Angus W. MacDonald, III with Dori Henderson University of Minnesota Associate Professor of Psychology & Psychiatry

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1 Angus W. MacDonald, III with Dori Henderson University of Minnesota Associate Professor of Psychology & Psychiatry

2 Working Memory and PFC Working memory refers to a collection of storage and executive processes required for adaptive responding Working memory manipulations will evoke activity associated with endogenous brain activity Working memory networks include: prefrontal cortex ventrolateral PFC dorsolateral PFC anterior cingulate parietal cortex Large overlap with networks for other executive functions ALE of N-back, Owen et al., 2005

3 PFC and Glutamatergic Functioning Working memory is associated with functions of reverberating circuits connecting pyramidal neurons in PFC, and is therefore tightly linked to NMDA functions. From Goldman- Rakic, 1995

4 PFC and Glutamatergic Functioning Lewis & colleagues, 2003

5 Paucity of Data at the Convergence of Methods Glutamate / NMDA /AMPA Manipulations (Pharmacology / Genes) Human Methods (Behavior, ERP s, Oscillations, fmri) Working Memory / Executive Functioning

6 Pharmacologic Challenges Ketamine Memantine

7 Pharmacologic Challenge Umbricht, et al., 2000 Ketamine (NMDA -) 0.24 mg/kg +.09 mg/kg/hour iv 20 volunteers Expectancy variant of AX Task 70% AX trials ERP data from this task are awaiting publication

8 Pharmacologic Challenge Van Wageningen, et al., 2009 Memantine (NMDA -) 20 mg/d 21 days 31 volunteers Dichotic listening test (auditory attentional control) No effect on performance

9 Genetic Systems From Moghaddam, 2003

10 Genetic Systems Stefanis, et al., military conscripts 1 NRG1 SNP predicted spatial WM performance 2 DTNBP1 SNP s predicted reduced sustained attention performance Not significant when controlling for multiple comparisons Kircher, et al healthy subjects No relationship between DTNBP1 SNP and WM performance

11 Genetic Systems 1030 healthy European Americans Screened top-hit SNP s from SzGene for RGS4 DTNBP1 GRIN 2 DAO (2 SNPS) N-Back and Context Processing T asks Multiple comparisons corrected by resampling Corrected Exploratory Analyses Uncorrected Confirmatory Analyses A. rs d' Percent Errors Percent Errors Letter 1 Back A. rs Letter AX AX AY B. rs DPX BX Trial Type DAO SNP s A/A A/T* T*/T* Genetic Risk BY B. rs d' d' d' Spatial 2 Back Letter AX A/A A/G* G*/G* Genetic Risk DPX C/C C/T* T*/T* Genetic Risk 0 AX AY BX Trial Type BY 2.0 C/C C/T* T*/T* Genetic Risk

12 Genetic Systems Egan, 2004 Egan et al., 2004 GRM3 SNP s hcv Did not predict WM performance among 548 mixed participants N-back during fmri (n=65 controls) Post-mortem EAAT2 expression (n=10-19 controls Sz patients) AA 39 > G 26

13 Genetic Systems Papassotiropoulos, et al., Swiss, 922 German, 523 Serbian healthy volunteers, various WM tasks GWAS analysis controlling for genome-wide error & stratification SCN1A (encoding the α subunit of the type I sodium channel) Predicted N-back response in 22 volunteers in fmri 2 back, AC > AA, p uncorrected <.001

14 Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia CNTRICS meeting 5 (April 2010) Validity - does it really reflect the targeted cognitive and neural mechanisms of interest? Reliability - does it have the necessary measurement properties? Predictive Validity - a drug effect in the animal will predict a drug effect in humans Practicality - can it work as a screen in a vertically integrated translational research program

15 Pharmacologic Challenge macaque Roberts et al., 2010 Ketamine (NMDA -) 10 non-human primate (macaque) Variables dosages Spatial Delayed Response T ask Figure courtesy of G. Williams and S. Castner CNTRICS II Meeting 2

16 Ketamine & WM Performance 75 Percent Correct * 40 Placebo 0.1 mg/kg Ketamine 0.3 mg/kg Ketamine 1.0* mg/kg Ketamine Roberts et al. Psychopharmacol 2010 Slide courtesy of G. Williams and S. Castner CNTRICS II Meeting 2

17 Dose-Dependent Repair of WM Performance with D1 Agonist A77636 Percent Correct * * Placebo +Ketamine mg/kg A Ketamine mg/kg A Ketamine 0.001mg/kg A Ketamine ine Roberts et al. Psychopharmacol 2010 Slide courtesy of G. Williams and S. Castner CNTRICS II Meting 2

18 Limitations? Literature on glutamate manipulations using WM or other executive functions in healthy humans is small? Studies of biomarkers (fmri, etc.) with these manipulations generally had small samples? No studies in the literature address the specificity (vs. generality) of cognitive deficits or biomarkers? Little has been published about the measurement characteristics (reliability, etc) of the available assays

19 Conclusions: Smoke. Fire? It is almost impossible to imagine that glutamatergic mechanisms are not central to working memory and other executive functions Pharmacologic and genetic studies have demonstrated effects on performance The appropriateness of such cognitive markers requires more definitive study In particular, direct comparison of sensitivity to simpler biomarkers

20 Acknowledgments Laboratory for Translational Research in Cognitive and Affective Mechanisms Michael B. Miller Dori Henderson Jazmin Camchong Seung Suk Kang Madelyn Steen Melissa Johnson Edward Patzelt Lindsay Swanson Other Collaborators Matt Chafee Scott Sponheim Steve Manuck Kelvin Lim Steve Silverstein Deanna Barch Cameron Carter Jim Gold Dan Ragland Research supported by NIMH grant R21MH079262