tools, devices
Stereotactic reference frame Vascular structure
Anatomical alignment of images
Fusion display, co-analysis of multiple
Intra-operative imaging Diffusion, perfusion MRI information sources
modalities, open MRI, low- Fine pathological
field information
What is needed for multimodality?
Positron Emission multi-modal imaging for planning
Using
CT, PET, MRI, SPECT, EEG, …
MR Spectroscopy
Tomographyimage-guided neurological interventions
PET
Brain metabolism
Brain metabolism
Biochemical mapping
Hybrid devices – PET-CT, PET-MRI
Brain function
Image processing skills to create image fusions,
etc.
Electro encephalography,
Functional MR imaging fMRI
LORETTA,
Brain function
Magnetoencephalography

Overview of the lecture
1. Image guided therapy – basics
and the modalities used
2. Stereotactic functional
neurosurgery
3. Radiosurgery and planning
R di d l i 1.
1 Image guided therapy -
4. Focused ultrasound basics
neurosurgery
5. VR applications in surgery

1

2012.10.30.

Image guidance AMIGO – Harvard, Boston
• Using preoperative images
to define target volumes in
a reference space
Treatment planning w/ Intraoperative imaging with
• Using intraoperative preoperative imaging MRI

imaging to monitor
Surgical robot for biopsies
treatment
– Intraoperative
ultrasound
– Intraoperative low-field
MRI
– Intraoperative high-field
Intraoperative open MRI, Brigham
open MRI and Women’s Hospital, Harvard,
Boston (credits: Prof. Ferenc Jolesz)

Intraoperative MR imaging
• Medtronic Polestar
• Low field (0.1-0.3T)
• Brain shift – a real problem
• Use of nonmagnetic tools
2.
2 Stereotaxy in functional
neurosurgery

Why use stereotaxy in
What is stereotactic?
neurosurgery?
• Space, spatial
• Coordinate frame • Very high (<1-2mm) precision needed
of the brain: • Minimal invasive procedures
– Intrinsic – Electrode implantation for ablation
– extrinsic – Permanent electrode implantation (DBS)
– Biopsy sampling from the brain
• Procedures without opening the skull
– Radiosurgery, LINAC, Gamma Knife,
Cyberknife
– Focused ultrasound surgery

2

2012.10.30.

Brain biopsy Imaging for brain biopsy
• Indications • CT
– Tumor suspect (enhancing CT, MRI, lesion)
• MRI (T1/T2+Contrast)
– Inflammation, Neurodegeneration, unknown
• Pathology+Radiological
• Procedure (1-2 hours): consultation – where to take
– St
Stereo f
frame attachment
tt h t the sample f
h l from??
– Computed tomography
– Planning
– General anaesthesia
– Small craniotomy
– Dexamethasone
– Control scan(s)

Functional neurosurgery Thalamotomy / pallidotomy
• Parkinson disease – associated tremor
• Alleviating symptoms by modifying alleviation
functional areas of the brain, subcortical • Essential tremor (unkown ethiology)
areas
• Two main approaches:
– Permanently cutting fiber pathways,
destroying specific nuclei
Thermoablation
Targets:
– Retuning / stimulating fiber pathways, specific VIM nucleus
nuclei in the brain Subthalamic
Deep brain stimulation nucleus, PTT
Ventral Pallidum

Thalamotomy
• Fantom pain (after amputation)
• Intractable tumor / stroke pain in limbs etc.
• CL / CM nucleus – central lateralis / centré median

3

2012.10.30.

Deep brain stimulation (DBS)
• FDA approval:
1997
• Implant in brain
+ subcutaneous
stimulator
(~pacemaker)
• Retuning
functional
pathways
(„arrhythmia”)

Deep brain stimulation Procedure
• Indications: • Localization,
stereotaxy
– Chronic pain, PD tremor,
ET, dystonia • Electrode trajectory:
– Tourette, OCD, Major • Trials and
depression
d i monitoring
• Pre/postop imaging
– Parkinsons
• Subthalamic nucleus
• Globus pallidus interna
• Zona incerta
• Pallidothalamic fibers

Targeting scheme
Targeting scheme • 2. Defining targets on the patient’s coordinate frame (using CT+MRI)

• 1. Target definition using stereotactic atlas Manually finding AC,
of the human thalamus and basal ganglia PC points on scans

(histology) Finding landmarks of
the reference frame
(stereotactic frame
attached to the head)
Getting x,y,z
coordinates
for your
target

Reference:
AC-PC
coordinate
system

4

2012.10.30.

3. Radiosurgery

Gamma ART 6000N Rotating Gamma System
American Radiosurgery Inc., San Diego, CA,
USA Challenges
• Morphological imaging by MRI
– 3D isotrop voxel acquisitio
• Good tissue contrast
• Good signal-to-noise
•only 30 Co60 sources • Minimal image distortion
•Rotating sources
•Collimator size:
4, 8, 14, 18 mm
• Optimal image resolution
•Stereotactic frame required
•0,3 mm accuracy
– MRI as reference system?
•Source half-life approx. 5 yrs
• Robust CT method is necessary

Challenges of multimodality
– fMRI
– DTI, fibertracking
– MRS, MRSI
• Postprocessing
– Registration, image fusion (need fast)
• PET, SPECT

5

2012.10.30.

3D T1 weighted images 3D T2 weighted images
• 1,2x1,2x1,2 mm
• 140 slices • 0,7x0,7x0,7 mm
• 6 minutes • 40-60 slices
• Gd contrast agent • 4 minutes

Our imaging protocolls
3D TOF acquisition
• 1,2x1,2x1,2 mm
(+indications)
• 190 slices • Metastasis, meningeoma
• 6 minutes • AVM
• g
Gd contrast agent • Cavernoma
• Acustic neurinoma
• Hypophysis microadenoma

AVM MRA Automatic radiologic image processing

Automated CT/MRI registration
CT/T1/T2 (gammaknife, neurosurgery

automated
T1 standardization, segmentation
(neurosurgery, neurology)
ImageSorter
DICOM server

automated
Tensor space calculations and
DWI, T1 regularization

automated
automated
fMRI, T1, T2 SPM analysis
SPM analízis

automated
Pet & Mri PET-MR registration
and roi analysis

6

2012.10.30.

T1-CT registration for radiosurgery
(gamma-knife) Image registration, alignment
gamma knife

- Automatic (maximalisation relative entropy)
- Manual correction (with internal „landmarks”)
To this time, manual correction was necessary in 60% of
the cases
- Optimalised automatic registration

T1-CT Fiesta-CT TOF-CT

Extracranial metastasis Acoustic neurinoma treatment plan
(epipharynx)
• 1 kezelési tervet betenni

Acustic neurinoma

Pre-treatment 6 months post 12 months post

7

2012.10.30.

Trigeminal neuralgia
Treating trigeminal neuralgia CT and FIESTA imaging

Validation of the T1-CT optimized
Dataflow Service available via a DICOM-server
registration method
REFERENCE IMAGES AUTOMATICALLY
REGISTERED IMAGES

MNI and M3I tools: S01
BrainCAD:
•Dicom-minc conversion
• 2D fusion
•Segmentation Comparison using normalized
S02
•Automatic registration SPM-analysis • 3D fusion relative entropy
• Fiber visualization
•Spatial standardization
•Automatic region analysis
S03

AUTOMATIC INTERACTIVE Sn
PRESENTATION MRI data revision by experts
IMAGE PROCESSING IMAGE PROCESSING (neuronavigation) (occassionaly manual registrations)

Further fancy options CT-DTI registration
PET/SPECT images
T2, PD etc.

SPM images

Precise T1-CT registration

Structures defined in the space of a brain atlas
DTI parametric images

8

2012.10.30.

CT-DTI registration

9

2012.10.30.

Proton therapy

DTI + MRI data in the CT frame. Metastatic
disease, 55/M
( Gamma Radiosurgery Centre, Debrecen )

The proton advantage:
Medulloblastoma
PHOTONS “dose bath” Nasopharynx
Photons (IMRT) Protons

Dose bath
100%

60%
PROTONS

10%

The proton advantage:
Paraspinal
Photons Protons

Dose bath

4.
4 Focused ultrasound
neurosurgery

10

2012.10.30.

Energy Conversion and Transport in Biosystems (09.12.10)
Welcome
Non-invasive Beat Werner
MR-Center
Interventions University Children’s Hospital Zurich

with www.kispi.uzh.ch/mr
beat.werner@kispi.uzh.ch
beat werner@kispi uzh ch
Focused dipl. phys. ETH

Ultrasound MR-Physics
Beat Werner HIFU surgery since 2005,
MR-Center research project as part of NCCR Co-Me
University Children‘s Hospital
Zurich Slide credits: Beat Werner, Ernst Martin

Intro: Image guided interventions Intro: Image guided interventions
Image Guided Interventions
Improve accuracy
Decrease intervention risks
Minimally invasive / Non-invasive Interventions

Slide credits: Beat Werner, Ernst Martin Planning and navigation Complex interventions in cranio-maxillo-facial surgery.
Slide credits: Beat Werner, Ernst Martin

Intro: Image guided interventions Intro: Image guided interventions
"Multimodal" Imaging Enabling technologies used here:
Multimodal: US, CT, MR, ... MR
Multidomain: Anatomical, physiological, statistical Closed-loop intervention control
information US field calibration
Multi-Timescales: Static (Pre-/intra-intervention), Focused Ultrasound
Realtime Mechanical / Thermal therapy
Augmented reality: condition, fuse, model (Targeted) drug delivery
Enhanced visualization: 2D, 3D, ..., force feedback (Targeted) drug activation
Nano-Particles
Molecular markers
Contrast agents
Drug carriers
Computer-assisted support in ORL surgery Werner, Ernst Martin
Slide credits: Beat Therapeutic devices Beat Werner, Ernst Martin
Slide credits:

11

2012.10.30.

Motivation: Non-invasive HIFU Surgery
Non- Motivation: Clinical value of
MR guided Focused US Surgery
Excellent soft tissue contrast for
target localization
Local therapy
Non invasive
Non-invasive
No dose accumulation effects
No long term toxicity
Immediate result –
no radiation necrosis
Treatments can be repeated
Closed-loop image guidance
Real time monitoring

Imaging <-> Focused Ultrasound
<- Phased-
Phased-Array Transducers
Imaging (Diagnostics):
want wide field of view with Phased-Array Transducer = Array of Transducers
uniform low acoustic intensity Each transducer element controlled individually
Transducer phases define superposition pattern of
waves -> Electronic steering

HIFU (Intervention / Therapy): Constructive Destructive Shift
want small focal spot with
Slide credits: Beat intensity
high acoustic Werner, Ernst Martin Slide credits: Beat Werner, Ernst Martin

Beam Forming / Focusing Phased-
Linear Array -> Plane Wave
Geometric focusing Lens focusing

Electronic beam forming Electronic steering Spherical Array -> Focus

Slide credits: Beat Werner, Ernst Martin Slide credits: Beat Werner, Ernst Martin

12

2012.10.30.

Phased-
Phased-Array Transducers Phased-

Spherical Array
Spherical Array

Pressure Distribution Temperature Distribution
Electronic Steering


Biological Effects Medical applications
The effects of Ultrasound on biological tissue Lithotrypsy
are a field of active research Physiotherapy
Many effects are not well understood HIFU Surgery (Tissue ablation)
Effects include: Blood-Brain-Barrier-Opening
thermal
th l non-thermal
non thermal Cell sonoporation Targeted
g
mechanisms ultrasound mechanisms drug delivery
Local drug activation
energy non-cavitation mechanisms cavitation mechanisms Vessel occlusion
absorption
Thrombolysis
temperature
increase radiation force non-inertial cavitation inertial cavitation Nerve activation / blockage

ablation enhanced Delivery lithothripsy


Development of HIFU Technology Development of HIFU Technology

1880 Piezoelectric effect (P. & J. Curie)
1918 Sonar (Langevin) W.Fry, circa 1960, with 4-beam HIFU system for neuro-
4- neuro-
1927 Effects on biological tissues (Looms, Wood) surgery in his
1942 First HIFU lesions in animal brains (J.Lynn, T.Putnam) bioacoustics
1950–
1950–2000 Pioneer work on (a) HIFU effects on tissue (brain laboratory.
tumors) and (b) LIU for soft tissue visualization (W Fry
(W.Fry
& F.Fry).
1951–
1951–1960 Technical development at MGH (Cosman)
1951–
1951–1967 HIFU stereotactic neurosurgery against pain, psycho-
psycho-
neuroses, anxiety, depression and epilepsy (Lindstrom)
and Radiosurgery (Leksell) gamma knife
Mid 1970s
1970s First stereotactic HIFU brain surgery with open cranium
(F.Fry & R.Heimburger).


13

2012.10.30.

Development of HIFU Technology Image guidance
First US-image guided
HIFU system to treat US-Imaging
brain cancer patients. Cheap
W.Fry in the 1970s
Limited feedback
F.Fry and R.Heimburger 1974
MR
Expensive
High-resolution imaging
Closed loop process


Development of HIFU Technology HIFU Surgery for Uterine Fibroids
Key technologies:
1. Phased array transducers
2. Acoustic field modelling
3. MR imaging for accurate real time monitoring

Early 1990s
l 1990s
990 Ultrasound phased arrays (Hynynen)
l d h d ( )
Mid–1990s
Mid–1990s MRI thermometry (Jolesz)
2001 First integrated MRgHIFU system (InSightec)
2001 Fibroadenoma of Breast and Uterine Fibroids
2004 FDA approval for Uterine Fibroid Application
…
2008 Functional Neurosurgery


InSightec Exablate 2000 Treatment process for
Uterine Fibroids
InSightec Haifa, Israel benign (non-cancerous) tumors
Technology originally GE most common pelvic tumors in women
FDA approved 20-40% in women of reproductive age
First & only worldwide Classical procedure: Hysterectomy
GE MR-Scanners
Ca. 200 systems installed


14

2012.10.30.

Patient interface Transducer
16 element array Mechanical positioning
MR-coil
Patient vertical electronic steering 4 axes
focal depth 12cm – 19cm Computer controlled

Coupling Target

Ultrasound

MR-compatible
Transducer Ceramic step motors

Safety checks Treatment planning

Air bubbles? Delineate
Metallic clips? region of
Scars? treatment
Bowels? System creates
treatment plan
p
Bladder?
Bl dd ? (array of
Nerves? sonications
to be done)
Plan can be
changed
manually
by operator


Real-
Real-time temperature monitoring Treatment assessment
MR-Thermometry
Proton resonance frequency shift ~ Temperature
Phase difference ~ Temperature difference
1.1 seconds 4.5 seconds 7.9 seconds 11.3 seconds

Blue dots = Cell Treatment control by
ablation as calculated contrast enhanced MR
by thermal dose

Very good agreement

15

2012.10.30.

Closed loop control
MRgFUS = Magnetic Resonance guided
Focused UltraSound

Planing Safety Real-Time Assement
checks Monitoring

Closed Loop

Clinical applications and research Uterine fibroids
T1w contrast
enhanced image
before treatment
Brain Tumors Brain Functional

Breast Cancer T2w planning
Liver Tumors image with
Uterine Fibroids dose overlay
Prostate

Bone Tumors

T1w contrast enhanced image
Slide credits: Beat Werner, Ernst Martin Courtesy of Sheba Medical Center, Tel Aviv, Israel immediately post-treatment

Prostate Liver tumors

Treatment effects in canine prostate

Thermal dose T1w contrast TTC stained
estimate enhanced image tissue Sagittal, Axial and coronal post treatment dose
imaging
maps (in blue) and post treatment T1W+C
Courtesy InSightec Courtesy of St. Mary’s Hospital, London, UK

16

2012.10.30.

Caution-Investigational Device
Limited by United States Law IDE

Breast Cancer Bone tumors (Pain palliation)
to Investigational Use.

10.0
Screening
9.0
Average
8.0
7
7.0

VAS score
6.0

5.0
4.0 1 Month
Follow Up
3.0
1.5 3 Months
2.0
Pre treatment T1w+C 2 weeks post treatment 1.5 Follow Up
1.0
0 0
MIP image T1w+C MIP image 0.0
0 10 20 30 40 50 60 70 80 90

Days post treatment
Courtesy of Breastopia Namba Hospital, Japan Courtesy InSightec

Non-
Non-invasive neuro-surgery
neuro- Skull: Anisotropic Aberration
in the MR-suite
MR-

Focused waves … … are distrorted after skull

Phase corrected waves … … are refocused after skull
Courtesy of ESPCI, Paris, F

InSightec ExAblate 4000 Patient Interface
3D-Positioner Frontend Degassed water used for acoustic coupling &
Amplifier cooling
InSightec ExAblate 4000 /
3.0T GE Signa HDx
Stereotactic frame for patient immobillization
Hemispheric 1024-element
phased-array transducer Transducer Sealing membrane
(650kHz)
Stereotactic frame
Water cooling of skull
surface
CT-based acoustic modeling
PRS-Thermometry
Transducer
Installation June 2006

Water Stereotactic frame

17

2012.10.30.

MRI-
MRI-HIFU Console Clinical phase I study
Centro-Lateral Thalamotomy against
chronic, therapy resistant, neuropathic
pain
Established procedure: RF-ablation
o minimally invasive
o n (pain) > 100 interventions

New procedure: Non-invasive TcMRgHIFU
o Minimize intervention risks (Collateral
damage, infections, bleeding, tissue
shift)
o Enhanced efficacy (no trajectory
restrictions, anatomically adapted
volume ablation, image guidance)
o Outpatient process

Bildfolge der Behandlung (sonication procedure) Bildfolge der Behandlung (sonication procedure)

X+20’: Stereotactic frame X+50: Positioning

X+1h20: Imaging X+3h: Verification sonications

18

2012.10.30.

X+3h: Verification sonications X+4h: Ablation

Dosemap 17 CEM 43°C
43°

Dosemap 240 CEM 43°C
43°

X+6h: End of treatment

Patient #4
#4 Patient #2
#2
immediately after 48 h after
the intervention the intervention

Trigeminal neuralgia Chronic lumbar pain syndrome
following disc hernia op L4/L5
L4/L5
X+7h: Happy End Slide credits: Beat Werner, Ernst Martin

19

2012.10.30.

Patient #4
#4 Patient #2
#2 Patient #4
#4 Patient #2
#2
immediately after 48 h after immediately after 48 h after
the intervention the intervention the intervention the intervention

T1WI + Gd T1WI + Gd DTI DTI

Combined Tumor therapy: Blood Brain Barrier
HIFU-
HIFU-Ablation & LIFU BBBD Brain protected by BBB:
Tumorvolume Structural and functional barrier in the vessel walls
Controls transport and diffusion from the
HIFU-
HIFU-Ablation vasculature to the central nervous system
Severely limits ability to deliver drugs to the brain

McDannold et al.
Neurosurgery 2010

BBB-
BBB-Opening with Low Intensity
Focused Ultrasound (LIFU)
and Adjuvant Chemotherapy

Reversible BBB-Disruption using
BBB- TcMRgFUS BBB-Disruption
BBB-
FUS and Microbubble UCA US freq. 220kHz – 1MHz
Microbubbles Lipid
monolayer Acc.Power < 1W
Phospholipid / Hexafluorid (2-4um) Sonication 10 – 200s
Commercial CE / FDA Duty cycle 1%
Tail vein injection
MR-contrast agent /
drug
Micro bubbles
Inj. Drug

Inj. Micro bubbles
Histo
MRI

MRI

Reversible opening of BBB by Low Intensity US
Cavitation (Bursts of 10ms/1000ms)

Shear stress (Acoustic streaming,
radiation force, ...)

20

2012.10.30.

TcMRgFUS BBB-Disruption
BBB- TcMRgFUS BBB-Disruption
BBB-
Duration
MR-Scanner: GE 3.0T several hours
Transducer: Imasonic (Aperture 8cm, f# 0.8)
Application
Microbubbles: Bracco
Neuro-
Positioner
P iti MR-Coil
MR C il Phamacology
Tumors
Alzheimer
Neuron
regeneration

Transducer Watertank Mouse

Targeted Drug Delivery
Targeted Drug Delivery Targeted Drug Delivery
Target specific
Carries contrast agents (Dye, fluorescent, magnetic, ...)
Carries drugs
Remote activation

Bubble constructs
Add specificity
Add payload
Remote activation

Targeted Drug Delivery Gene Delivery
Releasing drug by Ultrasound
Heat
Cavitation

21

2012.10.30.

Gene Activation: hsp-80
hsp- Summary
Image guided FUS is a new modality for non-invasive
interventions deep in soft tissue
Thermal ablation clinically established
Intense research on treatment strategies based on
mechanical effects
Very promising results in animal models for targeted
drug delivery based on transient BBBD / Sonoporation
Intense research on development of nano-constructs
for imaging and therapy
Clinical studies to come soon


Clot Lyses for Stroke
Outlook
Thank you !
Neurological
Disorders
Targeted Drug Delivery

In-vitro T2W MRI before
[l] and after[r] sonication


Thank you for your attention!
Presentation credits:

Dr. András Jakab, M.D. Ph.D.
Dr. Ervin Berényi, M.D. Ph.D.
Dr. Miklós Emri (Nuclear Medicine Institute, UD)
Prof. Ernst Martin – Uni. Zürich (Focused Ultrasound)
Beat Werner – Uni. Zürich (Focused Ultrasound)

22

Multimodal Neuroimaging Course Overview

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