The Nonhuman Primate as Model System for Mechanistic Studies of Glutamate System Function and Dysfunction

The Nonhuman Primate as Model System for Mechanistic Studies of Glutamate System Function and Dysfunction FORUM ON NEUROSCIENCE AND NERVOUS SYSTEM DISORDERS Board on Health Sciences Policy Glutamate-related Biomarkers in Drug Development for Disorders of the Nervous System Charles E. Schroeder, PhD Cognitive Neuroscience and Schizophrenia Program Nathan Kline Institute Department of Psychiatry Columbia University College of Physicians and Surgeons New York, New York

Cognitive Neuroscience Laboratory Collaborators at NKI: Dan Javitt -Pam Butler -John Smiley -Elisa Dias -Mark Klinger -Antigona Martinez -John Foxe -Gail Sillipo -Sophie Molholm -Nadine Revheim -Gary Linn

Issues -Things potentially relevant to human biomarker development -Behavioral cognitive effects that index brain operations -ERP neuronal mechanisms -C1, P1, N1, MMN, P3, ERN, selection negativity -EEG -- neuronal mechanisms -Frequency band delta, theta, alpha, beta1, beta2, gamma 1-9 -slow, infraslow -ERP / EEG -- Pharmacological mechanisms -Key Concerns -When is it necessary to use a monkey vs a rodent model? -Awake is important constrained is also -Local vs Systemic manipulations? -Difficulty of training?

Thumbtack

Methods: Laminar Profile Analysis

Averaged laminar profile analysis

Averaged laminar profile analysis Stim 100 200 ERP component generators

Averaged laminar profile analysis CSD Profile Source + + + + + + + Sink + + + + + + + Stim 100 200 ERP component generators Cellular population Neuronal process Source Sink 0.75mV/mm 2

Human-simian homologies - Visual C1 & P1 (Schroeder et al., 1991; 1995; Givre et al., 1994; 1995) - Visual Subcortical ripple components (Schroeder et al., 1992) - Visual N1 & P2 (Givre et al., 1994; Schroeder et al., 1998) - Visual Selection Negativity (Mehta et al., 2000a; 2000b) - Visual ERN (Woodman et al., 2010) - Auditory N8, P1 (P50) and N1 (Steinschneider et al., 1992) - Auditory MMN (Javitt et al., 1996; 1997; 2001) - Somatosensory N12, P25, N45 (Peterson et al., 1995; Allison et al., 1995) - Phase reset & Evoked Contributions (Shah et al., 2004)

Considerations for Establishing Human- Simian Homologies: - Approximation of brain region - Comparable task and stimuli - Effects of task and stimulus manipulations -3/5 rule

Human-Simian Homologies (Abnormal in schizophrenia) - Visual C1 & P1 (Schroeder et al., 1991; 1995; Givre et al., 1994; 1995) (e.g., O Donnell et al.,) - Visual Subcortical ripple components (Schroeder et al., 1992) - Visual N1 & P2 (Givre et al., 1994; Schroeder et al., 1998) - Visual Selection Negativity (Mehta et al., 2000a; 2000b) - Visual ERN (Woodman et al., 2007) - Auditory N8, P1/P50 and N1 (Steinschneider et al., 1992) -- (e.g., Light et a - Auditory MMN (Javitt et al., 1996; 1997; 2001) -- (e.g., Light et al) - Somatosensory N12, P25, N45 (Peterson et al., 1995; Allison et al., 1995) - Phase Reset & Evoked Contributions (Shah et al., 2004) Underlying Brain Circuitry, Neuronal Populations and Physiology/Pharmacology

Single trial laminar profile analysis (Lakatos et al., J. Neurophysiol., 2005) (Musacchia et al., work in progress)

Structure of ambient oscillations Phase-amplitude coupling.. X- Frequency (later). X-citability

Higher frequency oscillations and: theta band oscillations and phase-encoding of spatial information in hippocampus (O Keefe et al., 2003; Maurer and McNaughten, 2007 ) theta band oscillations and formation of mnemonic neuronal representations (Jensen et al., 2007) alpha band oscillations and internally-directed cognitive processes (Palva and Palva, 2008), gamma band oscillations and feature binding (Singer and Gray, 1995) gamma band oscillations and attention/sensory selection and CTC (Fries et al., 2002). Gamma/beta oscillations and top-down vs bottom-up operation (Buschman & Miller, 2006). gamma band oscillations and working memory maintenance (Pesaran et al., 2002).

Low frequency oscillations and: (the world according to us ) Generation of some ERP components (Shah et al, Cerebral Cortex, 2004) Visual enhancement of vocalization processing in auditory cortex (Schroeder et al.,. TICS, 2008) Fixation-related amplification in visual cortex --- Active Vision (Rajkai et al., Cerebral Cortex, 2007) (Chen et al., not-yet-rejected) (Barczak, Radman, et al., work in progress) Face/voice integration in auditory cortex (Kajikawa et al., work in progress) Multisensory enhancement in primary sensory cortex (Lakatos et al., Neuron, 2007) Attentional selection in primary visual cortex (Lakatos et al.,. Science, 2008) Attentional selection in primary auditory cortex (Lakatos et al., Neuron, 2009) Attentional selection in higher-order cortices in humans (Besle et al., not-yet-rejected) Attentional selection of conversational stream in humans (Zion-Golumbic et al., work in progress)

I. Attentional Selection

Intermodal Selection Paradigm (Lakatos et al., Science, 2008)

Intermodal attention in human e-cog studies (Besle et al, not-yet-rejected)

Attentional Modulation of Phase

Widespread Cortical Distribution

Monkey Intracortical studies (Lakatos et al., Science, 2008)

Attentional bias of oscillation phase

Attention (delta phase) and Inter-layer transmission

Significance re schizophrenia? -Hypo-entrainment -Hyper-entrainment -Oscillations and S/N

Patients vs Controls: Spectra (Lakatos et al., not-yet-rejected)

Patients vs Controls: Topography What about gamma (e.g., Uhlhaas et al.)?

Gamma as a Slave? Cross frequency coupling Differential coupling across operational modes Baseline increases in gamma with Ketamine (O Donnell talk) Different frequencies for different function scales?

Injectrode

Oscillatory Phase Modulation in natural vision Visual Sniffing Wealth? Age? Doing? Clothing? Positions? How long away? 1 subject, 7 viewing instructions, 3 min

Modulation of excitability by fixationin the dark (Rajkai et al., Cereb. Cortex, 2008) Driving vs Modulatory (supragranular) inputs

Importance of Attention in Phase Modulation (supragranular) (Lakatos et al., Neuron, 2009)

Quantified pattern of modulation across experiments

Oscillatory phase concentration at fixation onset Optimal Excitability Phase

Quantified pattern of fixation-related modulation across visual areas -LGN -V1 -V2 -V4 -MT -IT?? Non-visual Areas?? (Chen, Radman et al., not-yet-rejected)

amplitude ( mv/mm ) 2 amplitude ( mv/mm ) 2 Corresponding Effects in Auditory Cortex Cortical Layers 1 vis stim attend auditory aud stim vis stim attend visual aud stim 2/3 4 5 6 sink 0.4 mv/mm2 source -400-200 0 200 400-400 -200 0 200 400 time (ms) time (ms) Channel 5 CSD, Att. Audvs Att. Vis Filtered (1.2-2.4 Hz) CSD of Ch 5 0.6 0.09 0.3 0.06 0.03 0 0-0.3-0.03-0.6-0.06-0.9-400 -200 0 200 400-400 -200 0 200 400 time (ms) time (ms) -0.09 (Lakatos et al., Neuron, 2009)

Free viewing in natural vision (Radman, Barczak et al., work in progress)

Advantage of natural viewing

Implications: -Corollary discharge signals use phaseresetting to amplify (and suppress) driving inputs. -Effects biased toward supragranular layers -Salience implied *** Bosman et al., and µ-saccade effects

What happened to gamma? And for that matter Theta?

Monkey as a model for human? Based on Anatomical Similarity

-Rhythmic shifting of excitability!! ( optimal and non-optimal phases) Source + + + + + + + -What causes neurons to oscillate, and in synch? -Ubiquitous and Significant effects on operations Sink + + + + + + + Oscillations signify

Oscillations as Instruments (sensory perspective) 1) Oscillations have organized (hierarchical) structure - control baseline excitability

Oscillations as Instruments (sensory perspective) 1) Oscillations have organized hierarchical structure - controls baseline excitability 2) salient stimuli (any source) reset ambient rhythms

Oscillations as Instruments (sensory perspective) 1) Oscillations have organized hierarchical structure - controls baseline excitability 2) stimuli (any source) reset ambient rhythms, 3) subsequent input processing is then influenced by oscillatory phase, i.e.,.

Impact of phase re-set

Overlying Functional Domains

Charges for this Session Regarding: -Key factors impacting successful translation of rodent and primate biomarkers -Identify the key principles that should be considered with biomarker validation in primate models, including most relevant technologies for testing in primates

Behavioral Signs of Underlying Neuronal Entrainment

Rhythmic Mode: Behavioral Effects Jones, Large and Colleagues, e.g., (Jones et al, Perception, 2001) (Praamstra et al, J. Neurosci., 2006)

Cross-frequency coupling and phase-locking