PAN Komitet nauk neurologicznych – WARSZAWA 2014 THE HUMAN BRAIN PROJECT and how neuroimaging will contribute Richard Frackowiak (CHUV & EPFL Lausanne) MOTIVATION 1 Alzheimer’s disease: 2 people out of 10 concerned beyond the age of 80; dependency occurs within 3 to 5 years after the disease has appeared. Depression: the second most common condition in the world according to the WHO: it concerns 6 per cent of the population in the Western world. Cerebral vascular accidents: the first cause of motor disabilities in adults. 75 per cent of victims suffer from residual disability. Parkinson’s disease: second cause of motor disability. It affects 2 out of 1,000 people. Multiple sclerosis: concerns mainly young people and leads to a loss of autonomy in 30 per cent of cases. Epilepsy: 50 million people concerned in the world of which almost half bebefore age 10. The social and familial repercussions are lifelong. CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD CLINICAL NEUROSCIENCE AT A TIPPING POINT SYNDROMIC DIAGNOSIS REACHED ITS LIMITS HUMAN GENOME MODERN NEUROIMAGING MODERN NEUROSCIENCE MODERN INFORMATION TECHNOLOGY MODERN MATHEMATICS MECHANISTIC/CAUSAL DIAGNOSIS CLINICAL SYNDROMES AND FINAL PATHOLOGY IN CASES BEGINNING WITH FTD Kertesz et al, Brain 2005 ALZHEIMER’S DISEASE - DO WE NEED TO THINK AGAIN? WHAT CAUSES IT? What mechanisms? Role of genes? Abnormal proteins – amyloid? Abnormal neurotransmission – acetyl choline? What pathophysiological abnormalities are causes and which effects? HOW DO WE PREVENT IT? AND TREAT IT? Can we diagnose it? - NO Do symptoms matter? - A LITTLE What weight to pathology? - END STAGE Do we compensate? - REDUNDANCY What about pre-symptomatic diagnosis? - ??? Why don’t the treatments work? - TREAT WHAT And what about preventive treatment? - ??? THE DECLINING INTEREST OF PHARMA 4. 3. 2. 1. check Reality 5. 4. 3. 2. 1. lack we What Benefits for society beseem society to for Benefits increasingly is and knowledge Data exponentially is and knowledge growing Data based classification of diseases based classification symptom No plan go beyond to human animal to from knowledge transfer No plan to levels No planlink across to No data plan No integration to rapidly increasing burden Economic drugs) treatments, decreasing curation unsustainable (diagnostic accuracy, accuracy, (diagnostic fragmented plan MOTIVATION 2 MOTIVATION levels - 120000 - DATA FEDERATION & INTEGRATION FEDERATION DATA 100000 80000 Publications on the Brain / the Brain on Publications Number of Number 60000 40000 Reviewed Peer 20000 0 yr 0 1 2 3 5 6 7 8 9 0 1 2 3 5 6 7 8 9 0 1 4 4 9 9 9 9 9 9 9 9 9 0 0 0 0 0 0 0 0 0 1 1 9 0 9 9 9 9 9 9 9 9 9 0 0 0 0 0 0 0 0 0 0 0 9 0 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 2 1 2 2012 MOTIVATION 3 - INFORMATION TECHNOLOGY VON NEUMANN MACHINES MOORE’S LAW SUPERCOMPUTING ENERGY LIMITATIONS BEYOND EXASCALE INTERNET BANDWIDTH & ROUTING [HTML5, Cisco] DATABASE MANAGEMENT DISTRIBUTED [Oracle] CLOUD ENVIRONMENT SECURITY [Amazon, Dropbox, iCloud] DATABASE QUERYING & ADDRESSING LOCAL [Google] vs REMOTE [EPFL] REAL-TIME VISUALISATION FOR SUPERCOMPUTING [IBM, CRAY] NEUROMORPHIC COMPUTING Future and Emerging Technology Flagships (FET) Are ambitious large-scale, informatics-driven, research Initiatives that aim to achieve a visionary goal. The scientific advance should provide a strong and broad Basis for future technological innovation and economic Exploitation in a variety of areas, as well as novel benefits for society. The research is collaborative, internally non-competitive, inter- and trans-disciplinary, driven by a commonly agreed road-map BLUE BRAIN PROJECT + NEUROIMAGING COMMUNITY Using modern technology to dramatically improve our understanding of the human brain CLINICAL NEUROSCIENCE AT A TIPPING POINT SYNDROMIC DIAGNOSIS REACHED ITS LIMITS HUMAN GENOME BUILDING BLOCKS OF ORGANIC MATTER MODERN NEUROIMAGING MODERN NEUROSCIENCE MODERN INFORMATION TECHNOLOGY MODERN MATHEMATICS MECHANISTIC/CAUSAL DIAGNOSIS HUMAN “NEURO-DISEASOME” – DISEASETHE DISEASEOME SPACE AS A FUNCTION OF GENETIC ASSOCIATIONS THE POWER OF DATA MINING CLINICAL NEUROSCIENCE AT A TIPPING POINT SYNDROMIC DIAGNOSIS REACHED ITS LIMITS HUMAN GENOME BUILDING BLOCKS OF ORGANIC MATTER MODERN NEUROIMAGING INCREASINGLY SOPHISTICATED MODERN NEUROSCIENCE MODERN INFORMATION TECHNOLOGY MODERN MATHEMATICS MECHANISTIC/CAUSAL DIAGNOSIS PRE-SYMPTOMATIC DIAGNOSIS - BRAIN RESERVE HUNTINGTON’S DISEASE COMPENSATEDHUNTINGTON’S ATROPHY COMPUTER-BASED IMAGE CLASSIFICATION SUPPORT VECTOR MACHINE CLASSIFICATION PARADIGM SHIFT – BRAIN TISSUE CHARACTERISATION (VBQ) T1-weighted Thickness/Volume ? Statistical Interpretation inferences Quantitative and diffusion MRI Magnetisation Fractional Proton density R1 (1/T1) R2* (1/T2*) Mean diffusivity transfer anisotropy ! Interpretation Water Myelin Water motility Iron White matter « integrity » by A. Ruef DISEASE MODELLING AND TREATMENT PREDICTION Structural MRI and FDG-PET . GLM1: Establishing a voxelwise healthy aging model . GLM2: Modelling of Alzheimer’s disease related changes at different ages (orthogonalized for GLM1) Dukart et al., 2013, PLoS Comp Biology BASAL GANGLIA ARCHITECTURE A review of the entire tract-tracing literature of the STN between 1947- 2011 reveals connectivity between a broad array of cortical, sub-cortical and brainstem structures. BLUE = EFFERENT RED = AFFERENT Lambert et al., Confirmation of functional zones within the human subthalamic nucleus: Patterns of connectivity and sub-parcellation using diffusion weighted imaging NeuroImage Volume 60, 2012 83–94 FUNCTIONAL IMPLICATIONS The posterior aspect of the STN projects to structures consistent with a motor structure: Posterior putamen Posterior GPe Mid caudate nucleus Ventro-lateral thalamic nuclei Posterior Insula Posterior hippocampus The anterior aspect of the STN projects to structures consistent with a limbic structure: Baso-lateral amygdala Posterio-medial GPi Inferio-mid putamen Mid-GPe Ventral-anterior and ventral-lateral thalamus Anterior Insula Anterior hippocampus The middle “associative” STN projects to regions encompassing both the motor and limbic projections CLINICAL NEUROSCIENCE AT A TIPPING POINT SYNDROMIC DIAGNOSIS REACHED ITS LIMITS HUMAN GENOME BUILDING BLOCKS OF ORGANIC MATTER MODERN NEUROIMAGING INCREASINGLY SOPHISTICATED MODERN NEUROSCIENCE FRAGMENTED AND ATHEORETIC MODERN INFORMATION TECHNOLOGY MODERN MATHEMATICS MECHANISTIC/CAUSATIVE DIAGNOSIS NEUROSCIENCE METHODS IMAGES – IMAGES - IMAGES CLINICAL NEUROSCIENCE AT A TIPPING POINT SYNDROMIC DIAGNOSIS REACHED ITS LIMITS HUMAN GENOME BUILDING BLOCKS OF ORGANIC MATTER MODERN NEUROIMAGING INCREASINGLY SOPHISTICATED MODERN NEUROSCIENCE FRAGMENTED AND ATHEORETIC MODERN INFORMATION TECHNOLOGY EXPLOSIVE DEVELOPMENT MODERN MATHEMATICS MECHANISTIC/CAUSATIVE DIAGNOSIS MEDICINE AT A TIPPING POINT SYNDROMIC DIAGNOSIS REACHED ITS LIMITS HUMAN GENOME BUILDING BLOCKS OF ORGANIC MATTER MODERN NEUROSCIENCE FRAGMENTED AND ATHEORETIC MODERN CLINICAL NEUROSCIENCE INCREASINGLY SOPHISTICATED MODERN INFORMATION TECHNOLOGY MOORE’S LAW BUT ENERGY LIMITED MODERN MATHEMATICS FACILITATED BY CALCULATION POWER DISEASE SIGNATURES MECHANISTIC DIAGNOSIS THE HUMAN BRAIN PROJECT SIMULATING AND CONSTRUCTING A BLUEPRINT FOR THE BRAIN AT ALL SPATIAL SCALES FROM BASE PAIRS TO COGNITION MODELING: EQUATIONS FOR CELLULAR LEVEL BRAIN SIMULATIONS NEURONS 10,000 neurons ~ 4,000,000 Electrical compartments (Rall Equations) ION CHANNELS 80,000,000 Ion Channels (Hodgkin-Huxley Equations) SYNAPSES 10,000,000 Synapses (Tsodyks-Markram Equations) Tsodyks & Markram, PNAS,1997 NEURONS 10,000 neurons ~ 4,000,000 Electrical compartments (Rall Equations) ION CHANNELS 80,000,000 Ion Channels (Hodgkin-Huxley Equations) SYNAPSES 10,000,000 Synapses (Tsodyks-Markram Equations) MODELS ARE DATA DRIVEN Markram et al., In vitro MODELS ARE MATHEMATICALLY EXPRESSED In silico Nature Reviews MODELS ARE BIOLOGICALLY VALIDATED Neuroscien ce, 2004 A SIMULATED PYRAMIDAL NEURON MODELLED LFPs IN A CORTICAL COLUMN MODELLED MULTI-COLUMNAR PATCH PROPAGATION Neural Computation: Causal Chain of Events leading to Cognition Processor Sensory Input Motor Output Sensing, Learning, Memory, Adaptation, Decisions, Cognition, Behavior MEDICAL INFORMATICS PLATFORM 912 Alzheimer’s patients MRI data 5566 Healthy controls MoAE PET data MODALITIES Gene data CSF data Protein data PET CSF Organising Processing… Tabulating MRI CLINICAL SCALES & MEASUREMENTS PROTEINS Genes HYPERCUBE Scientist Internet Computer architecture Launch HyperCube Separate dedicated Data Source Learning matrix calculation network HyperCube interface •SAS •Oracle •Data Audit •Access •Correlations •Excel •Rule Builder •Extraction of internal or external data •… •Rule management •Scenario simulation Set of rules Automatic rule recovery 37 AD Rule NL Rule MRI Data PET Data Proteomics CSF Genetics Principles of Reconstructing Simulating and Reverse Engineering the Human Brain Brain Atlases Biological Parameter Constraints & Biological Principles Multi-constraint Algorithms Data source Configurations Brain Reconstruction Workflows Measured Derived Manual Disease Measured Volumizer Vacularizer Segmenter Measured Derived Manual Disease Measured Volumizer Vacularizer Segmenter Measured Derived Manual Disease Measured Volumizer Vacularizer Segmenter Measured Derived Manual Disease Measured Volumizer Vacularizer Segmenter Bouton Disease DiseaseDistributor Tracter Modularizer Data Principles Volumizer Vacularizer Segmenter densityBouton Data Principles Distributor Tracter Modularizer densityBouton