1. All Hands Meeting 2005 Human Morphometry and Function BIRN Testbeds Christine Fennema-Notestine, Ph.D. Jessica Turner, Ph.D. CBiO/BIRN Workshop 2006

2. MBIRN/FBIRN “Ontology” Needs  GOAL: User will employ BIRN interface and Mediator to perform scientific queries on data from  structural and functional MRI experiments,  clinical assessments,  psychiatric interviews,  and/or behavioral experiments  BIRN needs for common vocabularies Mediator needs to talk across databases to find relevant/similar information; this requires linking of concepts to table columns and values Query interface needs semantic network to find related information  Example queries: “Find all datasets of schizophrenics with structural and functional imaging data related to working memory” “Find the correlation between hippocampal volume and working memory performance in AD subjects”

3. MRI Scanner  Structural images, such as T1, PD, T2  Measures of function, e.g., Blood Oxygenation Level Dependent (BOLD) signal FMRI: Measures the ratio of oxygenated/deoxygenated hemoglobin in the blood Neurons fire -> blood flows in -> the ratio changes

4. Slice Thickness e.g., 6 mm Number of Slices e.g., 10 SAGITTAL SLICE IN-PLANE SLICE Field of View (FOV) e.g., 19.2 cm VOXEL (Volumetric Pixel) 3 mm 6 mm Slice Terminology Matrix Size e.g., 64 x 64 In-plane resolution e.g., 192 mm / 64 = 3 mm From: http://defiant.ssc.uwo.ca/Jody_web/fmri4dummies.htm

5. Clinical Neuroimaging Problems of mBIRN  To develop the capability to analyze as a single data set MRI and associated data acquired across multiple sites, using tools developed at multiple sites  Examine clinical, demographic, and genetic correlates of human neuroanatomical data  Emphasis on depression, mild cognitive impairment, and AD

6. Imaging Methods Derived data: Cortical thickness Volumes of subcortical and cortical gray and white matter Shape derived metrics Diffusion metrics of anisotropy

7. Common studies of structural data  Examine the relationship between normal aging and hippocampal volume  Using a combination of volumetric measures and clinical data, predict classification of individuals as healthy controls or individuals with AD

8. MBIRN priorities To relate clinical assessments, cognitive function, and neuroanatomy within mBIRN’s multi-site AD sample, with future branching into neuropsychiatric measures (e.g., fBIRN schizophrenia interviews, etc.). The common acronym for the "California Verbal Learning Test" (a neuropsychological assessment of learning and memory) "CVLT" needed to be added as a synonym. More importantly, the CVLT concept only has defined relationships with the concept "Assessment Scales" and links to other assessments scales; no meaningful relationships are between this measure and the concepts for cognitive (memory), anatomical (hippocampus), or disease (AD) terms

9. Existing neuroanatomical ontology Need to create related “function”- based ontology Brain Cerebellum Cerebrum Cerebral white matter … Frontal cortex Temporal cortex Superior temporal Mesial temporal AmygdalaHippocampus … Cerebral cortex … … … Memory CVLT

10. Brain Cerebrum Temporal Mesial temporal Hippocampus Cerebral cortex CVLT Task and score description Frontal Cognitive impairment Cognition Assessment Neuropsychology Amnesia Memory Learning

11. Memory Recognition Recall Free recall Cued Recall CVLT Retrieval Hippocampus Frontal lobe

12. Functional Imaging Methods T2*-weighted, gradient-echo echo-planar imaging sequence TE: 40 ms, TR: 3 sec, Flip Angle: 90° Acquisition matrix: 141 x 64, interpolated to 256 x 256 Final in-plane pixel size: 0.94 x 0.94 mm 2 Slice thickness: 5 mm 14-16 axial slices covering the superior half of the cortex Image acquisitions: 70

13. Statistical Map superimposed on anatomical MRI image ~2s Functional images Time Condition 1 Condition 2... ~ 5 min Time fMRI Signal (% change) ROI Time Course Condition Activation Statistics Region of interest (ROI) From http://defiant.ssc.uwo.ca/Jody_web/fmri4newbies.htm

14. 30s-R Tap Task Image Box-car Design: Comparing Active to Rest States Stimulus (3Hz)...

15. Individual Time Courses Remove linear trends Scale as a percentage of the baseline

16. Learn 3t 1t 5t 3t 5t 1t Encode14 probes 37.8 +.2 at end” Sample Run…… (total time = 360”, including DDAs) Order of WM blocks randomized 0 2 1 3 8 9 7 2 4... 7 * 5 * 4 * * 9 * * Prompt 1.5” +.5” Learn 5t 3t 1t + + +… Learn fix 6” 2.7” each, 1.1 appearance, 1.6 jitter, minimum pre.300, response time for each probe =~1.5s Average 12”, minimum 4”, max 20”, multiple of 2’’, randomized total fix time = 78” = 46”q block 2 blocks @ each WM load 6 blocks = 276” DDAs (6sec) fix(14s)fix 6 Cognitive working memory task (SIRP)

17. SIRP Recall Probe Contrasts (N=1) P<.001, uncorrected, ext Green = Set 5 – Set 3 Red = Set 3 – Set 1 Results or “derived data” storage still being standardized. --with fMRI, can analyze a single subject, or groups of subjects

18. Human BIRN data includes  Participant demographics such as age, gender, …  Clinical and psychiatric information Assessments used, data type Diagnostic information  Behavioral data during fMRI tasks Need to know how to interpret that (“is a button 1 response a yes or a no?”)  Raw structural and functional images Need information about data collection and preprocessing methods  Single-subject and group level analyses and results Need information about analytic methods used

19.  Bottom-up: ?When reviewing data, user questions what a given assessment measures and what the score means.  Must include assessment name as a term that will link to clinical data provenance information (task description and score interpretation)  Must provide link to term for assessed function(s) (cognitive, behavioral, psychiatric domain)  Must provide link to potentially related brain regions  User could then simply enter assessment name to find description and related clinical and anatomical terms Clinical research questions define structure

20.  Top-down: ? User investigates brain-behavior relationships, e.g., between the hippocampus and memory performance  Must include cognitive terms such as: cognitive assessment, memory, recognition, recall  Link terms to existing assessment terms (e.g., CVLT)  Link as appropriate to neuroanatomical ontology (e.g., hippocampus)  User could then search via specific cognitive domain or through “hippocampus” to reach relevant assessments

21.  California Verbal Learning Test (CVLT) Comprehensive assessment of memory and learning Widely used, often in head injury including frontal lobe damage, amnesia, dementia (e.g., Alzheimer’s), depression, learning disorders, etc. Provides numerous measures including:  Recognition discriminability  memory disorders, hippocampus, …  Measurement of retention across time  amnesia, Alzheimer’s, …  Free recall of information  retrieval, frontal lobe, Huntington’s,…  Cued recall of information  memory disorders, Alzheimer’s, …  Response bias  malingering, depression, motivation, …  Serial position effects  short term memory, primacy & recency effects, …  Single trial learning  learning disorders, attention, frontal lobe, …  Learning over several trials  retention, frontal lobe, hippocampus, …  Semantic organization  association cortex, superior temporal lobe, …  and more… Highly complex assessment example

22. Bottom-up search: User’s dataset contains the CVLT – what does it measure?  Search for CVLT  Related to PARENT concepts like “Neuropsychological tests” or “Assessment Scales” or SIBLING concepts of other tests  What is the CVLT? This doesn’t answer the user’s question.  Need relationship links to function: memory and learning Addition of terms covered under memory and learning such as recognition, recall, attention, motivation, serial position effects, episodic memory, semantic memory, … will be related to various subscores of this test  Need relationship links to structure: anatomical regions reflected in change of performance on this measure  hippocampus Link by subscore and/or by overall measure E.g., CVLT can assess recognition memory, usually linked to hippocampus, but also retrieval of information, often linked to frontal lobe function.

23. Top-down search: User interested in studying the relationship between hippocampal volume and memory performance in Alzheimer’s disease.  Search for measures of memory  Would like to see memory linked to CVLT  Would like to see memory linked to hippocampus at a very basic level  Would like to see links to potential disorders assessed, e.g., amnesia or AD

24. Brain Cerebrum Temporal Mesial temporal Hippocampus Cerebral cortex CVLT Task and score description Frontal Cognitive impairment Cognition Assessment Neuropsychology Amnesia Memory Learning

25. Memory Recognition Recall Free recall Cued Recall CVLT Retrieval Hippocampus Frontal lobe

26. Data gathering from federated databases “Find all the schizophrenic subjects with fMRI data doing a working memory task.” This involves  Demographics: Find database tables which contain Age, Gender, Handedness, Diagnosis, etc.  Clinical aspects: What clinical assessments were used to measure schizophrenia symptoms?  Cognitive taxonomies: Which tasks are ‘working memory tasks’?  Scanning parameters: Type of scan: structural, functional If structural, what kind of scan: SPGR? Other? If functional: Transversal of k-space: Linear? Spiral? Other? And other imaging parameters, e.g.: TR, TE, Number of slices? (whole brain or single-slab?), Slice thickness/gap thickness, Slice acquisition order (interleaved or serial)

27. Taxonomy of fMRI Experiments (from BrainMap)

28. Taxonomy of Experiments

30. Brain Cerebellum Cerebrum Cerebral white matter … Frontal cortex Temporal cortex Superior temporal Mesial temporal AmygdalaHippocampus … Cerebral cortex … … … Memory CVLT SIRP Assessment Behavioral Paradigm

31. Memory CVLT SIRP Assessment Behavioral Paradigm Cognitive Process Attention Working memory Long Term memory SCID-Patient Breathhold Action

32. The issue of multiple identifiers  A cerebellum cannot be a thalamus  But a cognitive task can be a measure of both working memory and attention (e.g., SIRP) a measure of both recognition memory and executive retrieval (e.g., CVLT) and reflected then by more than one anatomical region  Other issues crossing domains: “memory” is associated with the hippocampus, generically, but is much more complex requiring neural circuits working memory activation patterns from the SIRP are not found in the hippocampus (and everyone knows that)

34. Ontology Experiences  Derived fMRI data: Mean activations or some such summary data (z-scores, e.g.) for various cortical regions (ROIs) may be stored as a result of single-subject analysis. That way, the activation in various cortical areas can be summarized and data mining and other techniques then can be applied.  In the short-term, users will probably download the data or analyses and extract the results using their preferred methods.  In the long term, however, that will become infeasible the databases will have to be made interoperable with standard datamining software.  This is where the neuroanatomy ontologies come in. We will need to know what the ROI is and which naming scheme it came from (e.g., a Brodmann’s area, or a sulcal/gyral area, etc.). We’ll need to know how it was defined (Talairach atlas? MNI atlas? LONI atlas? Or subject-specific regions?) and what the statistic is.

35. Basic clinical assessment example:  Mini-mental State Examination (MMSE; Folstein et al., 1975 ) Brief standardized measure of cognitive status  to monitor progression/stabilization in medical setting  to screen research participants Often used in cognitive disorders and dementia (e.g., Alzheimer’s) or other illnesses; not disease specific Relatively non-specific relationship to general brain changes Usually reflected as a single score  Based on brief assessment of orientation, attention, immediate recall, short term recall, language, ability to follow simple verbal commands

36. Bottom-up search: User’s resultant dataset contains the MMSE – the user asks what does it measure?  Search for MMSE concept  Related to PARENT concepts like “Neuropsychological tests” or “Assessment Scales” or SIBLING concepts of other tests  What is the MMSE? This doesn’t answer the user’s question.  Need relationship links to function: general cognitive ability, cognitive impairment, dementia severity, brain damage …  Need relationship links to structure: anatomical regions reflected in change of performance on this measure, although a relatively non-specific measure  brain

37. Top-down search: What variables exist that would provide a measure of general cognitive function and dementia severity?  Search for measures of (general) cognitive function  Would like to see general cognitive ability, cognitive impairment, dementia severity linked to MMSE  Would like to see general cognitive ability, cognitive impairment, dementia severity linked to neuroanatomical regions, simply brain in this case  Would like to see links to potential disorders measured, e.g., AD

38. Brain Cerebrum Temporal cortex Mesial temporal Hippocampus Cerebral cortex MMSE Cognitive impairment Dementia severity Cognition Assessment Neuropsychology Alzheimer’s Task and score description