Experimental Methods: Theory and Application of … · Theory and Application of Functional...

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Experimental Methods:Experimental Methods:Theory and Application ofTheory and Application ofFunctional Functional NeuroimagingNeuroimaging

Emiliano RicciardiLaboratory of Clinical Biochemistry and Molecular Biology,

University of Pisa, Italy

emiliano.ricciardi@bioclinica.unipi.it

10th International Training Seminar in Child & Adolescent PsychiatryJune 23‐28, 2013 - Monastero Santa Croce, Bocca di Magra, Italy

Pietrini et al. Am J Psychiatry 2003;160:1907-1908

Functional Imaging Evolution

Friston K., Science 2009

• Bioengineering• Statistics• Physics

• Psychology• Neurology• Pharmacology

• Marketing/Business• Moral and Ethics• Law

In vivo brain functional methodologies

• Qualitative and functional characterization

Functional Brain Imaging : Advantages

• Dissection of the different steps of information

processing

CentralExecutive

Phonologicalloop

EpisodicBuffer

VisuospatialSketchpad

LanguageLong-termMemory

SemanticMemory

• Versatile approach (e.g. variation of acquisition parameters, experimental modulation, pharmacological probing, etc.)

1 s delay 6 s delay

11 s delay 16 s delay

Functional Magnetic Resonance Imaging : Advantages

• Correlation with different diagnostic tools

Pietrini et al., Am J Psychiatry 1999

White et al., Field Strenght 2008

Peripheral parameters Peripheral parameters (HR, SCR, etc.),(HR, SCR, etc.),neuropsychological neuropsychological characterization, characterization, behavioral measuresbehavioral measures

Structural dataStructural data (e.g. (e.g. anatomy, fiber tracking, anatomy, fiber tracking, cortical thickness, etc.)cortical thickness, etc.)

• Acquisition of original information

Haxby et al., Science 2001

Why in vivo?1. in vitro and in vivo differences2. Anatomical ‘constraints’

Functional neuroimaging

Why in vivo?3. Functional segregation and integration

Why in vivo?4. Limitations

of animalmodels

The legacy of Angelo Mosso

Angelo Mosso (1881):Concerning the Circulation of the Blood in the Human BrainVerlag von Viet & Company: Leipzig, pages 66-67

Petzold e Murthy, Neuron 2011

The cerebrovascular unit:where the ‘signal’ comes from

↑ Neuronalsynapticactivity

↑ ActivityNa+/K+

↑ ATPRequest

↑ Glucoseand

oxygenrequest

↑ Cerebralbloodflow

sypply

↑ Glucoseoxydative

metabolismand ATP

production

EEG, MEG, TMS

EEG, EEG, MEG, TMSMEG, TMS

H215O‐PET,

fMRI, ASLHH22

1515OO‐‐PET, PET, fMRIfMRI, ASL, ASL

18FDG‐PETsMRI

1818FDGFDG‐‐PETPETsMRIsMRI

The cerebrovascular unit:where the ‘signal’ comes from

Positron Emission Tomography

Positron-emitting nuclides (es. 18Fluoride, 15Oxygen)

• Resting condition

• Visual stimulation

occhi chiusi 1 occhio 2 occhi scenacomplessa

60Corteccia Visiva

18FDG -glucosio

18F-fluorodopa

18F-fluoroetilspiperone

Towards a biochemistry of mind?

Borg et al., Am J Psychiatry, 2003

Positron Emission Tomography:single patient evalutation

GROUP A GROUP B

RESULTS

SPATIALREALIGNMENT

ANDNORMALIZATION

(e.g. MNI, TalairachAtlas)

STATISTICALEVALUATION

(ANOVA, T-TEST, CORRELATION)

Positron Emission Tomography:Group comparison

((DrevetsDrevets e e collcoll., 2000)., 2000)

Positron Emission Tomography:Group comparison

TASK REST DIFFERENCE

STATISTICAL AVERAGE

SPATIAL NORMALIZATIONINDIVIDUAL DIFFERENCES

Positron Emission Tomography:Task condition comparison

Calarge et al., Am J Psychiatry, 2003

Magnetic Resonance Imaging Structural

Functional

Diffusion Spectroscopy

And much more, such as perfusion, angiography, ASL,

CDI, SWI, etc. Modified from Brain Imaging Center website

Neural activity oxyhemoglobin fMRI signal

MRI fMRI

Single image

Several images(e.g, every 2-3 s for 5 minutes)

High resolution(1 mm)

Low Resolution(~3 mm)

fMRIRelies on Blood Oxygenation Level Dependent (BOLD)

MRI vs. fMRI

Scanner and tissue-related parameters influence image acquisition

T2WT2W

PDWPDW

T1WT1W

What does happen to oxygen use?

BOLD: Blood Oxygenation Level Dependent

BOLD Contrast Imaging

BASELINEBASELINE

ACTIVATIONACTIVATION

L. Pauling, C. D. Coryell, PNAS, 1936.K.R. Thulborn, J. C. Waterton, et al., Biochim. Biophys. Acta., 1982S. Ogawa, T. M. Lee, A. R. Kay, D. W. Tank, PNAS, 1990.

deoxyHb

Oxygenated and deoxygenated hemoglobin have different magnetic properties

deoxyhemoglobin T2* MR signal

blood flow deoxyhemoglobin T2* MR signal

Data analyses (Data analyses (postprocessingpostprocessing))

reconstructionreconstruction registrationregistration smoothingsmoothing

RationaleRationale: define your : define your hypothesishypothesis

Preprocessing and Preprocessing and experimental sessionexperimental session

Results interpretation, Results interpretation, correlation with behavioral correlation with behavioral and clinical findingsand clinical findings

Experimental paradigmExperimental paradigm

Subject selection and Subject selection and screeningscreening

Experimental brain Experimental brain imaging flow chartimaging flow chart

Measuring skin conductance and peripheral parameters (e.g. EKG, pO2)

Visual, tactile and aural stimulation with MR-compatible devices

Movement control

Functional MRI experimental setup

1. Block Design

2. Mixed Block Design

3. Slow Event-Related

4. Fast Event-Related

5. Self-Paced

6. Sparse intermixed

Different strategies to neural recruitment

STIMULI – ACTIVATIONNO STIMULI - BASELINE

BASELINEBASELINE

ACTIVATIONACTIVATION

Overview of Analysis/1

MotionCorrection

Smoothing

SpatialNormalisation

General General Linear Linear ModelModel

fMRI time-series Design matrix

Anatomical Reference

•Conventional analysis of fMRI data focuses on finding macroscopic brain regions that are involved in specific mental activities•After reconstruction, the output of the scanning session consists of a series of 3D images of the brain

• Correction for head motion and physiological effects, spatial and/or temporal filtering (smoothing) are generallyapplied

• A variety of methods are usedto correlate the voxel time series with the task in order toproduce maps of task-dependent activation (e.g. common hypothesis-driven methodspredict the shape of the response to the stimulus, and calculate correlationcoefficients between each pixel time course and this reference waveform)

Cortical surface representation of specific neural patterns

2D3D surfingROI analyses

Correlation analysis though modeling the hemodynamicresponse

Significant correlationsare reported as

‘activated’ voxels

Once you get you stimulus-specific response:

•Connectivity: structural, functional and effective

•Psychophysiological interaction: correlations with

behavioral/clinical/peripheral measures

•Multivariate and machine learning approaches

• Signal variability and complexity measures

Different steps of a research line...

Gentili et al., Brain Res Bull, 2008

What fMRI Can Do(routine fMRI)

Help in understanding healthy brain organization-map networks involved with specific behavior, stimulus, or performance-characterize changes over time (seconds to years)-determine correlates of behavior (response accuracy, etc…)

Current Clinical Applications-presurgical mapping

Current Clinical Research-assessment of recovery and plasticity-clinical population characterization with probe task or resting state

Courtesy of Peter Bandettini

What fMRI Can’t Do(what are the problems with fMRI?)

•Too low SNR for routine clinical use (takes too long)

•Requires patient cooperation (too sensitive to motion)

•Too low spatial resolution (each voxel has several million neurons)

•Too low temporal resolution (hemodynamics are variable and sluggish)

•Too indirectly related to neuronal activity

•Too many physiologic variables influence signal

•Requires a task (BOLD cannot look at baseline maps)

•Too confined space and high acoustic noise.

Courtesy of Peter Bandettini

Looking to the future…

Technology

Applications

Metodology

Interpretation

BOLD Contrast Imaging…

StimulusNeuralActivity

BloodVolume

OxygenMetabol.

BloodFlow

[Hb] change

BOLDRESPONSE

InterpretationInterpretation

Stimulusprocessing,

sensory deficits,

compliance to the task and to

MR environment

Disease-related aspects that could affect BOLD signal

Neuronal loss, brain

atrophy, etc.

Angiopathy

Drug modulation,

aging-related disorders,

Sereno et al.@3T, 1995

Yacoub et al.@7T, 2008

HighHigh--field MRIfield MRITechnologyTechnologyRetinotopyRetinotopy

The The ‘‘boostboost’’ of novel of novel analytical approachesanalytical approaches

AnalyticalAnalytical

Decoding techniques

Action Non-action

Stimuli presentation

Non-action Action…

Action Non-action Non-action Action…

Patterns of brain activity

Training set

Action Non-action Non-action…

Test set

Classifierf(v)

Accuracy of classification

Hierarchical clustering

Action Non-action Non-action Action…

Similarityof

representation

Actions Non-actions

Classification principle

Discriminationmaps

“[…] the DSM diagnoses are based on a consensus about clusters of clinical symptoms, not any objective laboratory measure. […] Indeed, symptom-based diagnosis […] has been largely replaced in the past half century as we have understood that symptoms alone rarely indicate the best choice of treatment.”, Tom Insel, NIHM Director

Memory disorders (e.g. Alzheimer)

Mood disorders (e.g. depression)

Language disorders

Poldrack et al., 2012, Plos Comp Biol

Research Domain Criteria to assess CNS disorders?

languagedisorders

mood/anxiety disorders and

drug abuse

psychotic and externalizing

disorders

autism and memory

disorders

The restless brainThe restless brainApplicationsApplications

From imaging to From imaging to imagenesimagenesApplicationsApplications

What fMRI May Do

Complementary use for clinical diagnoses-utilization of clinical research results for diagnoses-prediction of pathology

Clinical treatment and assessment of therapy-better understanding mechanism of pathology for focused therapy--understanding of drug effectunderstanding of drug effect-assessment of therapy progress, biofeedback-epileptic foci mapping-neurovascular physiology assessment

Non clinical uses-lie detection-prediction of behavior tendencies -brain/computer interface

cellular

nanomolecular

brain areas

social

In vivo brain functional methodologies In vivo brain functional methodologies

Pietrini et al. Am J Psychiatry 2003;160:1907-1908

Experimental Methods: Theory and Application of … · Theory and Application of Functional...

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