Gioacchino Tedeschi Department of Neurological Sciences Second University of Naples Naples, Italy

Experimental Set-Up MR Image and Data Acquisition GE HDX 3.0T MRI Scanner AW1 Console Stimulation Exam Monitor Magnet 8-ch Coil Screen Physiological Monitor Post-Processing AW2 Linux x64 Win-XP x64 Linux x64 Win-XP x64

Experimental Set-Up MR Image and Data Acquisition LAB NETWORK Post-Processing

MR Image and Data Post-Processing Short-term Post-processing (GE diagnostic tools) XP-64 LINUX Cortical Thickness Atrophy VBM Lesion Study Functional MRI Connectivity RS-fMRI DTI Back-Up Functool Perfusion Diffusion Spectroscopy 2D-3D CSI Functool LINUX-64 Long-term Post-processing (Research tools)

MR Image and Data Post-Processing GE and Research tools Workstation Advantage Windows (GE Functool) –BrainWave (Real-time fMRI) –Diffusion (DTI, Tractography) –Perfusion (Dynamic Susceptibility Contrast) –Single-Voxel Spectroscopy / 2D-Chemical Shift Imaging –3D-Chemical Shift Imaging (SAGE) Workstation Linux x64 –FreeSurtfer (Cortical Thickness) –FSL / SIENA(X) (Atrophy, Voxel-Based Morphometry) –MIPAV (Lesion study) Worstation WinXP x64 –BrainVoyager QX (Functional MRI, DTI, Cortical Thickness) –SPM (Functional MRI, Voxel-Based morphometry) –TrackVis (Diffusion, DTI, Tractography)

fMRI - Blood Oxygenation Level Dependent fMRI task performance: motor visual cognitive Increased signal in T2* BOLD-response mapsSynaptic activity Decreased Deossi-Hb Increased metabolic activity Increased CBF Increased O 2 Increased CBV

~2s Functional images Time Condition 1 Condition 2... ~ 5 min Time fMRI Signal (% change) Condition Statistical Map superimposed on anatomical MRI image BLOCK DESIGN fMRI paradigm

Segmentation Cortex reconstruction Statistical localization of brain activation, functional maps Coregistration of functional and anatomical data Anatomical images Correction of head motion Spatial and temporal filtering Recorded time series (EPI) Group analysis I Talairach space Fixed effects Random effects Single subject analysis Spatial normalisation Functional MRI Flow Chart of Basic Analysis Steps

10 Controls 10 PD patients (Hoehn and Yahr Stage I and II) “practical” drug-off and drug-on “emotion task” Dopamine modulates the response to human amygdala: a study in Parkinson’s Disease Tessitore et al. J Neurosci 2002

fMRI Results L R N = 10; Hoehn and Yahr I-II; SPM 99, p<0.05 corrected Amygdala Possible role in psychiatric disorders in PD

Transient Components Sustained Components Right temporal lobe Left temporal lobe Heschl's gyri Anterior poles 0 20 Sustained components Transient components Spatio-Temporal Pattern of Neural Proceesing in the Human Auditory Cortex Seifritz et al Science 2002

Functional MRI Functional Connectivity (Functional Integration) y y x x y[t] x[t] y y x x When two regions are “functionally connected” the local fMRI signals (X and Y) are temporally correlated

From 2 regions to the whole brain (~70000 voxels) Independent Component Analysis (ICA) C#1 C#2 C#3 C#n Measured fMRI time-series Time (scans) The correlations between (groups of) voxels are extracted automatically based on the spatial independence of the networks (regions with the same time-course should not systematically overlap [McKeown et al., HBM 1998])

Resting-state components (15 healthy subjects, Mantini et al., PNAS 2007) Resting-State Functional MRI Analysis of “Spontaneous” Functional Connectivity Default-mode component (regions of de-activation during cognitve task, -> focused attention, “task-unrelated thought supprression”) Executive component (regions of activation during cognitive task, e.g. working-memory) Visual component (regions of primary visual activitation, e.g. foveal activity) Auditory component (regions of primary auditory activation) Sensori-motor component (motor pattern with primary motor cortex and supplementar motor area)

Stability and EEG correlates of RS networks ** ** ** ** ** ** * * * * * * Resting-State Functional MRI Analysis of “Spontaneous” Functional Connectivity

Group-level Analysis of ICA components High stability of the DMN component in the normal population Esposito et al NeuroImage 2005, Magn Reson Imag 2008 Resting-state Time-series (2mins, TR=2s, 10 healthy subjects, age < 50) Similarity study of ICA components in groups of subjects Component 2: Default-mode Network (high intersubject consistency) Single- subject Component

The “Default-mode” network (DMN) The main nodes of the DMN are in the Anterior and Posterior cingulate cortex (ACC/PCC) and right/left inferior parietal cortex (IPC) Typically, DMN also recruits bilateral Hyppocampus, Medial Pre-frontal cortex (MPFC) and infero-lateral temporal cortex (ILTC) ACC PCC R-IPC L-IPC HYPP ILTC MPFC

N-back task in 10 normal volunteers N-back task in 10 normal volunteers To investigate the possible spatial modulation or re- organization of the default-mode network when the cognitive engagement (load) of the subject was varied To investigate the possible spatial modulation or re- organization of the default-mode network when the cognitive engagement (load) of the subject was varied Esposito F et al., Brain Research Bullettin 2006 Independent component model of the default mode brain function: assessing the impact of the cognitive load Esposito F et al., Brain Research Bullettin 2006

0-back 1-back 2-back The network was globally stable in its architecture. However, a variable recruitment of the cingulate regions was observed under different conditions of load modulation when switching from lower to higher working memory loads.

EEG-fMRI Correlates of the default-mode function (Esposito et al., Magn Res Imag 2009, in press) Positive Change 3B>1B Tmin (P<5E-2) BOLD FMRI (Subject 1) Tmin (P<5E-2) Negative Change 3B<1B Tmax (P<5E-12) BOLD FMRI (Subject 2) Paramatric Theta Increase 3B>2B>1B THETA EEG (Subject 1)THETA EEG (Subject 2) T-STAT

Age < 50 N = 10 Age > 50 N = 10 DMN in the population: Effect of AGING Esposito et al. MRI 2008

Whole DM network ACC PCC L-IPC R-IPC L-ILTC L-H R-H L-MPFCR-MPFC R-ILTC Age VS Level of “RS Functional Connectivity” in DMN regions

Brain Connectivity Studies Anatomical connectivity A direct anatomical connection (Diffusion Tensor Imaging) Brain Functional connectivity: Correlations between (remote) active brain regions

Diffusion Tensor Imaging ADC mapFA map First Eigenvector (Anisotropy Direction) Fiber Reconstruction

Lesion studyAtrophy Cortical Thickness 0 CT [mm] 5

A Di Costanzo (Univ Mol) M Papa R Grassi G Cirillo S Bonavita A Tessitore A Gallo S Cirillo M Cirillo F Tortora F Esposito (Fed. II) A Aragri F Di Salle (Univ Pisa) B Alfano (CNR Napoli) JR Alger (UCLA) J Duyn (NIH) Centro Regionale di Competenza Diagnostica e Farmaceutica Molecolare