1. Attention, Working Memory, and Executive Function [Processes Under Construction] Graham Williams and Stacy A. Castner Department of Psychiatry, Yale University School of Medicine VA Connecticut Healthcare System, West Haven, CT

2. Critical Factors in Cognition  An internal representation is guiding behavior  There is a model pertaining to relevant events and the demands of the situation  Data is held in an abstract form that can be translated  Response decisions are guided by motivation

3. Internally guided behavior: Precept vs Percept  Expectations in the environment vs ability to change the environment  Choosing optimum goals and deciding relevant events and outcomes  Attending to relevant stimuli and biasing against other environmental events  Holding on to key information while relevant and holding back from responding to non-goal-selective stimuli  Motivation to maintain goal and test behavioral hypothesis  Monitoring outcome and adjusting behavioral hypothesis vs holding fast to a predetermined rule

4. Working Memory: A Core Cognitive Function Affected in Many Neuropsychiatric Disorders  Working memory: the ability to hold information transiently in mind and process it to use later. Maintenance vs. manipulation?  Patients with schizophrenia and their unaffected siblings are impaired across a variety of paradigms (Park et al., 1999). How is spatial working memory tested?  Working memory performance is the best predictor of propensity for relapse and social reintegration. How far is this true? Is the dependent on the way in which it is tested?  Working memory deficits are also prevalent in other disorders such as PD, Alzheimer ’ s and normal aging. Does this mean there is no specificity of working memory deficits to schizophrenia?

5. What is Spatial Delayed Response?  Attend to a spatial sensory stimulus  Maintain goal of acquiring preferred food treat  Understand the basic limitations and provisions of the task (only one choice, only limited time)  Remember target location (e.g., where well was baited vs. where to respond)  Motivation to remember target location  Overcoming distraction

6. 6-OHDA Dopamine Depletion in Primate dlPFC Impairs Working Memory Control DA- Depletion Ablation Adapted from Brozoski et al. Sci.1979 205:929-932 % Correct Response 30 40 50 60 70 80 90 100 510204060 Delay (s) % Correct Responses

7. Spatial Delayed Response Measure:Improvement of performance from stable baseline of mean = 65 - 75% correct and SEM ≤2.5% over 10 – 20 test sessions

8. Ketamine Profoundly Impairs Working Memory 40 45 50 55 60 65 70 75 Percent Correct 0.1 mg/kg Ketamine 0.3 mg/kg Ketamine 1.0* mg/kg Ketamine Placebo * F[3,36] = 11.852; p = 1.51E-05. * Significantly differs from placebo (p < 0.05) Roberts et al. Psychopharmacol 2010

9. 40 45 50 55 60 65 70 75 Percent Correct Placebo +Ketamine 0.00001mg/kg A77636 +Ketamine 0.0001mg/kg A77636 +Ketamine 0.001mg/kg A77636 +Ketamine Overall ANOVA: F[3,36]=6.266; p = 0.002. Significant post hoc comparisons for 0.0001 and 0.001 mg/kg + ketamine compared to placebo/ketamine (p = 0.003 and 0.039 respectively); 0.00001 mg/kg + Ketamine is not significant compared to placebo/ketamine (p = 0.393) Linear, F[1,36] = 2.876; p = 0.099 Quadratic, F[1,36] = 14.036; p = 0.001 Dose-dependency of the Full D1 Agonist Shows an Inverted-U Function * * Roberts et al. Psychopharmacol 2010

10. Percent Correct Delayed Response Performance following Pretreatment with the GlyT1 Inhibitor PF3463275 1 st 2 nd Placebo 0.010.050.17 PF3463275 (mg/kg) Ketamine Placebo0.010.050.17 PF3463275 (mg/kg) 40 45 50 55 60 65 70 75 80 40 45 50 55 60 65 70 75 80 Significant main effects of PF3463275 (F[3, 21] = 6.437; p = 0.003) and ketamine (F[1, 7] = 47.469; p < 0.001); Significant interaction (F[3, 21] = 9.534); * indicates significance vs. placebo/ketamine by Scheffe post-hoc comparison (p = 0.047 for low dose; p = 0.001 for mid and high doses) * * *

11. Oculomotor Delayed Response Tasks

12. What is different about oculomotor testing?  Stimuli are discrete, with only one visible at a time  Fixation control keeps spatial measures parametric and prevents position/gaze biasing  Many more trials can be performed (sometimes 500 – 1000 in one session)  Lack of interference from other stimuli in mnemonic tasks  Allows for many task alternatives, including antisaccade and control tasks such as those requiring visually guided saccades  Gives measures not only of correct responses but also reaction time and accuracy

13. Prefrontal Circuitry in Spatial Working Memory

14. Neurobiological Constructs in Spatial Working Memory  Cellular basis hinges on recurrent excitation and persistent activity. Inhibition and synchronization are required  Prime circuitry involves dlPFC, posterior parietal cortex LIP, and anterior cingulate cortex. Subcortical structures involve striatum and MD thalamus  Performance has shown to be dependent on dopamine signaling by a number of different measures  Functional requirements depend on working memory load. Sensory information is encoded

15. Functional imaging of D1 agonist reversal of ketamine induced cognitive deficits in the nonhuman primate as shown by regional cerebral glucose metabolism

16. FDG-PET Methods Preparation: The study was performed on 8 young adult rhesus macaques that were pretrained to stable performance (65 – 75%  2.5% correct over 20 trials in 20 test sessions) on a standard spatial delayed response task. Animals were required to work for 15 – 25 min, often using highly preferred treats. Experimental design: A pseudorandom Latin squares design for D1 agonist (A77636) and placebo (sterile water) pretreatments vs. ketamine and placebo (sterile saline) treatments prior to FDG injection and cognitive testing. Delayed response Chairing Catheter Ket Anesthesia85+ min 15 min Transmission Scan 10 min D1 / Pl 0 min / Pl 45 min FDG 55+ min 20 min Emission Scan 6 min 120 min140 min

17. Placebo/ketamine – Placebo/placebo contrast Effect of Ketamine on rCMGlu in Relation to PFC Ketamine (1.0 mg/kg IM; 1.7mg/kg in one animal) as compared to placebo, produced an elevation of glucose metabolism in multiple brain regions, including infralimbic/prelimbic cortices, dlPFC Areas 46/8a, and anterior cingulate cortex in the frontal lobes, as well as large areas of parietal cortex and posterior cingulate cortex. Williams et al. Soc Neurosci Abstr (2008); manuscript in preparation

18. Interaction of A77636 (0.0001 mg/kg) and Ketamine: PFC Placebo/ketamine – D1 high/ketamine contrast The high dose of A77636 provided a greater protection from ketamine’s ability to elevate rCMGlu not only in Area 46 but also in parietal cortex. Williams et al. Soc Neurosci Abstr (2008); manuscript in preparation

19. Is There an Ideal Spatial Working Memory Task?  How well does it parametize what is being remembered?  How consistent is the attentional component and attentional load  How well is distraction quantified?  What is the precise metric measured and how informative is it of the efficiency of the neural systems involved?

20. Target locations: Spatial Working Memory with Intervening Stimuli 20° 16° 12°

21. A single trial with four intervening stimuli

22. The Space – Color Translocation Task

23. Attentional Set-Shifting Recruits Homologous Regions of Prefrontal Cortex in Human and Nonhuman Primates Nakahara et al. (2002) Science 295(5559): 1532-1536

24. Translational Approaches in Cognition: Sim-GMLT Development in Collaboration with Dr. Peter Snyder (then of PGRD) and D. Holden of Forza-Bassett

25.  Attention is almost obligatorily measured by reaction time and very dependent upon detection. Competing for attention is a critical construct, where at any time stimuli can be picked out and responded to  Thus, an alternative way to view attention is by having multiple potential stimuli to respond to rather than utilizing particular distracting stimuli. If the outcome for responding to certain stimulus is better than that for others, performance can be measured as total yield over time or propensity to choose high value stimuli  For working memory, attention may be a vital factor for establishing and maintaining sufficient neural representation  For executive function, it can be hypothesized that a model is constructed which predicts outcomes dependent on what is being attended to From Attention to Executive Function

26.  Cognition utilizes a model of potential salient events and outcomes related to responses. This model guides attention and biases against processing/storage of non-salient events  It is not necessarily just sensory information that is being represented by neural activity but also precepts that are part of the model. Thus, “working-memory buffers” and “executive function” may occupy much of the same circuitry  Multiple choice tasks optimize the potential for observing effects of “competing” or “distracting” stimuli  For assessment of working memory, we need to understand how far translation (e.g., space to color) and abstraction of information is involved rather than just “delay” or “intervening stimuli” Construction Towards Understanding Deficit States