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    Slide 1 Slide 1 Presentation Transcript

      • Animal Models of
      • Gain Control
      • in Schizophrenia
      • Steven J. Siegel, M.D., Ph.D.
      • Director, Tranlational Neuroscience Program
      • [email_address]
      • CNTRICS - 11/24/10
      Steven J. Siegel, M.D., Ph.D. Translational Neuroscience Program
      • EEG - clinically relevant & foster preclincal translation
        • Sensory systems - provide stimulus / input control
        • Evaluate neural response a stimulus - i.e. can assess gain
        • Rodent equivalents to human measures
      • Disease models - Schizophrenia
        • Pharmacological, endocrine, genetic
      • Treatment models
        • Examples of medication effects
      • Limitations:
        • Averages vs. single trial analysis
      Scope & framework for modeling gain control Steven J. Siegel, M.D., Ph.D. Translational Neuroscience Program
      • EEG - clinically relevant & foster preclincal translation
        • Sensory systems - provide stimulus / input control
        • Evaluate neural response a stimulus - i.e. can assess gain
        • Rodent equivalents to human measures
      • Disease models - Schizophrenia
        • Pharmacological, endocrine, genetic
      • Treatment models
        • Examples of medication effects
      • Limitations:
        • Averages vs. single trial analysis
      Scope & framework for modeling gain control Steven J. Siegel, M.D., Ph.D. Translational Neuroscience Program
      • Auditory Event Related Potentials
      • EEG responses to sensory stimuli - evaluate the I/O function
      • Mouse & human analogy for response properties & pharmacology
      Steven J. Siegel, M.D., Ph.D. Translational Neuroscience Program S1 S2 S1 S2
    • Control Schizophrenia
      • Original phenotype in unmedicated schizophrenia was reduced S1 response amplitude - i.e. reduced gain (Adler, L.E. et. al., Biol Psych., 1986, Freedman, R., et. al. Biol. Psych. 1983 ; Jin, Y. et.al., Psych. Research 1997)
      • Schizophrenia patients noted to have smaller visual ERP amplitude and less increase in amplitude with increasing stimulus intensity - i.e. reduced gain (Landau, S, et. al. Arch Gen Psych 1975)
      Relevance to Schizophrenia Steven J. Siegel, M.D., Ph.D. Translational Neuroscience Program
    • Generation of human components P50 : Auditory thalamus and STG N100 : STG & other places P200 : Association auditory cortex Picton et al., Electroencephalogr Clin Neurophysiol. 1974 Human component qualities P50 Increases amplitude 0.25-1 sec Adler, L.E., et. al. N100 Gating 0.5s, ISI 0.25-8 sec & Intensity dependence Boutros, N., et. al. Psychiatry Res, 1999, Javitt, D., et. al. Clin Neurophys, 2000 P200 Intensity dependence Hegerl, U., et. al. Psychiatry Res, 1992 Rodent equivalents for human measures Umbricht et. al, Brain Research 2004 Steven J. Siegel, M.D., Ph.D. Translational Neuroscience Program
    • P1 N1 P2 Mouse latency is 40% of that in humans Steven J. Siegel, M.D., Ph.D. Translational Neuroscience Program
      • EEG - clinically relevant & foster preclincal translation
        • Sensory systems - provide stimulus / input control
        • Evaluate neural response a stimulus - i.e. can assess gain
        • Validation of rodent equivalents to human measures
      • Disease models - Schizophrenia
        • Pharmacological, endocrine, genetic
      • Treatment models
        • Examples of medication effects
      • Limitations:
        • Averages vs. single trial analysis
      Scope & framework for modeling gain control Steven J. Siegel, M.D., Ph.D. Translational Neuroscience Program
      • Disease Models
      • Ketamine - NMDA R antagonists
      • Corticosterone - stress
      • G  s transgenic mice
      • Amphetamine
      Steven J. Siegel, M.D., Ph.D. Translational Neuroscience Program
    • Human 0 100 200 300 400 500 MSEC Pre-attentive Cortical Activation Stimulus Evaluation Active Attentional Shifts Task-Dependent Activity: Salience detection Working Memory Sensory Perception Stimulus Mouse 0 40 80 120 160 200 MSEC MMN Consider N1 and MMN as examples of gain control Steven J. Siegel, M.D., Ph.D. Translational Neuroscience Program
    • Ketamine causes lasting reduction of initial response - i.e. Gain Pattern similar for N40 & P80 at 3 & 5 weeks post treatment S1 S2 Sal Sal Ket Ket Steven J. Siegel, M.D., Ph.D. Translational Neuroscience Program
    • Ketamine effects on deviance ERPs Steven J. Siegel, M.D., Ph.D. Translational Neuroscience Program
    • Ketamine Disrupts Deviance ERPs - MMN Steven J. Siegel, M.D., Ph.D. Translational Neuroscience Program Control Ketamine
    • High dose Corticosterone used to model stress-induced alterations in symptoms: Reduces S1 amplitude - i.e. Gain Steven J. Siegel, M.D., Ph.D. Translational Neuroscience Program
    • Corticosterone alters gain, not gating Steven J. Siegel, M.D., Ph.D. Translational Neuroscience Program
    • G  s mice show many endophenotypes of schizophrenia including deficits in spatial & associative learning as well as PPI
      • ABR
        • No differences in threshold - similar to schizophrenia (Pfefferbaum, 1980)
        • Wt & Tg differ in stimulus intensity response (p = 0.02) - i.e. gain
      • N40
        • Tg have smaller N40 amplitude than Wt - similar to schizophrenia
        • Tg have reduced N40 intensity function
      Steven J. Siegel, M.D., Ph.D. Translational Neuroscience Program
      • Haloperidol eliminates Tg intensity function deficit
      • Amphetamine approximates Tg intensity function deficit
      • Reverse translational question - Do patients differ on ABR and N100 intensity function?
      Steven J. Siegel, M.D., Ph.D. Translational Neuroscience Program Haloperidol Amphetamine
      • EEG - clinically relevant & foster preclincal translation
        • Sensory systems - provide stimulus / input control
        • Evaluate neural response a stimulus - i.e. can assess gain
        • Validation of rodent equivalents to human measures
      • Disease models - Schizophrenia
        • Pharmacological, endocrine, genetic
      • Treatment models
        • Examples of medication effects
      • Limitations:
        • Averages vs. single trial analysis
      Scope & framework for modeling gain control Steven J. Siegel, M.D., Ph.D. Translational Neuroscience Program
      • Treatment & Translational Models
      • Antipsychotics
        • Haloperidol & Olanzapine increase amplitude
        • Drug-target evaluation using gain models - PDE4 inhibitors
      • Nicotine & nicotinic agonists alter S1 amplitude
        • Translational validity with varenicline
      Steven J. Siegel, M.D., Ph.D. Translational Neuroscience Program
    • Olanzapine & haloperidol increase amplitude at long ISI no effects at short ISI - i.e. antipsychotics increase the gain of the system leading to an apparent change in gating * * Steven J. Siegel, M.D., Ph.D. Translational Neuroscience Program
    • * Nicotine & Varenicline increase S1 amplitude of Human - P50 Steven J. Siegel, M.D., Ph.D. Translational Neuroscience Program
    • Nicotine & Varenicline increase S1 amplitude of Mouse - P20 * Steven J. Siegel, M.D., Ph.D. Translational Neuroscience Program
    • Translational model of gain control Rolipram acts like an antipsychotic to increase S1 response Steven J. Siegel, M.D., Ph.D. Translational Neuroscience Program
      • EEG - clinically relevant & foster preclincal translation
        • Sensory systems - provide stimulus / input control
        • Evaluate neural response a stimulus - i.e. can assess gain
        • Validation of rodent equivalents to human measures
      • Disease models - Schizophrenia
        • Pharmacological, endocrine, genetic
      • Treatment models
        • Examples of medication effects
      • Limitations:
        • Averages vs. single trial analysis
      Scope & framework for modeling gain control Steven J. Siegel, M.D., Ph.D. Translational Neuroscience Program
    • Latency jitter hypothesis - low ITC Amplitude hypothesis - low signal Several potential mechanisms to explain changes in amplitude on an averaged response Low amplitude Low amplitude Steven J. Siegel, M.D., Ph.D. Translational Neuroscience Program
    • Translational Neuroscience Program Previous studies suggest increased latency jitter in schizophrenia Mouse amphetamine & haloperidol models suggest changes in single trial amplitude as well Steven J. Siegel, M.D., Ph.D. 180 ms 700 ms Amphetamine Saline Haloperidol Saline
    • Reduction of gamma ITC in Schizophrenia previously shown by Roach and Mathalon Schizophr Bull. 2008; 34: 907-926 Auditory Evoked Potential Phase-Locking Plot wavelet decomposition Penn subjects display reduced gamma PLF in schizophrenia n = 20/group ( p < 0.04 ), consistent with previous findings Steven J. Siegel, M.D., Ph.D. Translational Neuroscience Program
    • NR1 hypomorphic Mice have deficits in Gamma ITC
      • 12% normal expression of NMDA R1
      • social, self care, learning & memory impairments
      • Reduction of PV interneurons related to generation of gamma oscillations
      • However, ERP amplitudes are larger in NR1 hypomorphs - suggesting that gain and ITC are not entirely synonymous
      Steven J. Siegel, M.D., Ph.D. Translational Neuroscience Program
    • Summary
      • Schizophrenia patients display a reduced relationship between stimulus intensity and response intensity for ERPs - i.e. reduced gain.
      • ERP data are often expressed as an average of multiple trials to a single stimulus, obscuring effects of latency jitter versus gain in single trials
      • May be helpful to evaluate intensity functions and single trial data for S1 responses in schizophrenia.
      • Animal models can assess the potential determinants of reduced and increased gain control using highly translatable EEG and ERP methods
      Steven J. Siegel, M.D., Ph.D. Translational Neuroscience Program
    • Thank You Steven J. Siegel, M.D., Ph.D. Translational Neuroscience Program
    • Ketamine disrupts deviance ERPs * * ** ** Steven J. Siegel, M.D., Ph.D. Translational Neuroscience Program
    • Gamma Activity & Intertrial Coherence
      • Disrupted in schizophrenia & autism
      • Rhythmic activity in 30 – 100 Hz range
        • Local coupling of neuronal assemblies
      • Mechanism: synchronization of pyramidal cells by fast-spiking interneurons
      • Cognitive correlates, e.g. working memory
      • ITC - measure of EEG synchronization with an external stimulus at a particular frequency = consistency of response
      Stimulus Evoked Response 2 Trial 1 3 4 Phase Steven J. Siegel, M.D., Ph.D. Translational Neuroscience Program
    • Use models for therapeutic development: GABA Rescue of Gamma Deficits
      • Baclofen , selective GABA B agonist: rescues gamma PLF deficits in NR1 neo -/-mice
      * p < 0.02; ** p < 0.004 Steven J. Siegel, M.D., Ph.D. Translational Neuroscience Program
    • Use models for therapeutic development: GABA Rescue of Gamma Deficits
      • Clordiazepoxide , non-selective GABA A positive modulator: reduces gamma PLF in both groups
      * p < 0.02 Steven J. Siegel, M.D., Ph.D. Translational Neuroscience Program
    • Bupropion - indirect monoamine agonist & nicotinic antagonist Primary effects are on amplitude - only see the effects of nicotine on gating with illness plus treatment in the model Steven J. Siegel, M.D., Ph.D. Translational Neuroscience Program
      • Normal mouse
      • Mouse on chronic bupropion
      • Mouse on bupropion + haloperidol
      • Mouse on bupropion + haloperidol + nicotine
      Steven J. Siegel, M.D., Ph.D. Translational Neuroscience Program
    • Medicated schizophrenia patients have abnormalities in gamma & theta oscillations Steven J. Siegel, M.D., Ph.D. Translational Neuroscience Program
    • Supplemental Summary
      • Intertrial coherence influences amplitude if ERPs, similar to latency jitter, but is not the only factor involved.
      • Gating abnormalities may represent a mixed phenotype that results from a combination of reduced gain from the illness and effects of medication.
      Steven J. Siegel, M.D., Ph.D. Translational Neuroscience Program
      • Previous Post Docs:
        • Jenny Phillips, Ph.D.
        • Tobias Halene, M.D., Ph.D.
      • Previous Students:
        • Jonathan Kahn
        • Danielle Trief
        • Sonalee Majumdar
        • Michelle Mergenthal
        • Jennifer Fleisher
        • Jonathan Abelson
        • Jack Kent
        • Danit Mayor
        • Karen Rudo
        • Josh Stillman
        • Julia Glasser
        • William Beckerman
        • Neal Ghandi
        • Rachel Klein
        • Suzanne Wilson
        • Omid Motobar
        • Cara Rabin
        • Jon Talmud
        • Steve Luminaise
        • Julie Sisti
        • Christina Bodarky
        • Randal Toy
        • Viral Gandhi
        • Karen Ryall
        • Jing-Yuan Ma
        • Joe Crisanti
        • Stephen McKenna
        • Amar Bains
        • Xavier Readus
        • Lillia Rodriguez
        • Jimmy Suh
        • Jennifer Croner
        • Rachel Rosenberg
        • James Wang
        • Mia Wang
        • Marcella Chung
        • Kimia Pourrezai
        • Victoria Behrend
        • Philip Santoiemma
      • Staff :
        • Yuling Liang, MD
      • Post-Docs
        • Robert Featherstone, PhD
        • Valerie Tatard, Ph.D.
      • Graduate Students
        • Mike Gandal
        • Robert Lin
        • John Saunders
        • Hiren Makadia
      • Undergraduate Students
        • Tony Thieu
        • Stefanie Fazio
        • Dheepa Sekar
        • Eric chu
        • Sarah Doherty
        • Mili Mehta
        • Yufei Cao
      • NIMH, NIDA, NCI
      • Commonwealth of PA
      • SMRI, NARSAD
      • NuPathe, AstraZeneca, Lilly
      • ITMAT, Abramson Cancer Center
      • Previous Staff:
        • Mary Dankert
        • Farzin Irani
        • Christina Maxwell
        • Kayla Metzger
        • Patrick Connolly
        • Breanne Weightman
        • Wendy Zhang
        • Debbie Ikeda
        • Jake Burnbaum.
        • Chalon Majewski-Tiedeken.
        • Noam Rudnick
        • Richard Ehrlichman
        • Laura Amann
        • Brianna Weightman
      • Collaborators
        • Basic:
          • Steve Arnold, Konrad Talbot
          • Chang-Gyu Hahn, Greg Carlson
          • Ted Abel, Diego Contreras
          • Julie Blendy, Ted Brodkin
          • Lief Finkel, M. Lazarewicz
        • Clinical:
          • Raquel Gur, Ruben Gur, Bruce Turetsky - Neuropsychiatry
          • Caryn Lerman, Andrew Strasser TTURC
          • Tim Roberts & Chris Edger, CAR/CHOP
      Steven J. Siegel, M.D., Ph.D. Translational Neuroscience Program