Validity with PragmatismSpecific Issues in experimental design and implementation

II-A

– 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?

Translational Cognitive Neuroscience in Psychiatry

Cognitive Mechanism Maladaptive Behavior

Molecular Mechanisms

Neural Circuits

Courtesy of Peter Balsam

Neurobehavioral assays!

– 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?

Translational Neuroscience (How model potential pathogenic mechanisms)

Behavioral Abnormality

Molecular Targets

Risk Genes

Circuits

Molecular Mechanisms

Adapted from Peter Balsam

Risk factors

Disease Model

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?

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

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?

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 ?

Sensitivity to disease mechanismsand 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

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?

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 ?

Task #2: Find Homologous Neural Substrates

Which neural substrates are we studying?

Hypothesis 1: Something’s missing – how do we identify it?Neural circuit recruitment versus necessity for normal functionWhich 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)

Homologous Neural Circuits (con’t)

Efficiency and Cost-effectivenessCan 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?

Neurobehavioral

Construct Validity

The criteria must be met with high reliability and reasonable throughput

Etiologic (a.k.a. content) Validity

Predictive ValidityReliable signal of efficacy in patients

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.

QUESTIONS FOR ALL PARTICIPANTS

Operationalization :Task Structure

What properties must a task possess in order to isolate, manipulate and measure the construct of interest?

Easy Hard012345

Acc

urac

y

Con Sick

Treatment Targets

Experience

Pathophysiology

Maladaptive behavior

Protein function

Environmentconcurrent with illness

DRUGS

Cognitive and PsychosocialTherapy

Neural Circuit Function Cognitive processes

Summary and [of] Challenges

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

• 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

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

The Cascade of Pathogenesis

Experience

Maladaptive behavior

susceptibilityfactors

environmentprotein synthesis and regulation

Neurodevelopment

neuro-physiology

Embryonic

Postnatal

Late Juvenile

Periadolescent

Morbidity in adulthoodDevelopment