Mapping Cognitive and Motivational Domains Across Levels of Analysis: Challenges and Opportunities for Target Specification

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April Curtis
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1 Mapping Cognitive and Motivational Domains Across Levels of Analysis: Challenges and Opportunities for Target Specification Robert M Bilder, PhD Michael E. Tennenbaum Family Professor, and Chief of Medical Psychology Neuropsychology, UCLA Jane & Terry Semel Institute for Neuroscience & Human Behavior, Stewart & Lynda Resnick Neuropsychiatric Hospital, Departments of Psychiatry & Biobehavioral Sciences and Psychology David Geffen School of Medicine at UCLA, and College of Letters & Science at UCLA

2 Rzhetsky et al 2009 genetic overlap derived from 1.5M medical records

3 Mapping Research Domains Impact of the NIMH Research Domains Criteria (RDoC) Initiative RDoC offers new dimensions to move psychiatry beyond current diagnostic taxonomy and towards rational therapies Consensus meetings generated lists of elements at different levels of analysis Challenges: defining the true causal paths that lead from level to level (genome to syndrome) Opportunities: defining targets of treatment aligned with biological and psychological science

4 Self-reports Personality, symptoms Behavior Rating scales, cognitive assessments Physiology MRI, EEG, MEG, psychophysiology Circuits Neuroanatomic nodes; imaging, basic RDoC Levels of Analysis Cells Cell physiology Molecules Genetics, expression, proteomics

6 RDoC Matrix Specification: Expectancy/Reward Prediction Error

7 RDoC Working Memory Matrix

8 Genes Molecules Cells Circuits Unit of Analysis NRG1/Neuregulin DISC1 DTNBP1/Dysbindin BDNF COMT DRD2 DAT1 Active Maintenance Flexible Updating Limited Capacity Interference Control Dopamine X X X X D1 X X X (gain) X D2 X X? X Glutamate X X X X NMDA X AMPA? GABA X? X X A? B? Pyramidal Distinct Types of Inhibitory Neurons Parvalbumin Calbindin Calretinin Medium Spiny Neurons (Basal Ganglia) X X Key Circuit: PFC- Parietal-Cingulate- Dorsal Thalamus- Dorsal Striatum DLPFC X X VLPFC X X Dorsal Striatum X Dorsal Parietal X Inferior Parietal X X MD & VA Thalamus (by virtue of their role in circuit) X X? X X X

9 Unit of Analysis Active Maintenance Flexible Updating Limited Capacity Interference Control N-Back X X (?) X X (if you include non-target lures) Delayed Match to Sample X --- X X (if you use repeated items, or delay period interference) Delayed Match to Non- Sample Sequence Encoding and Reproduction X --- X X (if you use repeated items, or delay period interference) X --- X --- Behavior and Paradigms Sternberg Item Recognition (including recent negative variations) X X (recent negative task increases demand on updating) X X (if you use repeated items, recent negative variation) Complex Span Tasks X X X X Letter Memory/Running Memory X X (?) X X (?) Letter Number Sequencing X X X X Simple Span Tasks (may be more appropriate for developmental X (if you use concurrent interference, X --- X populations, in adults as in Digit Span Distraction) may not capture all key elements of WM) Change Detection Tasks X --- X --- Keep Track Task X X X X AX-CPT/DPX X X X --- Self-Ordered Pointing X X (?) X X

10 Is there a better way?

11 Classic (psychometric) approach Network (causal modeling) approach chronic stress depressed mood self-reproach insomnia fatigue concentration Borsboom & Cramer 2013 Annual Rev Psychology

12 In sum, not only do we not know that symptoms are caused by mental disorders, but it is in fact extremely unlikely that they are. As a result, the hypothesis that such disorders are the proper entities to steer the organization of research, diagnosis, and treatment is, at best, awaiting scientific justification. Borsboom & Cramer 2013 Annual Rev Psychology

13 What are the proper entities?

18 Can we link those to real behavior in human 1 patients 2? 1 homo sapiens 2 with real-life problems

19 RO1MH082795, and Consortium for Neuropsychiatric Phenomics (UL1DE019580, PL1MH083271, RL1LM009833)

20 Architectures for cognitive ontology development The Cognitive Atlas is conceptualized as a related set of maps. A given map may contain sets of related concepts, quantitative models of literature association, annotated effect size statistics, raw data, summaries of voting, and qualitative free-text inputs. For cognitive concepts (e.g., the phonological buffer ) there are associated cognitive concepts, and a test layer comprising objective indicators of the concepts RO1MH082795, and Consortium for Neuropsychiatric Phenomics (UL1DE019580, PL1MH083271, RL1LM009833)

It might be argued that the task of the psychologist, the task of understanding behavior and reducing the vagaries of human thought to a mechanical process of cause and

21 It might be argued that the task of the psychologist, the task of understanding behavior and reducing the vagaries of human thought to a mechanical process of cause and effect, is a more difficult one than that of any other scientist. (D. O. Hebb, 1949, p. xi) Consortium for Neuropsychiatric Phenomics (UL1DE019580, PL1MH083271, RL1LM009833)

23 Managing assertions about brain-behavior relations using a neural circuit description framework Bilder, Howe & Sabb, 2013 Journal of Abnormal Psychology

24 Multi-Level Assays of Working Memory and Psychopathology: R01 MH Models to Validate Circuit Constructs

25 Multi-Level Assays of Working Memory and Psychopathology: R01 MH Validating Cognitive Markers of Circuit- Level Constructs

Mapping to Functional Status Do symptoms or diagnosis add useful prediction over basic measures of circuit, cognitive or neuropsychological measures?

26 Mapping to Functional Status Do symptoms or diagnosis add useful prediction over basic measures of circuit, cognitive or neuropsychological measures? Diagnosis (DSM-V) Symptom (CIDI, DSM-CC, BPRS, PROMIS) Neuropsych (5 indicators) Disability (WHODAS 2.0) To avoid extreme group bias, sampling strategy is agnostic to diagnosis, and comprises two groups: - Care-seeking - Not Care-seeking Cognitive (8 indicators) Circuit (5 fmri, 3 smri/ DTI, 6 EEG indicators) Diagnoses assigned after enrollment, as one of the dependent variables under study Multi-Level Assays of Working Memory and Psychopathology: R01 MH101478

27 Matching Measurements to Samples The statistical power for a given rating scale may be reduced if it is applied in a mixed population (e.g., PANSS in SZ+BP). A new endpoint (e.g., g from bifactor model) may show greater invariance across samples, and thus increase power. Ariana Anderson, supported by Janssen R&D/UCLA Pharmacogenomics Research Collaboration

28 Conclusions RDoC matrix implies causal links across multiple levels from genome to syndrome Causal models can help specify what to measure and how to measure Validation can proceed directly to function if the functions and populations are well defined New paradigm: specify models of dimensions and targets without disease entity assumption Caveat: new models must be explicit

29 Many thanks! Consortium for Neuropsychiatric Phenomics investigators (52) including PI s: Freimer, Cannon, London, Jentsch, Parker, Evans Cognitive Atlas investigators including: Poldrack, Toga, van Horn, Sabb RDoC WM investigators including: Rissman, Loo, Bearden, Gitlin, Makeig Janssen R&D/UCLA team including: Anderson, Salvadore, Chung, Wilcox, Savitz, Alphs, Wang, Li

Devils, Details, and Data: Measurement Models and Analysis Strategies for Novel Technology-Based Clinical Outcome Assessments

Devils, Details, and Data: Measurement Models and Analysis Strategies for Novel Technology-Based Clinical Outcome Assessments ISCTM 2018 Autumn Meeting Robert M Bilder, UCLA Michael E. Tennenbaum Family