Specific Issues in experimental design and implementation IIA The schizophrenias Bleuler are neurobiological disorders diagnosed solely on the basis of behavioral changes Schizophrenia ID: 497293
Download Presentation The PPT/PDF document "Validity with Pragmatism" is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.
Slide1
Validity with Pragmatism
Specific Issues in experimental design and implementation
II-ASlide2
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 phenotypesWhat are the neurocognitive/neurobehavioral processes underlying these phenotypes?Slide3
Translational
Cognitive Neuroscience in Psychiatry
Cognitive Mechanism
Maladaptive Behavior
Molecular Mechanisms
Neural Circuits
Courtesy of Peter Balsam
Neurobehavioral assays!Slide4
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?Slide5
Translational Neuroscience (How
model potential pathogenic mechanisms)
Behavioral Abnormality
Molecular Targets
Risk Genes
Circuits
Molecular Mechanisms
Adapted from Peter
Balsam
Risk factors
Disease ModelSlide6
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?Slide7
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, ZSlide8
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?Slide9
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 ?Slide10
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 modelsSlide11
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?Slide12
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 Slide13
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)
Homologous Neural Circuits (
con’t
)Slide14
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?Slide15
Neurobehavioral
Construct Validity
The criteria must be met with high reliability and reasonable throughput
Etiologic (a.k.a. content) Validity
Predictive Validity
Reliable signal of efficacy in patientsSlide16
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 PARTICIPANTSSlide17
Operationalization :
Task StructureWhat properties must a task possess in order to isolate, manipulate and measure the construct of interest?
Accuracy
Con
SickSlide18Slide19
Treatment Targets
Experience
Pathophysiology
Maladaptive behavior
Protein function
Environment
concurrent with
illness
DRUGS
Cognitive and Psychosocial
Therapy
Neural Circuit Function
Cognitive processesSlide20
Summary and [of] ChallengesSlide21
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 deficitsThe diagnostic
syndrome may reflect many different etiologies
No consensus on the underlying neurobiologyCognition is not a unitary concept
5 – 12 cognitive domains
are affected, each with different substratesIs 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
StecklerSlide22
CNTRICS IIdentify cognitive processes that are disrupted in patients diagnosed with schizophrenia
Use data from research in patients to propose candidate neural substrates for these processesCNTRICS II – ANIMAL MODELSIdentify homologous neurocognitive processes in animal models
Use animal models to Increase understanding of neural mechanisms underlying the constructCharacterize 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 strategySlide23
The Cascade of Pathogenesis
Experience
Maladaptive behavior
susceptibility
factors
environment
protein synthesis and regulation
Neurodevelopment
neuro
-
physiology
Embryonic
Postnatal
Late Juvenile
Periadolescent
Morbidity in adulthood
Development