Validity with Pragmatism Specific Issues in experimental design and implementation

1. Validity with Pragmatism Specific Issues in experimental design and implementation II-A

2. The “schizophrenias” (Bleuler) are neurobiological disorders diagnosed solely on the basis of behavioral changes • Schizophrenia is characterized by a cluster of cognitive, affective, and motor phenotypes • What are the neurocognitive/neurobehavioral processes underlying these phenotypes?

3. Translational Cognitive Neuroscience in Psychiatry Cognitive Mechanism Maladaptive Behavior Neurobehavioral assays! Neural Circuits Molecular Mechanisms Courtesy of Peter Balsam

4. Multiple pathogenic pathways, variably combined, converge onto common neurobehavioral processes to produce these phenotypes • How do we identify these pathogenic mechanisms and determine their effect on cognition?

5. Translational Neuroscience (How model potential pathogenic mechanisms) Behavioral Abnormality Risk factors Circuits Disease Model Molecular Mechanisms Molecular Targets Risk Genes Adapted from Peter Balsam

6. At a pragmatic level, how do we go about this? What issues need to be addressed as we ‘translate’ a construct across species or assay this construct in a disease model?

7. Task #1: Operationalize(and use tasks that are true to our operational definition) Defining and measuring the construct in your species • How is the construct operationally defined for your species? How does that differ from how it is defined in human studies? • What properties must a task possess in order to isolate, manipulate and measure the construct of interest? • What behavioral output is used to measure the operation of the construct? • Change in Motor Output or Neuronal Output Y as a function of Task Manipulations X, Z

8. Parametrics and Reliability • Can we parametrically vary task demands? (or is the nature of the construct such that behavior can report an all-or-none effect) • Can the construct be manipulated/assessed in the context of steady-state performance on aspects of the task not related to our construct of interest? • Do we have enough trials to reliably assess the effect of drugs on performance?

9. Outcome Measures • What is the temporal and spatial “structure” of the behavioral expression system? • How reliable/stable/spontaneous is the expression of the behavior (competing behaviors)? • How sensitive is the behavior to changes in the construct? • What other cognitive, affective or motor processes impact the behavior? Are we affecting those processes with our manipulations? • What are the neural substrates of the behavioral response ?

10. Sensitivity to disease mechanisms and common drug treatments • How is the neurobehavioral construct affected by • hypothesized pathogenic mechanisms of the disease? • Drugs commonly prescribed to the patients? • Assessed by measuring the construct in disease and pharmacological models

11. Sensitivity to disease mechanismsand common drug treatments (con’t) • How does the hypothesized disease mechanism affect the behavioral expression system? • How do candidate drugs and - commonly-prescribed drugs – impact the behavioral expression system? • How is the behavior reinforced, with positive or negative reinforcement? Is the construct differentially sensitive to positive versus negative reinforcement? Does the disease mechanism differentially impact appetitive versus avoidant behaviors?

12. Task #2: Find Homologous Neural Substrates • Neural Circuit Homology– conservation across species of the neural circuits and neurobiological processes that underlie the cognitive construct • Which neural circuits are hypothesized to mediate this construct in humans? • Do these circuits have homologues in the experimental animal species ?

13. Homologous Neural Circuits (con’t) • Which neural substrates are we studying? • Hypothesis 1: Something’s missing – how do we identify it? • Neural circuit recruitment versus necessity for normal function • Which circuits are recruited by task demands that manipulate the construct? • Which of these are necessary for the operation of the construct? • Hypothesis 2: Something’s in the way - Active mechanisms of disruption – neural circuit intrusion • Convergent validity in determining neural circuit homology • Complementary methods of determining homology of neural circuits • neurodevelopment • anatomical hodology (connectivity)

14. Efficiency and Cost-effectiveness • Can I train sufficient number of animals and assess the effects of candidate drugs using a task with construct validity before I die or at least before I go broke? • Training time • Throughput – how many animals can I test at once? • Recycling – can I reuse a trained animal?

15. Neurobehavioral Construct Validity Etiologic (a.k.a. content) Validity Predictive Validity Reliable signal of efficacy in patients The criteria must be met with high reliability and reasonable throughput

16. QUESTIONS FOR ALL PARTICIPANTS • 1. As an animal or human neurocognition researcher who wants to help develop tasks to measure constructs affected in schizophrenia… • What additional information do you need from clinical and neurocognitive studies of schizophrenia patients? • How would you suggest they change their task designs to get information that you need to understand what is going on in the patients? • 2. As an animal ‘disease modeler’, what information do you need from animal neurocognition researchers? From studies of schizophrenia patients (incl. risk factor, neurocognitive, and drug treatment studies)? • 3. As a clinical researcher in schizophrenia, what do you need from animal modelers? What do need less of? More of? (understanding of relationships between dependent variables and neural and cognitive operations) • 4. Who else should be at this meeting – please give us names/locations and we’ll try hard to make sure they are at the next meeting.

17. Operationalization :Task Structure • What properties must a task possess in order to isolate, manipulate and measure the construct of interest? Accuracy Con Sick

19. Environment concurrent with illness Treatment Targets DRUGS Pathophysiology Cognitive processes Neural Circuit Function Protein function Maladaptive behavior Experience Cognitive and Psychosocial Therapy

20. Summary and [of] Challenges

21. Challenges for Pro-cognitive Treatments for Schizophrenia • Understanding of the neuroscience behind cognitive changes in schizophrenia is partial • There is no unitary hypothesis for the cause(s) of cognitive deficits • The diagnostic syndrome may reflect many different etiologies • No consensus on the underlying neurobiology • Cognition is not a unitary concept • 5 – 12 cognitive domains are affected, each with different substrates • Is it realistic to seek treatments that will improve cognition globally? • What would be the most relevant domains that need to improve? • No reliable and valid biomarkers for cognitive dysfunction have been validated as yet • No validated drug targets exist for improving cognition that can be used as positive controls, although many suspected targets exist Adapted from Thomas Steckler

22. How do we do a better job of identifying targets for new drugs, and combining drug and cognitive/behavior therapies to achieve a sustained improvement in the function of a neural circuit? A better treatment strategy • CNTRICS I • Identify cognitive processes that are disrupted in patients diagnosed with schizophrenia • Use data from research in patients to propose candidate neural substrates for these processes • CNTRICS II – ANIMAL MODELS • Identify homologous neurocognitive processes in animal models • Use animal models to • Increase understanding of neural mechanisms underlying the construct • Characterize candidate pathophysiologies that can disrupt the construct (prioritizing on the basis of plausibility in schizophrenia) • Predict the effects of treatment on those neural mechanisms

23. The Cascade of Pathogenesis environment susceptibility factors neuro- physiology protein synthesis and regulation Experience Neurodevelopment Embryonic Maladaptive behavior Postnatal Late Juvenile Periadolescent Morbidity in adulthood Development