Diencephalic Mechanisms of Visuomotor Integration · 2008-07-18 · DepartmentofHealth and Human...

DepartmentofHealth and Human Services

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1. TITLE OF PROJECT

Diencephalic Mechanisms of Visuomotor Integration

PI: STANFORD, TERRENCE R

2 R01 EY012389.05.42.

Dual:

IRG: CVP

Form Approved Through 05/2004_I_ Nn-Ag_5-0001

Council: 05/2004

Received: 11/01/2003

2. RESPONSE TO SPECIFIC REQUEST FOR APPLICATIONS OR PROGRAM ANNOUNCEMENT OR SOLICITATION [] NO [] YES

(If "Yes," state number and title)

Number: Title:

3. PRINCIPAL INVESTIGATOR/PROGRAM DIRECTOR New Investigator [] No [] Yes

3a. NAME (Last, first, middle) 3b. DEGREE(S)

Stanford, Terrence R. Ph.D3d.3c, POSITION TITLE

Assistant Professor3e. DEPARTMENT, SERVICE, LABORATORY, OR EQUIVALENT

Neurobiology and Anatomy3f. MAJOR SUBDIVISION

School of Medicine

4. HUMAN SUBJECTS

RESEARCH

[] No

[] Yes

6. DATES OF PROPOSED PERIOD OF

SUPPORT (month, day, year--MM/DD/YY)

From Through

07-01-04 06-30-099. APPLICANT ORGANIZATION

Name

Address

39 TELEPHONE AND FAX (Area code, number and extension)

TEL: 336-716-0359 FAX:336-716-4534

4a. Research Exempt [] No [] Yes

If "Yes," Exemption No.

4b. Human Subjects 4c. NIH-defined Phase IIIAssurance No.

Clinical Trial

FWA00001435 [] No [] Yes

7. COSTS REQUESTED FOR INITIAL

BUDGET PERIOD

7a. Direct Costs ($)

$225,000

Wake Forest University Health SciencesMedical Center Boulevard

Winston-Salem, NC 27157

Institutional Profile File Number (if known) 9021205

12. ADMINISTRATIVE OFFICIAL TO BE NOTIFIED IF AWARD IS MADE

Name

Title

Address

MAILING ADDRESS (Street, city, state, zip code)



E-MAIL ADDRESS:

[email protected]

5. VERTEBRATE ANIMALS [] No [] Yes

5a. If "Yes," IACUC approval Date 5b. Animal welfare assurance no

07-15-03 A3391-01

8. COSTS REQUESTED FOR PROPOSED

PERIOD OFSUPPORT

7b. Total Costs ($) 8a. Direct Costs ($) 8b. Total Costs ($)

$318,525 $1,125,000 $1,607,85010. TYPE OF ORGANIZATION

Public: --_ [] Federal [] State [] Local

Private: -_ [] Private Nonprofit

For-profit:--_ [] General [] Small Business

[] Woman-owned [] Socially and Economically Disadvantaged

11. ENTITY IDENTIFICATION NUMBER

-------------------- DUNS NO. (if available)

937727907Congressional District 5th

13. OFFICIAL SIGNING FOR APPLICANT ORGANIZATION

Marty DozierDirector, Grants Management, Controllers OfficeWake Forest University Health SciencesMedical Center BoulevardWinston-Salem, NC 27157

Name

Title

Address

Sheila L. Vrana, Ph.D.Assistant Dean for Research



Tel (336) 716-2406

E-Mail [email protected]

FAX (336) 716-6705

14. PRINCIPAL INVESTIGATOR/PROGRAM DIRECTOR ASSURANCE: I certify that thestatements herein are true, complete and accurate to the best of my knowledge. I amaware that any false, fictitious, or fraudulent statements or claims may subject me tocriminal, civil, or administrative penalties. I agree to accept responsibility for the scientificconduct of the project and to provide the required progress reports if a grant is awarded asa result of this application.

15. APPLICANT ORGANIZATION CERTIFICATION AND ACCEPTANCE: I certify that thestatements herein are true, complete and accurate to the best of my knowledge, andaccept the obligation to comply with Public Health Services terms and conditions if a grantis awarded as a result of this application. I am aware that any false, fictitious, or fraudulentstatements or claims may subject me to criminal, civil, or administrative penalties.

Tel (336) 716-4548 FAX (336) 716-4480

E-Mail [email protected]

SIGNATURE OF PI/PD NAME_IN 3a.

(Inink. "Pef_naturenotap/pta_

SIGNATURE OF OFFICIAE NAMED IN 13.

DATE

DATE

OC 29 2o03

• PHS 398 (Rev. 05/01) Face Page Form •

• PrincipalInvestigator/ProgramDirector(Last,first,middle):Stanford, Terrence R.

DESCRIPTION: State the application's broad, long-term objectives and specific aims, making reference to the health relatedness of the project. Describe

concisely the research design and methods for achieving these goals. Avoid summaries of past accomplishments and the use of the first person. This abstractis meant to serve as a succinct and accurate description of the proposed work when separated from the application. If the application is funded, this

description, as is, will become public information. Therefore, do not include proprietary/confidential information. DO NOT EXCEED THE SPACEPROVIDED.

Decisions about where to look within a typical visual scene are governed by the relative salience of

individual stimuli and current behavioral objectives. To date, the majority of studies examining the cognitive

control of visual orienting have targeted frontal cortex. However, there is growing evidence to suggest that

signals related to working memory and decision-making are critically dependent on interactions between

frontal cortex and subcortical structures such as the basal ganglia, cerebellum, and thalamus. Thalamus is

unique among these subcortical structures; in addition to providing direct input to cortex, its constituent

nuclei mediate the influences of both the basal ganglia and cerebellum on their respective cortical targets.

Despite its critical anatomical position, virtually nothing is known about the nature of the information

represented in central thalamus. The current experiments seek to fully characterize the central thalamic

representations of cognitive factors relevant for producing visually-guided saccadic eye movements. The

proposed studies will be the first to examine the potential importance of central thalamic nuclei, and the

subcortical-cortical interactions they mediate, to the cognitive control of goal-directed saccadic eye

movements. In doing so, these experiments will help to define the essential neural substrates for visuomotor

cognition.

PERFORMANCE SITE(S) (organization, city, state)

Wake Forest University School of Medicine

Department of Neurobiology and AnatomyMedical Center Blvd.


KEY PERSONNEL. See instructions. Use continuation pages as needed to provide the required information in the format shown below.

Start with Principal Investigator. List all other key personnel in alphabetical order, last name first.

Name Organization Role on Project

Terrence R. Stanford, Ph.D. Wake Forest Univ. School of Medicine Principal Investigator

Disclosure Permission Statement. Applicable to SBIR/STI'R Only. See instructions. [] Yes [] No

• PHS 398 (Rev. 05/01) Form Page 2 •

• Principal Investigator/Program Director (Last, first, middle): Stanford, Terrence R.

The name of the principal investigator/program director must be provided at the top of each printed page and each continuation page.

RESEARCH GRANT

TABLE OF CONTENTS

Face Page ..................................................................................................................................................

Description, Performance Sites, and Personnel ...................................................................................Table of Contents .....................................................................................................................................

Detailed Budget for Initial Budget Period (or Modular Budget) ...........................................................

Budget for Entire Proposed Period of Support (notapplicablewith Modular Budget)...........................

Budgets Pertaining to Consortium/Contractual Arrangements (not applicable with Modular Budget)

Biographical SketchmPrincipal Investigator/Program Director (Not to exceed four pa,qes) ..................

Other Biographical Sketches (Not to exceed four pages for each - See instructions)) ........................Resources .................................................................................................................................................

Research Plan

Introduction to Revised Application (Not to exceed 3 pages) .........................................................................................................

Introduction to Supplemental Application (Not to exceed one page) ..............................................................................................

A. Specific Aims ......................................................................... _1 .................................................................................... r"--

B. Background and Significance ................................................ '-t" ................................................................................... |'

C. Preliminary Studies/Progress Report/ _ (Items A-D: not to exceed 25 pages*) .,_Phase I Progress Report (SBIPJSTTR Phase II ONLY) _ * SBIR/STTR Phase h/tems A-D limited to 15 pages1

I I

D. Research Design and Methods ............................................. _ .....................................................................................

E. Human Subjects .................................................................................................................................................................

Protection of Human Subjects (Required if Item 4 on the Face Page is marked "Yes")

Inclusion of Women (Required if Item 4 on the Face Page is marked "Yes") .................................................................

Inclusion of Minorities (Required if Item 4 on the Face Page is marked "Yes") ...............................................................

Inclusion of Children (Required if Item 4 on the Face Page is marked "Yes") .................................................................

Data and Safety Monitoring Plan (Required if Item 4 on the Face Page is marked "Yes" an.__da Phase I, II, or III clinical

trial is proposed ......................................................................................................................................................

F. Vertebrate Animals .............................................................................................................................................................

G. Literature Cited ...................................................................................................................................................................

H. Consortium/Contractual Arrangements ...............................................................................................................................

I. Consultants ........................................................................................................................................................................

J. Product Development Plan (SBIPJSTTR Phase II and Fast-Track ONLY) ..........................................................................

Checklist ....................................................................................................................................................

Appendix (Five collated sets. No page numbering necessary for Appendix.)

Appendices NOT PERMITTED for Phase I SBIPJSTTR unless specifically soficited.

Number of publications and manuscripts accepted for publication (not to exceed 10)

Other items (list):

1 publication

Page Numbers

1

2-3

4

N/A

N/A

5-7

8

9-11

1213-1616-22

22-3334

3435-38

N/AN/A

39

Check ifAppendix isIncluded

• PHS 398 (Rev. 05/01) Form Page 3 •

• PrincipalInvestigator/ProgramDirector(Last,first,middle):Stanford, Terrence R.

BUDGET JUSTIFICATION PAGE

MODULAR RESEARCH GRANT APPLICATION

Initial Budget Period Second Year of Support Third Year of Support Fourth Year of Support Fifth Year of Support

$ 225,000 $ 225,000 $ 225,000 $ 225,000

Total Direct Costs Requested for Entire Project Period

$ 225,000

I $ 1,125,000

Personnel

Terrence R. Stanford (PI): As the primary objective of my research effort, I plan to devote ----- of my time to

this project. Effort will be distributed across all phases of the project. I will participate in and/or provide direct

oversight for the development and maintenance of software/hardware, behavioral training of monkeys,

electrophysiological experiments, data analysis, and manuscript preparation. Flexibility in my appointment

allows for ------- ---------- effort to be devoted to research. At this time of this submission, however, a level of

----- effort will require some reduction in effort currently allocated to funded collaborative efforts (See Other

Support - Overlap).

Postdoctoral Fellow: Support for a postdoctoral fellow (at current NIH level) is requested. With the recent

addition of a second experimental rig, there is opportunity to significantly enhance production given the right

personnel. The advanced skills of a post-graduate would be a major asset at this point in time.

Laboratory Technician, Valerie Leach: A dedicated laboratory technician will be critical to the success of this

project. The awake-behaving primate preparation is a particularly labor intensive model for neurophysiological

study. It is critical that each animal, whether or not the subject of study on that particular day, be monitored

closely. Institutional and USDA regulations and NIH guidelines mandate strict record keeping and monitoring

procedures for animals that participate in experiments involving dietary restriction. Animals must be weighed

daily and strict controls over state of hydration must be maintained by lab personnel. Surgical implants must be

cleaned and inspected (daily or at least 4 times/wk). These would be primary responsibilities of a laboratory

technician. In addition, there are several tasks that are greatly facilitated when performed by more than one

person. Early stages of behavioral training (i.e., training the animal to go from cage to primate chair) are safer

and more easily accomplished when two people are involved. Stereotaxic surgical procedures require at least 1

assistant (in lieu of a technician, veterinary staff would need to be hired on an "as needed" basis at great cost).

Other technical responsibilities include: behavioral training that occurs in parallel with experiments; ordering

and maintaining inventories of laboratory supplies; setup and routine maintenance of equipment, fabrication of

electrodes. The salary requested was determined in consultation with the Department of Human Resources and

is based on ranges specified by the institution for this job description class.

Graduate Student: Support is requested for the continued training of Melanie Wyder, a Ph.D. candidate in the

Program in Neuroscience who has contributed significantly to this project.

Consortium

N/A

Fee (SBIR/STTR Only)N/A

• PHS 398 (Rev. 05/01 ) Modular Budget Format Page •

a Principal Investigator/Program Director (Last, first, middle): Stanford, Terrence R.

BIOGRAPHICAL SKETCHProvide the following information for the key personnel in the order listed for Form Page 2.

Follow the sample format for each person. DO NOT EXCEED FOUR PAGES.

NAME

Terrence R. Stanford

POSITION TITLE

LAssistant Professor

EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, and include postdoctoral training.)

INSTITUTION AND LOCATION DEGREE YEAR(s) FIELD OF STUDY(if applicable)

Connecticut College, New London, CT B.A. 1982 Zoology

Univ. Connecticut Health Ctr., Farmington, CT Ph.D. 1989 Neuroscience

Univ. of Pennsylvania, Philadelphia, PA Post-Doc 1990-1995 Psychology

A. Positions and Honors

1995-Present Assistant Professor, Department of Neurobiology and Anatomy, Wake Forest University School ofMedicine; Winston-Salem, NC

1989-1995 Postdoctoral Fellow, University of Pennsylvania, Department of Psychology, P.I.: Dr. David Sparks

Teaching Experience:

1991 Lecturer, College of General Studies, University of Pennsylvania, P.I.: Dr. Shigeyuki Kuwada1987-1989 Graduate Assistant, Dept. of Anatomy, Univ. of Connecticut Health Ctr. P.I.: Dr. Shigeyuki Kuwada

1982-1987 Predoctoral Fellow, Dept. of Anatomy, Neuroscience Program, Univ. of Connecticut Health CenterHonors and Awards1990-1993 National Research Service Award

1987-1989 Graduate Assistantship

1986-1987 Doctoral Dissertation Fellowship

1982-1986 Biomedical Sciences Fellowship1982 Graduated Cum Laude

1982 E. Francis Botsford Prize in Zoology, Connecticut College

B. Selected publicationsJournal Articles:

Kuwada, S., Stanford, T.R., and Batra, R. (1987): Interaural phase sensitive units in the inferior colliculus of the

unanesthetized rabbit: effects of changing frequency. J. Neurophysiol. 57, 1338-1360.Batra, R., Kuwada, S., and Stanford, T.R. (1989): Temporal coding of envelopes and their interaural delays in the

inferior colliculus of the unanesthetized rabbit. J. Neurophysiol. 61,257-268.Kuwada, S., Batra, R., and Stanford, T.R. (1989): Monaural and binaural response properties of neurons in the

inferior colliculus of the rabbit: effects of sodium pentobarbital. J. Neurophvsiol. 61,269-282.

Stanford, T.R., Kuwada, S., and Batra, R. (1992): A comparison of the interaural time sensitivity of neurons in theinferior colliculus and thalamus of the unanesthetized rabbit. J. Neurosci. 12, 3200-3216.

Batra, R., Kuwada. S, and Stanford, T.R. (1993) High-frequency neurons in the inferior colliculus that are sensitive

to interaural delays of amplitude-modulated tones: evidence for dual binaural influences. J.Neurophysiol. 70, 64-80.

White, J.M., Sparks, D.L., and Stanford, T.R. (1994): Saccades to remembered target locations: An analysis of

systematic and variable errors. Vision Research 34, 79-92.

Stanford, T.R. and Sparks. D.L. (1994): Systematic errors for saccades to remembered targets: Evidence for adissociation between saccade metrics and activity in the superior colliculus. Vision Research 34, 93-106.

Freedman, E.G., Stanford, T.R. and Sparks, D.L. (1996) Combined eye-head gaze shifts produced by electrical

stimulation of the superior colliculus in rhesus monkeys. J. Neurophysiol. 76: 927-952.

Stanford, T.R., Freedman, E.G. and Sparks, D.L. (1996) Site and parameters of microstimulation: Evidence for

independent effects on the properties of saccades evoked from the primate superior colliculus. J. Neurophysiol.76: 3360-3381.

Fitzpatrick, D.C., Batra, R., Stanford, T.R., and Kuwada, S. (1997) A population code for sound localization. Nature.28:871-874.

• PHS 39812590 (Rev. 05/01) Biographical Sketch Format Page •


Kuwada, S., Batra, R., Yin, T.C.T., Oliver, D.L., Haberly, L.B., and Stanford, T.R. (1997) Intracellular recordings in

response to monaural and binaural stimulation of neurons in the inferior colliculus of the cat. J. Neurosci.17:7565-7581.

Stein, B.E., Wallace, M.T. and Stanford, T.R. (1999) Development of multisensory integration: Transforming

sensory input into motor output. Mental Retardation and Development Disabilities Research Reviews 5:72-85.Stein, B.E., Jiang, W., Wallace, M.T., and Stanford, T.R. (2001)Nonvisual influences on visual information

processing in the superior colliculus. Prog. Brain Res. 134: 143-156.

Stein, B.E., Wallace, M.T., Stanford, T.R., and Jiang, W. (2002) Cortex governs multisensory integration in themidbrain. The Neuroscientist 8:306-314.

Stanford TR (2003) Signal coding in the primate superior colliculus revealed through the use of artificial signals. In:

The Superior Colliculus: New Approaches for Studying Sensorimotor Integration (Hall WH, Moschovakis A,

eds): CRC Press.

Wyder MT, Massoglia DP, Stanford TR (2003) Quantitative assessment of the timing and tuning of visual-related,saccade-related, and delay period activity in primate central thalamus. J of Neurophysiology 90:2029-2052.

Abstracts:

Batra, R., Kuwada, S., and Stanford, T.R. (1992): Sensitivity of neurons in the inferior colliculus of the

unanesthetized rabbit to interaural temporal disparities of the envelopes of high-frequency tones. Soc. Neurosci.Abstr. 18, 841.

Henis, E.A., Stanford, T.R., and Sparks, D.L. (1992): A computational model for modified saccade trajectories. Soc.Neurosci. Abstr. 18, 700.

Freedman, E.G., Stanford, T.R., and Sparks, D.L. (1993): An analysis of the metrics and dynamics of stimulation-

induced gaze shifts in the monkey. Soc. Neurosci. Abstr. 19, 786.Stanford, T.R., Freedman, E.G., Levine, J.M., and Sparks, D.L. (1993): The effects of stimulation parameters on the

metrics and dynamics of saccades evoked by electrical stimulation of primate superior colliculus. Soc. Neurosci.Abtsr. 19, 786.

Barton, E.J., Kalesnykas, R.P., Stanford, T.R. and Sparks, D. L (1995): Superior colliculus activity during orbitally-

dependent remembered saccades. Soc. Neurosci. Abtsr. 21.1194.

Nozawa, G., Stanford, T.R., Vaughan, J.W., Quessy, S., Kadunce, D., and Stein, B.E. (1997) A functional approach

to modeling multisensory integration in the superior colliculus. Soc. Neurosci. Abstr. 23:451

Quessy, S., Sweatt, A., Stein, B.E and Stanford, T.R. (2000) The influence of stimulus intensity and timing on

multisensory responses of superior colliculus (SC) neurons. Soc. Neurosci Abst.

Wyder, MT and Stanford, TR (2000) Single-unit activity in visuomotor thalamus associated with performance of

delayed and remembered saccade tasks. Soc. Neuroscience Astr 26:967McHaffie, J.G., Prescott, T.J., Montes Gonzales, F., Gumey, K., Humphries, M., Stanford, T.R., and Redgrave, P.

(2001) Why is efference copy information directed to the basal ganglia? Inspiration from an embodied model.Soc. Neurosci. Abst. 27.

Stein, B., McHaffie, J., Stanford, T., Redgrave, P., and Meloni, E. (2002) Basal ganglia - superior colliculus

relationships: Novel perspectives, new directions. Winter Conference on Brain Research, p. 115-116.

Deadwyler, S.A., Hodge, S.R., West, C.L., Stanford, T., Daunais, J., Porrino, L.J., Pons, T.P., and Hampson, R.E.

(2002) Activity of n. accumbens neurons during cocaine and juice reinforcement in the nonhuman primate. Soc.

Neurosei. Abst. 28, Program No. 898.4.

Massoglia, D.P., Wyder, M.T., and Stanford, T.R. (2002) Activity of neurons in primate oculomotor thalamusassociated with saccades to remembered visual goals. Soc. Neurosci. Abst. 28, Program No. 265.12.

Procacci N, Stanford TR (2003) A non-human primate model of egocentric and allocentric coordinative constraints.

In: Society for Neuroscience.Wyder MT, Massoglia DP, Stanford TR (2003) Single-unit activity in primate central thalamus associated with a

visually-guided saccade choice task. In: Society for Neuroscience.

• PHS 398/2590 (Rev. 05/01) Number pages consecutively at the bottom throughout the application. Do not use suffixes such as 3a, 3b.

Biographical Sketch Format Page •


C. Research Support

Terrence R. Stanford, Ph.D.

Ongoing Research Support

NIH (NICHD) (Pons) 02/01/98-01/31/04

Implications of Cortical Plasticity for Rehabilitation

The major goal of this project is to understand how compensatory plasticity after brain injury underlies recovery of

motor function in primates.

Role: Principal Investigator - Project IV

Completed within the last three years

NIH 5P50 DA06634-09 (Deadwyler) 02/01/99-11/30/03NIH/Center Grant

Center Grant: Center for Neurobiologieal Investigation of Drug Abuse. Project VII Title: NeurophysiologicalAssessment of Cocaine Reinforcement in Nonhuman Primates.

The principal focus of this project is to understand the neurophysiological substrate of cocaine addiction in primates.Role: Co-P.I.

• PHS 398/2590 (Rev. 05/01) Number pages consecutively at the bottom throughout the application. Do not use suffixes such as 3a, 3b.

Biographical Sketch Format Page •


RESOURCES

FACILITIES: Specify the facilities to be used for the conduct of the proposed research. Indicate the performance sites and describe capacities,pertinent capabilities, relative proximity, and extent of availability to the project. Under "Other," identify support services such as machine shop,electronics shop, and specify the extent to which they will be available to the project. Use continuation pages if necessary.

Laboratory:

Dr. Terrenee Stanford - Laboratory space consists of 5 rooms. Two electrophysiological/behavioral rigs are

fully operational and consist of a total of four rooms (2 pair of adjoining rooms). A 5tn room is dedicated to off-

line data analysis, electrode fabrication, etc.. These resources are dedicated solely to the proposed project.

Clinical:

N/A

Animal:

Animals are procured through the institution's Animal Care Facility. Housing is provided within the facility

that is accredited by the American Association for the Accreditation of Laboratory Animal Care.

Computer:

On-line stimulus presentation, monitoring of eye movements, and all data acquisition are controlled via Pentium

PC. Four dedicated Pentium PCs (P3 and P4) are designated for off-line data analysis.

Office:

An office is provided in the Dept. of Neurobiology and Anatomy in

Trainees will have office space within the laboratory.

close proximity to the laboratories.

Other:

An equipped sterile surgery suite is available within the animal facility in close proximity to animal housing

areas. A histology core facility is available for processing of brain tissue at the conclusion of an experimental

sequence. The department has full time secretaries and an administrative assistant

MAJOR EQUIPMENT: List the most important equipment items already available for this project, noting the location and pertinent capabilities of each.

Currently, there are two complete electrophysiological/behavioral setups available to this project. Major

equipment for each setup includes, a tricolor LED board and/or a 24 inch flat panel CRT for presenting visual

stimuli, an extracellular recording amplifier and window discriminator, a hydraulic microdrive and electrode

positioning system, a programmable microstimulator, a PC based system for data acquisition and stimulus

control, and a primate chair with head-restraint capabilities.

• PHS 398 (Rev. 05/01) Resources Format Page •

• Continuation Page Principal Investigator/Program Director

(Last, first, middle) Stanford, Terrence, R.

Introduction.

Summary of major changes

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PHS 398/2500 (Rev. 5/01) Page g Continuation Formal Pa.qe

response to prior review--evaluation criteria

response to prior review--evaluation criteria



a. Specific Aims

At any moment, our choice of where to look is governed by the inherent salience of stimuli within the

visual scene and by less tangible internal states that may reflect previous events or future expectations. To

date, the majority of studies examining the cognitive control of visual orienting have targeted frontal cortex, a

natural choice for examining visuomotor cognition. However, there is growing evidence to suggest that

cognitive processes, such as working memory and decision formation, are not solely the province of frontal

cortex. Instead, the formation of such signals in frontal cortex may be critically dependent on processing in

subcortical regions such as the basal ganglia, cerebellum, and thalamus. Indeed, to fully appreciate the nature

of computations local to cortex, it is critically important to understand the nature of the information that it

receives from these subcortical areas. As the main conduit for subcortical input to frontal cortex, thalamus is in

a unique position to either relay or transform the input it receives from subcortical structures enroute to cortex.

Despite its critical anatomical position, virtually nothing is known about the nature of the information

represented in central thalamus. Is cognitive information relevant for visuomotor control conveyed through

thalamus? If yes, is there evidence of significant signal transformation? Is the timing of this information

appropriate for guiding goal-directed behavior? Do different thalamic regions make differential contributions

to visuomotor cognition? The proposed studies will be the first to examine these questions in an effort to

elucidate the importance of central thalamic nuclei, and the subcortical-cortical interactions they mediate, to

the cognitive control of goal-directed saccadic eye movements.

Aim 1: To examine the role of OcTh in perceptual discrimination: visual search.

A decision to act first requires comprehension of current circumstances. Simply put, one needs to

know 'what is there' and 'what it means' before deciding 'what to do' about it. We have recently

demonstrated that OcTh neurons convey information about both the nature of physical stimuli and their

meaning in the current context. We propose that OcTh neurons participate in the perceptual decision

processes that guide goal-directed saccades. The proposed experiments test the hypothesis that OcTh neurons

participate in the earliest stages of perceptual decision-making.

Aim 2: To explore the role of OcTh in sensorimotor decision making: expected outcome.Determining "what is there" is the first stage of the sensorimotor decision-making process, the result of

which may lead to a range of different actions. Decisions regarding "what to do" are made on the basis of

weighing the expected consequences of any given action. These experiments test the hypothesis that OcTh

neurons, specifically those in regions that are anatomically associated with the basal ganglia, participate in the

process of ascribing "reward value" to stimuli and actions.

Aim 3: To examine the contributions of OcTh to visuospatial working memory.

It has been suggested that thalamus participates in the spatial memory loops necessary to sustain

spatial working memory representations found in dorsolateral prefrontal cortex (PFCdl). We have previously

demonstrated that OcTh neurons continue to convey spatial information after targets are extinguished in a

memory-guided saccade task. However, like most studies of this type, these data do not distinguish between a

true mnemonic signal representing the prior sensory event and a motor preparation signal for the impending

saccade. The proposed experiments test the hypothesis that OcTh neurons, specifically those in regions that

project to PFCdl, convey information about the locations of past sensory events.

Beyond thalamic signal coding, the proposed studies will help to define ideas about what constitutes

the essential substrate for cognitively-mediated behaviors. The notion of a strict hierarchical relationship

whereby neocortex sends the results of a local decision process to downstream effectors will need to be

reconsidered to include specific roles for subcortical structures like basal ganglia, cerebellum, and thalamus.

More specifically, understanding the nature of the information that thalamus conveys to cortex will be

critically important for tmderstanding subtleties of normal behavior and the complexities of behavioral

impairments consequent to pathological processes in basal ganglia, cerebellum, or thalamus.

PHS 398/2590 (Rev. 5/01) Page _12 Continuation Format PaQe



b. Background and Significance

Motor actions and behavioral context

Humans and nonhuman primates rely on voluntary, purposeful action to function successfully in a

complex and dynamic environment. A goal-directed action may be as simple as looking toward a bird singing

in a nearby tree or reaching to pick up a coffee cup. The relative ease with which we carry out these seemingly

trivial activities belies a high degree of computational complexity. Our choices of action are informed by whatour senses tell us about the current set of circumstances as well as by less tangible internal states that may

reflect previous events or future expectations. To study sensorimotor integration is to investigate how the

brain generates actions that are both timely and appropriate for a given context.

From previous neurophysiological studies, we know a great deal about the neural signals that generate

motor output and even more about how the brain encodes sensory information. However, much less is known

about the types of neural signals found at the sensorimotor interface. Consequently, our understanding of

how sensory signals are translated into appropriate motor commands is less well developed. As alluded to

above, this transformation is not a simple one. The path from sensory input to motor output is necessarily

complex, as many context-sensitive processes must be carried out. One stimulus/action pair must be selected

at the exclusion of all others with each choice influenced by both prior experience and expected consequences.

Understanding the anatomical and physiological bases of these context-specific computations represents a

major experimental challenge but one that will ultimately lead to a more fundamental understanding of both

normal and pathological sensory-guided behaviors.

Primate oculomotor thalamus and cortical - subcortical interactions in visuomotor cognition

Nearly two decades ago, Schlag and Schlag-Rey published a series of two papers on the visuomotor

properties of neurons in primate oculomotor thalamus (Schlag-Rey & Schlag, 1984; Schlag & Schlag-Rey, 1984).

Until recently, these papers stood as the only accounts of gaze-related activity in primate thalamus. Although

these reports considered only the most basic visual and saccade-related activations of central thalamic

neurons, the authors were struck by both the diversity of response types and the apparent lack of anatomical

segregation exhibited by response classes within this relatively small region. Juxtaposed with the strict

topography and stereotyped responses observed in the superior colliculus (SC), these findings led Schlag and

Schlag-Rey to postulate a higher order role for this region (see Schlag and Schlag-Rey, 1986; Schlag-Rey &

Schlag, 1989 for reviews). In their view, oculomotor thalamus (OcTh) might well provide the control signals

necessary to engage and disengage cortical processing modules as required during the course of performing a

particular task.

Though never explicit about how this thalamic "controller" would be realized in neural terms, Schlag

and Schlag-Rey's ideas now seem prescient in light of ever increasing focus on the cognitive aspects of

visuomotor control. Their decidedly cognitive view of central thalamic function can be placed in a much more

specific context today as numerous studies have begun to examine the integration of cognitive processes such

as attention, working memory, and decision-making with those that encode sensory stimuli and issue motorcommands.

Cortical substrates ofvisuomotor control To date, the vast majority of studies that have examined the

cognitive aspects of visuomotor integration have focused on cortex. Evidence from anatomical,

electrophysiological, and imaging studies suggests that a distributed network of visuomotor cortical territories

participates in the process of linking saccades to visual goals. These regions include dorsolateral prefrontal

cortex (PFCdl), the frontal eye fields (FEF), and the supplementary eye fields (SEF) in frontal cortex; and Area

7a, and a region located in the lateral bank of the intraparietal sulcus (LIP) in posterior parietal cortex (PPC)

(See Houk & Wise, 1995; Pierrott-Deseilligny et al., 1991; 1995 for reviews). Individually, or in concert, these

highly interconnected cortical regions influence motor outflow via direct midbrain projections to the SC wheresaccadic motor commands are formed.

While the specific contributions of each cortical domain are not fully understood, some of the highest

order computations, like those subserving working memory and decision making, are thought to be carried

out in prefrontal cortex. Thus, PFCdl and the FEF are thought to participate in working memory and

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decision-processes that link past and present sensory signals to appropriate saccadic commands (see Goldman-

Rakic, 1997; Gold & Shadlen, 2001; Schall, 1999; Glimcher, 2001 for reviews). That PFCdl plays a preeminent

role in spatial working memory is generally accepted on the basis a numerous studies showing that its

constituent neurons maintain task-relevant information long after the informative stimulus has been

extinguished (Joseph & Barone, 1987; Funahashi et al., 1989, 1993; see Goldman-Rakic, 1997; Owen, 1997;

Miller & Cohen, 2001 for reviews). Likewise, neural correlates of a putative perceptual decision process has

been observed within the activity of neurons in FEF (Thompson et al, 1996; 1997; Bichot & Schall, 1999; Bichotet al., 2001) and PFCdl (Kim & Shadlen, 1999). In all cases, the defining result is that perceptual judgment is

reflected in the vigor and/or the timing of the neuron's activity and that this modulation of activity is

correlated with the monkey's behavioral performance. For example, neurons in FEF discriminate between

relevant and irrelevant stimuli in their response fields when monkeys are required to search for a visual target

embedded among distracting stimuli. While the early stimulus-related response of an FEF neuron does not

reflect the significance of the stimulus, over the course of approximately 150 ms, activity evolves to

discriminate between a target or distracter in its response field with this discrimination maintained until a

saccade to the target is issued (Thompson et al., 1996; Murthy et al., 2001). Using a task that required

discriminating the direction of a motion stimulus, Kim & Shadlen (1999) reported analogous results for

neurons in both FEF and PFCdl. In these studies, the "neural discrimination" evolves during the stimulus

viewing period and is presumed to reflect the accumulation of sensory evidence favoring a particular saccadic

response (see Gold & Shadlen, 2001 for review).

Studies like those described above illustrate that neurons in prefrontal cortex participate in the process

of linking existing or remembered stimuli to specific actions. Indeed, these neurons can acquire sensitivity to

previously unrepresented stimulus features (e.g., color) or for even more abstract conceptual information (e.g.,

numerosity) when this information is required to achieve a behavioral goal.

Subcortical contributions to visuornotor cognition While most studies of working memory and decision formation

remain focused on cortex, there is increasing evidence that subcortical areas such as basal ganglia and

cerebellum make essential contributions to these cognitive processes (Kim et al., 1994; Middleton & Strick,

1994; Graybiel et al., 1994; Albin, 1989, 1995; Mink, 1996; Houk et al., 1996; Thach, 1996; Hikosaka et al., 2000).

Compelling anatomical data suggest the existence of functionally segregated channels, each presumed to

convey somewhat different information to motor and cognitive regions of frontal cortex (Fig. 1A-C) (Ilinsky &

Kultas-Ilinsky, 1984; Middleton & St-rick, 2000, 2001, 2002). For example, the efferent projections of the

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_Figure 1. Connectivity of oculomotor thalamus. See text. Abbreviations: DLPFC - dorsolateral prefrontal cortex; FEF - frontal eye

fields; MD - mediodorsal nucleus; SNr - substantia nigra pars reticulata; SEF - supplementary eye fields; VA - ventral anterior nucleus,

VL - ventrolateral nuclear complex.

substantia nigra pars reticulata (SNr) distributes basal ganglia output to several different thalamic nuclei

(MD, VA, and anterior intralaminar nuclei) (Ilinsky et al., 1985) which in turn, convey this information,

presumably transformed, to several targets in frontal cortex (Fig. 1A & 1C, Lynch et al., 1994, 1996). Likewise,

PHS 398/2590 (Rev. 5/01) Page _14 Continuation Format Pa.qe

•ContinuationPageStanford, Terrence, R.

Principal Investigator/Program Director

(Last, first, middle)

the dentate nucleus distributes the results of cerebellar processing to yet another thalamic region (VL) (Ilinsky

& Kultas-Ilinsky, 1984; Ilinsky et al., 1990) enroute to some of the same frontal cortex regions as that from the

SNr (Middleton & Strick, 2001, 2002).

In fact, each of these transthalamic channels is thought to be part of multi-synaptic loops that originate and

return to cortex. The concept of segregated information channels, first postulated by Alexander et al. (1986) as

a principle of organization for cortico-basal ganglia-thalamo-cortical loops, has been elaborated by Strick and

colleagues and extended to include anatomically identified cortico-cerebellar-thalamo-cortical loops as well.

Though the nature of the computations performed by these loops are not well understood, the anatomical

data, along with neurophysiological and clinical data suggest that these subcortical-cortical interactions would

have a profound effect on cognitive processing within frontal cortex.

Though there are relatively few studies concerning cerebellum, Strick and colleagues have reported that

dentate neurons respond in association with cognitively demanding reaching tasks (Mushiake & Strick, 1993).

They also note that, along with motor deficits, gross cerebellar lesions lead to cognitive impairments in

humans (see Middleton & Strick, 2000 for review). However, the role of cerebellum in cognitive processing is

still a matter of debate with some experimental lesion studies in monkeys failing to support this hypothesis

(Nixon & Passingham, 1999, 2000).

Neural and clinical data relating to the basal ganglia are much less ambiguous in this regard. Early single-unit studies established that subsets of neurons within the caudate nucleus and the SNr maintain spatial

information in the absence of a visible target when monkeys are required to make saccades to remembered

locations (Hikosaka & Wurtz, 1983; Hikosaka et al., 1989). This, along with deficits in performing memory-

guided saccades following experimental lesions of the caudate nucleus, has led to the suggestion that activity

within a basal ganglia thalamocortical loops contributes to sustaining working memory representations in

prefrontal cortex (see Hikosaka et al., 2000 for review). Clinical data as well are consistent with the view that

basal ganglia thalamocortical circuits are critical for fronto-cognitive function with basal ganglia disorders

such as Parkinson's Disease and Huntington's Disease having numerous visuomotor and cognitive

manifestations, including those relating to remembered saccade generation and movement selection

(Crawford et al., 1989; Lueck et al., 1990; Dominey & Jeannerod, 1997; Lasker et al., 1997; see Middleton &Strick, 2000; Hikosaka et al., 2000 for reviews).

OcTh contributions to visuomotor cognition Since the

pioneering studies of Schlag and Schlag-Rey, there have been

only a handful of studies to examine the visuomotor properties

of neurons in OcTh. We have recently sampled the visual,

delay-period, and saccade-related activations in all the nuclei

comprising OcTh including MD, VL, VA, and nuclei of therostral intralaminar group (Pc, CL) (Wyder et al., 2003; see

Progress Report). Electrolytic marking lesions showing the

anterior-posterior extremes of the recording sites from this study

are shown along with corresponding cytoarchitectural

boundaries described by Olszewski (1952) in Fig. 2. (red arrows

- lesion sites; dotted line - electrode penetration)

Figure 2. Anatomy of oculomotor thalamus/histology. See text.

Abbreviations: AM: anterior medialis; AV: anterior ventralis; ; CL: centralis

dorsalis; CM: centrum medianum; CSL: centralis superior lateralis; MDmf:

mediodorsalis pars multiformis; LD: lateralis dorsalis; Pc: paracentralis;

VAmc: ventralis anterior pars magnocellularis; VL: ventralis lateralis; VPI:

ventralis posterior inferior; VPL: ventralis posterior lateralis; VPM: ventralis

posterior medialis; X: Area X. (After Olszewski, 1952). Right: Nissl stained

sections with lesion sites from 2 monkeys - See text for details.

As detailed below (see Progress Report), Wyder et al., revealed

that, along with activity related to visual stimuli and saccades,

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OcTh neurons maintained task-relevant spatial information throughout an instructed delay period. These data


oContinuationPage Principal Investigator/Program Director


were some of the first to show that activity in OcTh could link specific stimuli to rewarded saccades. Using

more complex tasks, we have subsequently shown that OcTh delay-period activity can persist in the absence of

a visible target and reflects both the nature of the physical stimulus and its behavioral relevance (Massoglia et

al., 2002; Wyder et al., 2003b). These latter findings are consistent with the hypothesis that OcTh is a

component of subcortico-cortical circuits that contribute to both spatial memory and sensorimotor decision

processes attributed to regions of prefrontal cortex. Consistent with these findings is a recent report showing

that neurons in MD show spatially-selective activity in the context of visually-guided and memory-guided

saccade tasks (Tanibuchi & Goldman-Rakic, 2003), a finding that is also consistent with known connections

between MD and PFCdl (Alexander & Fuster, 1973; Middleton & Strick 2001, 2002).

Experimental lesion studies of OcTh are few and clinical lesion studies are largely anectdotal.

However, they do at least point to a role for central thalamic regions in cognitive processing, with motor

thalamic lesions producing sometimes profound sensorimotor deficits (Rafal & Posner, 1978; Watson &

Heilman, 1979; Albano & Wurtz, 1982; Canavan et al., 1989; Gaymard et al., 1994). Commonly reported is

contralateral neglect, usually indicated by a decrease in the frequency of orienting (eyes/head) or reaching

movements to presented stimuli opposite the affected side. Contralateral neglect for visual targets following

lesions was reported by Orem et al., (1973) for cats with experimental lesions centered on the internal

medullary lamina, a band of fibers that bisects OcTh. In an experiment that dissociated the sensory and motor

components of a task, Watson et al., (1978) concluded that monkeys with lesions confined to the intralaminar

region suffered from a deficit of motor "intention".

What are the essential physiological and anatomical substrates for visuomotor cognition?

The anatomical, electrophysiological, and clinical studies summarized above suggest that subcortico-

cortical interactions may be the basis for many of the cognitive aspects of visuomotor control. Yet, while it

would be critically important to know if the evolution of context-depend signals in cortex depends on

computations performed within the basal ganglia, cerebellum, or both, we know very little about theinformation conveyed to cortex by thalamus. Clearly, fuU appreciation of the nature of the computations

carried out within cortex would require a complete accounting of the information that it receives from its

subcortical input structures. As the main conduit through which visuomotor information from the basal

ganglia and cerebellum reach cortex, OcTh provides a unique opportunity for examining the nature and

organization of these signals.

The current experiments seek to fully characterize the central thalamic representations of cognitive factors

relevant for producing visually-guided saccadic eye movements. Along with providing insights into the

coding capacities of individual thalamic neurons, by comparing the information represented in different

thalamic nuclei, these studies will test prevailing notions that functionally segregated channels are the rule ofsubcortico-cortical communication.

c. Progress report / Preliminary studies

Completed Studies

QUANTITATIVE ASSESSMENT OF THE TIMING AND TUNING OF VISUAL-RELATED, SACCADE-

RELATED, AND DELAY PERIOD ACTIVITY IN PRIMATE CENTRAL THALAMUS

Specific Aim I of the initial grant period proposed to quantify the spatial and temporal relationships of

neural activity in OcTh to significant sensory and/or motor events (e.g., stimulus onset, saccade onset). This

work is completed and published in the form of a full-length article (Wyder et al., Journal of Neurophysiology,

2003). These experiments employed a delayed saccade task that coupled a specific sensory stimulus, via an

instructed delay, to a specific saccadic response. This task readily distinguished between the sensory-

contingent and saccade-related activities of individual thalamic neurons and permitted separate quantification

of the timing and spatial selectivity of each of these response components.

Perhaps more importantly, these experiments revealed that many thalamic neurons are capable of

maintaining task-relevant spatial selectivity throughout an instructed delay period. This finding, the first to

demonstrate this capacity for gaze-related thalamic neurons is critical because spatially-selective "delay-

PHS 398/2590 (Rev. 5/01) Page 16 Continuation Format Pa_e

•Continuation Page Principal Investigator/Program Director


period" activity is the hallmark of a neuron with the potential to participate in "higher-order" aspects of

sensorimotor function. These findings thus laid the groundwork for the experiments completed to address

Aims 2 & 3 of the initial grant period, which examined the degree to which thalamic neurons could carry goal-

related information in the absence of the visible target (Aim 2) or convey information about the behavioralrelevance of a stimulus (Aim 3).

OcTh neurons carry spatial information during all phases of a visuomotor task.

The visual, delay-period, and motor-related activation of a neuron recorded in VL of OcTh is shown in

Fig. 3A (Fig. 4 from Wyder et al., 2003). This neuron, like many

others that we recorded, showed clear stimulus-related (Fig. 3A,

left) and saccade-related (Fig. 3A, right) transients that, when

quantified as a function of stimulus (Fig. 3B, left) or movement

(Fig. 3B, right) direction, showed consistent and similar ttming

preferences. Note that delay period activation is evident as a

sustained and increasing activity that effectively bridges the

gap between the sensory and motor-related bursts.

A. ml10530a_Target onset _rSaccade onset

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Figure 3. Visual-motor neuron with delay-period acitivity. A. Rasters (top)

and average frequency histograms (bottom, bin width 2 ms) are aligned on B.

target onset on the left, and on saccade onset on the right. In each panel, the 7o/

first horizontal solid black line indicates the baseline interval used for the timing 50

procedure; the second horizontal black line indicates the interval of significant ,_

activation; the horizontal solid grey line indicates the interval used to estimate _ 30

directional tuning. B. Average firing rate as a function of target direction _°1following stimulus presentation (left), and as a function of saccade direction

during the eye movement (right), with corresponding least squares fit Gaussian

curves.

0 200 400 600 -200

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Target Direction Saccade Direction

Delay- period activity carries veridical spatial information

A key finding of these studies was that delay period activity was

spatially selective and signaled locations congruent with those signaled by

the sensory and motor transients of the same neurons. Tuning was

quantified by fitting plots of firing rate versus direction with Gaussian

functions (see above Fig 3B), yielding several parameter estimates thatcould be compared. Figure 4 (Fig. 20 from Wyder et al., 2003) compares the

tuning widths (4A & B), maximum (4C & D) and minimum (4E & F) firing

rates, and preferred directions (4G & H) estimated for delay period activity

to those estimated for the sensory- (left column) or motor- (right colulim)

related activations. While correlated across all measures, it is perhaps most

important to note that the preferred directions estimated for delay period

activity were consistent with those estimated for both sensory- (Fig. 4G) or

motor- (Fig. 4H) related activations of the same neurons.

Figure 4. The relationship between directional tuning during the delay period to that during

the visual period (A, C, E, G) and the motor period (B, D, F, I). Filled circles (A-F) and bars

(G-H) indicate excitatory responses, while open circles and bars indicate inhibitory

responses. Only neurons significantly fit with a Gaussian function during both epochs

(visual and delay, or motor and delay) are shown. A., B. The relationship between delay

period tuning index and visual (A) or motor (B) period tuning index. C., D. The

relationship between delay period baseline and visual (C) or motor (D) period baseline. E.,

F. The relationship between delay period amplitude and visual (E) or motor (F) period

amplitude. Go, It. The difference in preferred direction during the delay period and during

the visual (G) or motor (H) period.

Delay-period activity is found within multiple OcTh nuclei

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Delay-period activity (red outlined symbols) was found in every central thalamic nucleus sampled,

including VL (Fig. 5A & B), the paracentral and central lateral nuclei of the rostral intralaminar group (Fig. 5APHS 398/2590 (Rev. 5/01) Page_17 Continuation Format Pa_e

•ContinuationPage PrincipalInvestigatodProgramDirector(Last,first, middle) Stanford, Terrence, R.

& B), MD (Fig. 5C), and VA (Fig. 5E) (Fig. 21 from Wyder et al., 2003). Thus, the presence of delay-period

activity does not distinguish among thalamic nuclei (e.g., VA, VL, MD) presumed to participate in distinct

functional loops. The proposed experiments use a series of tasks designed to distinguish thalamic nuclei based

on the information carried within delay-period activity of their constituent neurons.

Figure 5. Locations of recorded units from monkeys ML (A. - D.) and SQ

(E.). Locations were reconstructed from electrolytic lesions made near

recording sites. Units are labeled according to the sign of their visual

and/or motor responses. Symbol sizes indicate the number of units

recorded; the smallest indicates 1-2 units, medium-sized symbols indicate

3-4 units, and the largest symbol indicates 5-6 units. Symbols with slightly

bolder outlines indicate locations of neurons with tuned delay period

activity. Symbols with red outlines indicate locations where neurons with

delay period activity were recorded. The approximate anterior-posterior

(AP) location of each section and the number of units recorded on each

section are shown next to the panel label. The large hole extending

downward from the left lateral ventricle in panel E. is the result of a

muscimol injection performed in a separate experiment. Abbreviations:

AD, anterior dorsal; CM, centromedian; CL, central lateral; LD, lateral

dorsal; MD, medial dorsal; PC, paracentral; VA, ventral anterior; VL,

ventral lateral; vi, visual increase; vd, visual decrease; mi, motor increase;

md, motor decrease.

CONTEXTUAL MODULATION OF CENTRAL THALAMIC

DELAY-PERIOD ACTIVITY: REPRESENTATION OF

VISUAL STIMULI AND SACCADIC GOALS

Our finding that many central thalamic neurons

maintained spatial-tuning throughout an imposed delay

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period (Wyder et al., 2003), though suggestive, does not constitute strong evidence for involvement in a

context-dependent process of linking sensory stimuli to saccadic commands. Follow-up studies were

conducted to determine if in fact these neurons carry information about both the stimulus and its relevance

within the context of the behavioral task. To do so we evaluated activity in association with visually-guided

and memory-guided versions of a two-target saccadic choice task, each illustrated in Fig. 6A & B. This

manuscript (Wyder, Massoglia, and Stanford) has been completed and, assuming a timely and favorable

review, can be provided as supplementary material prior to convening of study section.

In each version of the choice task, the response field stimulus remained physically invariant, but

changed status from neutral to either "target" or "distracter" during the trial. In both visual and memory

versions, trials began with the presentation of a yellow central fixation stimulus (Panel 1; fixation) which the

monkey had to look to within 500 ms. A. Bdday peri_l

Figure 6. Visual (A) and memory-guided (B) saccadic choice tasks. Seedel_y _ri_t

text for details, g_,_co_do _ _o_.do

After a short delay, two eccentric stimuli were illuminated, a,o..... momo,

one red and one green (Panel 2; before-cue). The two _,_

stimuli were always of equivalent eccentricity and differed _'_......in direction by 180 degrees. During the pre-cue period, ' _"÷

each stimulus was a potential saccade target. After a ,_,_o,,second delay, the central fixation light changed color,

randomly, to either red or green (Panel 3; post-cue) cueing the monkey to the identity of the eventual saccade

target (color match) and distracter (non-match). The monkey was required to maintain fixation throughout the

post-cue period until either the fixation light was turned off (visual trials) instructing a saccade to the target

(Fig. 6A; Panel 4; GO/saccade) or the eccentric stimuli were turned off. The monkey was required to

remember the location of the target for an additional delay (Fig. 6B; Panel 4; memory) prior to making the

saccade (Fig. 6B; Panel 5).

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Delay period activity reveals functional distinctions among OcTh neurons.

Central thalamic neurons were not homogeneous, but differed in functionally significant ways with

respect to their ability to differentiate relevant from irrelevant stimuli and in their ability to convey this

information in the absence of the triggering stimulus. Figure 7 illustrates the 3 main types of response profile

that we observed. Here several neurons of each type are averaged to create the plots shown in Fig. 7A-C.

Borrowing from signal detection theory, each graph plots the degree to which neurons "discriminated"

the stimulus relevance as a function of time during the trial (See Aim 1: Data Analysis for more details).

Analogous to the area under an ROC curve, values near 0.5 indicate no differences in firing for a "target" or

"distracter" stimulus in the response field, whereas values above 0.65 were typically indicative of statistically

significant differences in firing (i.e., discrimination).

Figure 7. Average neural discrimination functions for 3 groups of OcTh neurons. See text for details.

From left to right, thediscrimination functions are

synchronized on stimuli onset (left

column), the cue identifying the target

and distraeter (middle column), andoffset of the eccentric stimuli on

memory trials (right column). Prior to

the cue (left column), the discrimination

functions hover near 0.5 as expected.

This simply indicates that neurons with

delay period activity fired equivalently

for stimuli that had equal potential to

become a target or distracter. However,

after the cue (Coltman 2), thediscrimination functions for the neurons

of Figs. 7B & 7C begin to rise. For these

neurons, firing rates tended to increase

if the response field stimulus was

identified as a target and decrease ifidentified as a distracter. In marked

contrast, neurons in the group shown in

single target trials

-- choice trials

stimuli off

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Fig 7A were ambivalent, discharging equivalently (near 0.5) for any stimulus, regardless of relevance, in their

response field.

The neural groups depicted in Figs. 7B & C each signaled the presence of behavioral goals. However,

these two "goal-related" groups could be differentiated on the basis of whether or not the representation wasmaintained in the absence of a persistently visible stimulus. Note that only the neurons shown in Fig. 7B,

continued to represent the saccadic goal after the stimuli were extinguished on memory trials (right column).

For comparison, the light traces represent firing rate differences on single target control trials and show

that all of neurons in each of these groups had spatially-selective delay-period for single, visible, targets. Only

those shown in Fig. 7B, however, maintain this representation throughout the memory interval.

Preliminary_ Studies

Time course and neural correlate of perceptual decision making

Neurons that differentiate targets from distracters may participate in the decision processes that link

stimuli to actions. However, to determine if a thalamic neuron participates in decision-making or merely

reflects the results of computations ongoing elsewhere (e.g. ,cortex), it will be necessary to precisely relate the

timing of neural discrimination to the evolving decision process.

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•Continuation Page Principal Investigator/Program Director


To obtain data with sufficient temporal resolution, we have devised a "time-response" task that yields

a moment-by-moment read-out of the state of an evolving decision process. The timed-response paradigm,

employed in Experiment 3 of Aim I permits a systematic manipulation of the amount of "perceptual decision

time" available for generating a saccade to a visual goal (See Fig. 13 for complete description). As shown

below (Fig. 8), behavioral performance improves systematically as a function of increasing decision time,

providing a psychometric function that can be related to the "neural discrimination" functions obtained forOcTh neurons.

The key to the task is a varying temporal relationship between the "GO" signal and the presentation of

the cue that reveals the identity of the target (i.e. color) that must be differentiated from the distracters. We

define processing time (PT) as the interval from the time the target is revealed to the time of saccade onset.

Because RT is strongly linked to the "GO" signal, saccades are generated after varying amounts of processing

time. Results are shown for two monkeys in Fig. 8. The left column plots distributions of processing time forcorrect trials wherein the first saccade was directed to the target (dark blue/up histogram) and error trials in

which the first saccade was directed to one of 3 distracters (light blue/down histogram). The right column

(blue symbols) plots performance (probability of a correct decision) as a function of processing time (blue line

indicates chance performance = 0.25) for the same data, which A)

correspond to a 4 stimulus (1 target, 3 distracter) set. The top row (A)

represents data from a single session with monkey SQ, the second row _,1,

(B), the average of multiple sessions for this monkey. The bottom two

rows show comparable data for a second monkey (SA). Performance ._is also plotted (histograms not shown) on the right (red symbols) for a

reduced stimulus set (2 stimuli) in which there is a single target and '_

single distracter (chance performance = 0.5).The histograms (left) and the psychometric functions (right) B) "

both illustrate a positive relationship between performance and _

processing time. For the 4 stimulus set (blue symbols), performance ._

improves smoothly from chance to an asymptote of between 0.8 (SQ)

and 0.9 (SA) as processing time increases from approximately 150 to

300 ms. Analogous, but slightly improved (shifted to left)

performance is evident for the easier 2 stimulus discrimination (red

symbols).

Figure 8. Behavioral performance as a function of perceptual decision time (PT) for

two monkeys. A. Single session for monkey SQ. B. Multiple sessions for SQ. C. 2

Single session for monkey SA. D. Multiple sessions for SA. See text for details.

C).®

These data show that the monkey can be induced to generate

saccades based on varying amounts of "sensory evidence". The D)

sigmoid performance curves can be compared directly to the similarly _0shaped neural discrimination functions (e.g., Fig. 7 above) based on _.the very same trials. Both functions can be fit (cumulative Weibttll) :_compared to quantify the relationship between neural and perceptual

discrimination. The temporal offset between the "neural" function

and the "decision" function will be a key comparator. To consider the '_

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extremes, a neural function that lags behavior would clearly not contribute to the decision process, whereas,

one that leads could. Clearly the relative timing (i.e., amount of lead or lag) of these functions would serve to

clarify the roles of different thalamic regions in the decision-making process and could be used to relate

thalamus to other visuomotor regions where decision-related signals have been observed (when we or others

apply this paradigm to other areas).

Neural correlate of reward contingency in basal ganglia recipient oculomotor thalamus

The experiments proposed in Aim 2 will assess the reward-signaling capacities within the various

nuclei that compose OcTh. We predict that those thalamic regions most closely associated with the basal

PHS 398/2590 (Rev. 5/01) Page 20 Continuation Format Pacle



ganglia (VA, intralaminar) will be those most likely to carry information related to learned reward

contingencies. Data consistent with this hypothesis has been published as part of our broad survey of task-

related thalamic activity (Wyder et al., 2003). Figure

9A-F, illustrates six neurons that anticipated reward

as evidenced by a steadily increasing rate leading up

to its delivery. These putative reward-related signals

were localized to VA (3 neurons) and the rostral

intralaminar group (3 neurons), each a major target of

basal ganglia output.

Figure 9. Six OcTh neurons with "reward-related" increases in

activity. Rasters aligned on saccade onset (t=0; vertical line).

Green ticks - Go signal; Red ticks - saccade offset; Blue ticks -

reward delivery. See text for details.

The experiments of Aim 2 propose to relate

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reward-related signals to RT. To show that RT can be used as an index of reward expectation, we trained

monkeys on the "location-reward bias" task (see Aim 2: Experiment 1; Fig. 14). We find that monkeys readily

discriminate changes in reward biases with RTs reflecting the change in reward contingency within just a few

trials. As anticipated, RTs to highly rewarded target locations are both shorter and less variable than those to

less rewarding targets. The time course of this effect illustrates a consistent reciprocity such that, as RTs to the

highly rewarded target decrease and become less variable, those to the less rewarded target increase and

become more variable. These behavioral effects are very robust, easily manipulated, and clearly of amagnitude that is sufficient for detecting a neural correlate in the activity of single OcTh neurons. As such,

these data will be particularly valuable for comparing the reward-related activities within different thalamic

regions.

Figure 10. Effects of reward contingency on saccadic reaction time. A. Right

target. B. Up target. C. Left target. D. Down target. The monkey was required A)

to make a saccade to one of 4 randomly presented target locations

(up/down/left/right). Reward value was varied in blocks of approximately 300trials during which I of the 4 targets was differentially rewarded (in this

experiment, one target was rewarded, remaining 3 unrewarded, i.e., 100% / 0%).

Reward bias was assigned pseudorandomly requiring the monkey to learn the

new reward assignment at each block transition. The scatter plots of A-D plot

RT as a function of trial number for each of the 4 targets. On each plot, trials for

the block in which the corresponding target was rewarded are shown in red T_al Number 1500

(block transitions are indicated by vertical lines). Inset histograms compare RTs for

rewarded (red/up histogram) and unrewarded (black/down histogram) trials

to that same target. For each target location, mean RT was significantly shorter

for saccades to rewarded target locations showing an average reduction of 35ms.

Publications

Wyder M.T. and Stanford, T.R. (2000) Single-unit activity in

visuomotor thalamus associated with performance of delayed andremembered saccade tasks. Soc. Neuroscience Abstr. 26:967.

C_ 180°

.... .

Trial Number 1500

B_0 "_._ 900

Trial Number 1500

D_l _ 270°

50Trial Numb_ 1500

Massoglia, D.P., Wyder, M.T. and Stanford, T.R. (2001) Properties of visual and visuomotor activity in primateoculomotor thalamus. Soc. Neuroscience Abstr. Vol. 27.

Wyder M.T., Massoglia, D. P., and Stanford, T.R. (2001) Activity patterns of saccade-related neurons in

primate oculomotor thalamus. Soc. Neuroscience Abstr. Vol. 27.

PHS 398/2590 (Rev. 5/01) Page _21 Continuation Format Pa_e



Massoglia, D.P., Wyder, M.T. and Stanford, T.R. (2002) Activity of neurons in primate oculomotor thalamus

associated with saccades to remembered visual goals. Soc. Neuroscience Abstr. Vol. 28.

Wyder MT, Massoglia DP, Stanford TR (2003) Quantitative assessment of the timing and tuning of visual-

related, saccade-related, and delay period activity in primate central thalamus. J Neurophysio190:2029-2052.

Wyder MT, Massoglia DP, Stanford TR (2003) Single-unit activity in primate central thalamus associated with

a visually-guided saccade choice task. Soc. Neuroscience Abstr. Vol. 29.

Stanford TR (2003) Signal coding in the primate superior colliculus revealed through the use of artificial

signals. In: The Superior CoUiculus: New Approaches for Studying Sensorimotor Integration (Hall WH,

Moschovakis AK, eds): CRC Press. p. 35-53.

-------- ------- ------------- ------ ---- ------------ ----- ------------- -------------- - --------- --------- -------------

------------- -- -------- ---------- --------------- --------- ----------------- -- ------- ---- ---------- -------

d. Research design and methods

As described above, anatomical considerations place oculomotor thalamus at a critical interface of sensory,

motor, and cognitive processes and argues for its importance in the integration of contextual cues and

visuomotor signals. Studies conducted during the initial grant period confirm that visuomotor activity in

OcTh bears similarities to that found in cortical regions thought to subserve visuomotor cognition (Wyder &

Stanford, 2000; Massoglia et al., 2001; Wyder et al., 2001; Massoglia et al., 2002; Wyder et al., 2003a,b). The

proposed experiments are designed to explore these signals in much greater detail to examine the precise

nature and topographic organization of cognitively relevant signals in OcTh.

AIM 1: TO EXAMINE THE ROLE OF OCULOMOTOR THALAMUS IN PERCEPTUAL JUDGMENT: VISUAL SEARCH.

General rationale The primary objective of Aim 1 is to determine if OcTh neurons participate in the

process of perceptual decision formation and, if so, is this capacity differentially represented in one or more

OcTh nuclei. As described above (see Progress/Preliminary Data), we have previously shown that the delay-

period activity of OcTh neurons can evolve to discriminate between relevant and irrelevant visual stimuli

(Wyder et al., 2003b). While these neurons are clearly influenced by the cognitive demands of the task, it is not

clear if this activity is an essential component of the evolving perceptual decision, the resulting motor plan, or

simply reflects the outcome of decision processes carried out elsewhere. Aim I seeks to systematically address

this question with a series of 3 experiments.

Experiment I varies the perceptual demands of a visual search task to determine if the timing of neural

discrimination in OcTh correlates with the difficulty of the perceptual discrimination. Experiment 2 uses a

task that entirely decouples the perceptual discrimination from any specific saccade to determine if regions of

OcTh can represent perceptual decisions independent of their linkage to a specific action. Finally, Experiment

3 uses a timed-response task (see Preliminary studies) to probe the precise timing of the decision process and

its temporal relationship to signals in OcTh.

While it is currently unknown if "decision-related" signals are disproportionately represented among

different thalamic nuclei, it will be of great interest to determine if a functional organization corresponding to

differences in the afferent and efferent coimections of individual thalamic nuclei emerges. Unlike the

experiments of Aims 2 and 3 in which cases for predicting differential distributions of reward signaling (Aim

2) and spatial memory (Aim 3) can be made on the basis of afferent and efferent connections, there is no a

priori reason to make a strong differential prediction in the case of decision formation. Nevertheless, it may be

that the ability to discriminate targets from distracters, which seems broadly distributed among frontal cortical

regions (e.g. FEF, and PFCdl), is derived from processing within a given thalamocortical channel that is

specifically associated with either more either the basal ganglia or the cerebellum. By probing several aspects

of the perceptual decision process, Experiments 1-3 will reveal the differential contributions, if present, of thedifferent thalamic nuclei.

Aim 1, Experiment 1: Discrimination of stimuli based on behavioral relevance.

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oContinuation Page Principal Investigator/Program Director


Specific rationale Studies in visual psychophysics have clearly shown that our choices of what to look at

in a complex visual scene are governed both by the inherent salience of an object (e.g., size, color) and by

salience conferred upon an object by our current behavioral objectives (e.g., am I looking for something in

particular?). Using a variety of search tasks, Schall and colleagues have shown that FEF neurons represent the

relative salience of competing visual stimuli. For example, in monkeys trained to make saccades to a single

target embedded in an array of distracting stimuli, they found that the visual responsiveness of neurons in the

FEF evolved over time, typically requiring between 130-160 ms to reliably discriminate between a target or

distracter in its RF. It has been argued that the time needed to discriminate between relevant and irrelevant

stimuli in the RF is a neural correlate of a perceptual decision process, the outcome of which informs the choice

of action (i.e., look to the target/ignore the distracter (e.g., Bichot et al., 1999)). Experiment I uses two versions

of a visual search task to manipulate the difficulty of the perceptual discrimination. In doing so, we seek todetermine if and how thalamic neurons participate in the formation of perceptual decisions.

Experimental design Monkeys will perform a conjunction search task (Bichot et al., 2001) in which they

must locate and make a saccade to an object defined by a specific combInation of color and shape (e.g., green

triangle). Prior to each session, the features of the search target will be revealed to the monkey during a series

of "training" trials in which only that particular item is presented. The search task (Fig. 11) begins with the

onset of a central spot that the monkey is required to fixate. After a variable period (300-700 ms), the fixation

light is extinguished and an array of either 4 or 6 objects appears. The monkey must make a saccade to the

object composed of the instructed combination of features (e.g., green triangle) to obtain a juice reward.

For any given neuron, the stimulus elements will be positioned so that on each trial one item falls in the

center of the neuron's RF (estimated from single target, delayed-saccade trials). Evaluating the relationship

between neural activity and formation of the perceptual decision (target or distracter) will rely on comparing

the vigor and timing of neural activity for cases when the target is in theRF to that when a distracter is in the RF. Each neuron will be studied

while the monkey performs the 4 stimulus (easy) and 6 stimulus

(difficult) versions of the conjunction task. Trials using the 4 and 6

element arrays will be randomly interleaved.

It is well known that the number of nontarget items in the search

display has a profound impact on the time needed to successfully

complete a conjunction search task. This is because conjunction search

is largely a serial process in which individual stimulus locations are

sequentially probed to determine if the item is the target or a distracter

(Triesman & Gelade, 1980; Nakayama & Silverrnan, 1986; Wolfe, 1989;

Wolf, 1994); this process must proceed covertly while the monkey

maintains fixation. Thus, reaction time will be our dependent measure

of behavioral performance.

Conjunction Search

I •

Figure 11 Conjunction search shown for two levels of difficulty. Four element (upper) and six element (lower) displays are shown. In

each case the target is a green triangle. See text for details.

Data analysis The object of the analysis is to relate the time course of target/distracter discrimination to

the difficulty of the perceptual decision. Neural discrimination functions will be similar to those shown in Fig.

7 (Progress Report). The analysis, based on signal detection theory, is patterned after that used in previous

studies (Britten et al., 1992; Thompson et al., 1996). At each point In time after onset of the stimulus array (e.g.,

5 ms increments), two distributions of spike rate are generated, one each for "target-in-RF" and "distracter-in -

RF" trials. For example, at t = 50 ms post-stimulus, such distributions would give the probability of observing

any particular spike rate conditional on whether a target or distracter was in the RF. The difference between

the target-in-RF and distracter-in-RF distributions is, therefore, a measure of the degree to which the neuron

discriminates between a target and a distracter during a given interval of time. These distributions are treated

as the data upon which a hypothetical psychophysical judgment is to be made.

The probability of a "correct decision" is plotted as a function of time (see Fig. 7) with each point

corresponding to the ratio of correct and incorrect decisions made on basis of firing rate differences. In

principle, neural discrimination values range between 0.5 and 1.0 with 0.5 indicating chance performance and

PHS 398/2590 (Rev. 5/01) Page _23 Continuation Format Pa.cle

=ContinuationPage Principal Investigator/Program Director


1.0 indicating perfect discrimination. We will determine both the degree to which a neuron discriminates

targets from distracters and the time at which this differentiation is maximal in each visuomotor neuron

studied (e.g., see Progress Report). Relating the time course of the neural discrimination to RT will be the

primary objective.

Possible outcomes Particularly critical will be comparison of the "easy" and "difficult" tasks with the

more difficult task expected to produce considerably longer RTs. We predict that longer RT's will be mirrored

by commensurate changes in the timing of neural discrimination functions within OcTh. Based on prior

observations (Wyder et al., 2003b), we know that not all OcTh neurons with delay period activity can

discriminate between targets and distracters. However, we predict that those that do, will display a sensitivity

to the difficulty of the discrimination that is reminiscent of that observed in their cortical targets, the FEF and

PFCdl (Thompson et al, 1996; 1997; Bichot & Schall, 1999; Bichot et al., 2001; Kim & Shadlen, 1999).

Aim 1, Experiment 2: Response-independent perceptual discrimination.

Specific rationale In most studies, sensory information and the required response are congruent from the

perspective of a neuron's response field. For example, the location of the target in a visual search paradigm

also specifies the vector of the saccade to look at it. Thus, the same neuron that signals the presence of a target

within its response field can be involved in planning the saccade. However, it is clear that at some level of

mental representation, the decision about what is perceived must be independent of the choice of overt

responses. Given the very close linkage between visual perception and eye movements, it is reasonable to ask

whether "visuomotor" neurons participate in the formation of perceptual judgments independent of thesaccadic requirement. In fact, Schall and colleagues argue that this is the case for neurons in the FEF. To

support this claim, they note that FEF neurons discriminate targets from distracters even when the task

explicitly requires withholding of saccades (Thompson et al., 1997). Even more recently, Gold and Shadlen

(2001) presented preliminary evidence that neurons in Area 46 of PFCdl can signal a decision about motion

direction independent of response preparation.Target Present

ReportTo determine the degree to which decision-

related activity in OcTh is linked to saccade _preparation, this experiment uses a task that so=. Pe,o,

uncouples the location of the search target from thevector of the saccade. P,x°.o. • •

Figure 12. Two alternative forced choice conjunction search. In

this example, the target is the red square. Left: depiction of a

target present trial. Right: depiction of a Target absent trial. Seetext for details.

\

F_aflon

Experimental Design Experiment 2 uses the

same conjunction search displays as in Exp. 1,

Report

Searoh Period _-_D

m& ) - +

i'::_/--Target Absent

however, rather than looking toward the location of the target, monkeys will report either the presence or

absence of a search target in a two-alternative forced-choice procedure (Fig. 12). Monkeys will be familiarized

with the search object as described above for Exp. 1. A trial begins with the onset of the fixation spot, which

the monkey must acquire. After a variable delay, the stimulus array is presented for a specified viewing

period during which time the monkey is required to maintain fixation. The stimulus array and fixation spot

are then extinguished and two symbols (a plus sign and minus sign) are displayed. The monkey must make a

saccade to the plus sign to report target presence and to the minus sign to report target absence. The correct

choice must be made within 500 ms to obtain reward. The level of performance will be varied by

manipulating either the number of elements in the display or the amount of time available to search the

display before a response is required. The number of items will be 4 or 6 (as above) while the choices of

display duration will be determined empirically to generate accuracy levels ranging from chance performance

to an asymptotic value (est. 90%).

As described above (Exp. 1), conjunction search proceeds serially requiring a covert evaluation of

individual stimulus locations to determine if the item is the target or a distracter. On target present trials, the

search is completed as soon as the target is located. On target absent trials, an exhaustive search is required so

PHS 398/2590 (Rev. 5/01) Pa.cle24 Continuation Format Pacle

• Continuation Page

Stanford, Terrence, R.Principal Investigator/Program Director


that each item in the array can be evaluated and rejected. Assuming 100% efficiency (no repeated locations)

and a random search strategy, search times in such tasks will be linearly related to the number of items in the

array and, on average, search times for target present trials will be half as long as those of target absent trials.

Performance then varies as a function of the number of elements and display time. For a given number of

stimulus elements, performance will decline as a function of decreasing search time. Likewise, for a given

search time, performance will decline with an increasing number of elements. For each display density and for

each search time, behavioral performance will be scored as percent correct. Correct trials will be further

broken down into hits and correct rejections and error trials into misses and false alarms.

Stimulus elements will be positioned so that on each trial one item falls in the center of the neuron's RF

(as previously determined using a single target, delayed saccade task). As in Experiment 1, comparing activity

for targets and distracters in the RF will reveal neurons that participate in the target discrimination process.Here, however, it is important that the location of the target in the RF is not congruent with the vector of the

saccade required to report the decision. Indeed, it is must be emphasized that within a block of trials, the

monkey will know in advance that the saccadic response will never correspond with the location of the target.

In this way, we will be able to determine 1) if thalamic neurons participate in perceptual decision processes

independent of required motor response and 2) if, as the task proceeds from the discrimination to response

phase, individual neurons transition from representing the location of the target (perceptual) to signaling the

impending saccade (motor planning).

Data analysis Neural data will be analyzed to determine if the magnitude or timing of activity

correlates with the monkey's report of either YES or NO. We will compare plots of average firing frequency

versus time (based on average instantaneous firing frequency histograms or spike density functions) after

stimulus presentation for positive (hits, false alarms) and negative (correct rejections, misses) responses for

both correct (hits, correct rejections) and incorrect trials (false alarms, misses). Conventional statistics will be

used to determine if measures such as mean firing frequency differ across task phases or task type.

Possible outcomes This experiment has the potential to yield some interesting outcomes. First, there is

the issue of whether or not we will encounter neurons that discriminate between targets and distracters when

there is explicit knowledge that the vector of saccadic report is not congruent with the localization of the

identified target. Second, for neurons that do signal the presence of a target versus a distracter in their RF, we

will determine if the degree to which activity discriminates the target from a distracters covaries with

performance level on the difficult and easy searches. Time permitting, neurons that fail to showdiscrimination will be tested on blocks of conventional search task (Aim 1: Exp. 1) to see if the spatial

congruence of the sensory and motor phases of the task is critical. Lastly, it is also likely that we will

encounter neurons for which activity evolves from representing the location of the target to representing the

vector of the impending movement during the course of the trial. The time course of this transition will

provide insights into mental chronometry of the covert processes of perceptual decision making and motor

planning.

Aim 1, Experiment 3: Neural/behavioral correlate as read-out of the time-course of perceptual decision

Specific rationale Experiments I and 2 manipulate the difficulty of the perceptual decision and measure

effects on the amount of time required for correct performance. The evolution of the neural discrimination

function is considered a correlate of accumulating "sensory evidence", evidence that is manifest as a

behavioral report (saccade) when sufficient to make a correct judgement. Experiment 3 employs an alternative

approach whereby the time permitted to make a perceptual judgement is under experimental control and the

behavior becomes a read-out of the current state of the decision process. In this case, neural activity is not

related to when the response occurs, but instead to the probability that the response is accurate when issued at

any given time point during the decision process. In doing so, the response becomes a read-out of the time

course of a normally covert decision process. Timed-response paradigms have been employed in studies of

human saccades (Stanford et al., 1990) and have shown systematic effects of processing time on movementmetrics and accuracy. As shown in Preliminary Data (Fig. 8), we have devised an analogous paradigm for use

with monkeys.

This paradigm provides the best opportunity for evaluating the relationship between the timing of

neural discrimination in regions of OcTh and the state of the decision process itself. As such, it has great

PHS 398/2590 (Rev. 5/01) Page _25 Continuation Format Pa.cle


(Last, first, middle) Stanford. Terrence, R.

potential for distinguishing between neurons or thalamic regions for their potential to participate in the

evolving decision process. Such timing information could also place thalamic activity within the temporal

hierarchy of decision formation if comparable data becomes available for basal ganglia, cerebellum, or frontalcortex.

Experimental Design Figure 13 illustrates the task. Each trial begins with the onset of either a red or

green central stimulus. The color of the central spot indicates the color of the eventual saccade target. While

the monkey fixates the central light, four yellow stimuli (potential targets) appear at eccentric locations (Panel

2). After a variable delay, two of the yellow stimuli change color, one to red (the target in this example) and

another to green (color change distracter). When given the "GO" signal (offset of central spot), the monkeymust make a saccade to the stimulus that matches

the color of the fixation spot (e.g., red).

Figure 13. Timed-response paradigm - In this example, the

target is a red circle -Top: Trial with long processing time.

Bottom: trial with short processing time. See text for details.

The key to this task is the varying

temporal relationship between the "GO" signal

(offset of fixation spot) and the revealing of the

target (color change). We define processing time

(PT) as the interval from the time the target is

revealed (stimuli color change) to the time of

saccade onset. Because RT is strongly linked to

I IFixation Stimulus

[ I

Target revealed GO

Saccade

GO Target revealed

the "GO" signal, saccades will be generated over a wide range of PTs (See Preliminary Results). This is

illustrated by comparing the hypothetical trials represented by the top and bottom rows of panels in Fig. 13. In

the top row, the target is revealed (Panel 3 color change) before the "GO" signal (Panel 4). Processing time isdefined as the interval of time from target revealed to saccade onset, which in this case, equals the time from

color change to the "GO" signal plus the reaction time (RT = time from "GO" signal to saccade onset). In

contrast, the bottom row shows a trial in which the target is revealed (Panel 4) after the "GO" signal (Panel 3).

Thus, if RT maintains a consistent relationship to the "GO" signal (i.e., if the monkey does not withhold

responding), processing time will be considerable shorter. (Note that the equally spaced graphical

representation distorts the time scales such that RT appears to differ from top to bottom).Data analysis Our preliminary data show that the probability that a monkey of arrives at the "correct"

decision increases smoothly with increasing time to process the sensory information (see Fig. 8). Analysis of

neural activity as a function of time will be as described above for Experiment 1. Briefly, sigTtal detection

methods will used to compare neural activity for correct and incorrect trials for both targets and distracters in

the neuron's response field. Rather than identify the time at which neurons discriminate between targets and

distracters (as in Exps. 1 & 2), in this case, we will correlate the degree of neural discrimination (varying a

function of processing time) with level of performance (i.e., percent correct).

Possible outcomes Our interpretation of the "error rate" is that it is a reflection of the average status of

the decision process for a particular response time; on average, earlier responses are based on "weaker"

evidence (and thus are more prone to error) than later responses. If present in OcTh, a neural correlate of this

decision process would manifest as a correlation between the level of neural discrimination and level of

performance. As noted above, the relative timing of the neural discrimination and behavioral performance

functions, especially if compared to similar estimates from other visuomotor areas, will be a strong indicator of

whether or not these thalamic neurons drive decisions or simply reflect the outcome of decisions madeelsewhere.

AIM 2: TO EXPLORE THE ROLE OF OCULOMOTOR THALAMUS IN SENSORIMOTOR DECISION MAKING : EXPECTED

OUTCOME.

General rationale The experiments proposed in Aim I (above) focus on the problem of perceptual

judgment and its potential correlate in neural activity in OcTh. However, determining "what is there" is but

one stage in the process of translating sensory signals into motor commands. In some cases, the outcome of a

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_Last, first, middle) Stanford. Terrence, R.

perceptual judgment is a prescription for how to act, while in other instances it merely points to range of

choices. Given a choice then, decisions about "what to do" are made on the basis of weighing the expected

consequences of any given action by making a determination of what outcomes are possible and what their

relative likelihood of occurrence is. Most behavioral strategies favor those actions that are most likely to

produce favorable outcomes (See Nichols & Newsome, 1999; Glimcher, 2001 for review). Recently, a number

of studies have begun to examine the influence of such decision variables on neural activity within the

visuomotor system. For example, Platt and Glimcher (1999) showed that the visual responsiveness of lateral

intraparietal (LIP) neurons is modulated by the expected magnitude of the reward associated with a

movement into their response fields. Similarly, Leon and Shadlen (1999) showed that the memory period

activity of neurons in dorsolateral prefrontal cortex (PFCdl) neurons is modulated by expected reward

magnitude. Perhaps most striking are results showing dramatic shifts in the spatial preferences of visually-

responsive caudate neurons in a task that varied the association between reward magnitude and

stimulus/response location (Kawagoe et al., 1998). Despite the fact that the task did not call for a speeded

response, reaction times were reduced for saccades to locations associated with higher reward value. In a

related experiment, Platt and Glimcher (1999) gave monkeys free choice to look at either of two targets that

differed only in their associated reward magnitude. As expected, the monkey's choices were predicted by the

reward differential, but most importantly, the magnitude of LIP visual responses correlated with the behavior.

As we have noted, by virtue of the anatomical association with basal ganglia, we predict that VA, MD,

or the nuclei of the rostral intralaminar group are most likely to participate in networks that ascribe reward

value to sensory signals and/or pending motor commands. The experiments of Aim 2 employ a variety of

tasks that to examine the interaction between anticipated reward (a top-down influence) and stimulus salience

(a bottom-up influence) on the visuomotor activity of OcTh neurons.

Aim 2: Experiment 1: Influence of expected reward on visuomotor activity.

Experimental design This experiment evaluates the influence of expected reward value on the

visuomotor response properties of OcTh neurons. The task design shown in Fig. 14 is closely based on the 1

direction rewarded (1DR) task used by Kawagoe et al., (1998) in which stimulus locations are differentially

rewarded (see Preliminary data; Fig. 10). The monkey will perform a simple saccadic reaction time task. Each

trial begins with a central fixation spot. After a variable fixation interval, the fixation light is extinguished and

a single eccentric stimulus occurs at one of 4 possible locations (90 degrees of separation with rotation and

eccentricity based on the neuron's RF). The monkey must make a saccade directly to the target within 500 msto obtain reward. Trials will be run in blocks (200-400 trials; e.g., see Fig. 10; Preliminary data), during which

time the monkey will learn the reward value of the 4 potential target locations. In a given block, one location

will have a significantly higher reward value than

the remaining three locations (e.g., 0.15 ml vs. 0.05

ml juice; Platt & Glimcher, 1999). Blocks withreward location bias will be interleaved with

control blocks, in which all potential target

locations have equal reward value.

Figure 14. Simple saccade task with reward location bias.

Panel 1: Bar height is symbolic of the reward magnitude

associated with a correct saccade to a given location. Reward

magnitude-location associations are varied across blocks.

Dotted circle: location of hypothetical RF. See text for details.

!

! i..... I

IReward + Location Association

Simple Saccacle

Data analysis The primary measures for the neural data will be response magnitude and timing. For

behavioral data, saccadic reaction time and percent correct will be the primary dependent measures (e.g. see

Fig. 10). Average firing frequency and the tinung of response modulations, based on average instantaneous

firing frequency histograms or spike density functions, will be compared for each possible stimulus location

and for movements to each target. Key comparisons will be for visuomotor activity associated with correct

responses to the same target but corresponding to different reward outcomes. A second important comparison

will be for activity associated with correct trials and error trials, assuming that misdirected saccades occur with

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sufficient frequency. Appropriate comparisons will also be made with data obtained from control blocks,which have no bias.

Possible outcomes If OcTh neurons integrate information about expected outcome with visuomotor

signals, we would expect this to be reflected in response magnitude such that the visual- and/or motor-related

activity associated with saccades to high-reward location will be greater than that for low-reward targets. The

difference in magnitude and time course over which this difference evolves will be examined for a relationship

to any observed reaction time differences. We will be particularly interested to see if the locations of reward-

sensitive neurons is consistent with a basal ganglia origm and, if so, which basal ganglia recipient zones

specifically (VA, MD. or intralaminar) convey this information.

Aim 2, Experiment 2: Interaction between expected reward and visual feature detection: reward+locationassociation.

Specific rationale Studies that have examined the influence of reward estimation on neural activity and

behavior have typically employed very simple visuomotor tasks. However. it is a given that in everyday life,

our perceptual judgments can be influenced by prior knowledge, expectation, and/or the anticipated

outcomes associated with a particular event. In this experiment, we look for the neural representation of

interaction between top-down (reward expectation) and bottom-up (stimulus salience) influences in the

activity of visuomotor neurons. To do so, we conjoin the reward-location association task of Exp. 1 with a

simple feature search task. This search task, also known as the "oddball" task (Bichot & Schall, 1996), reqmres

the monkey to locate and make a saccade to the stimulus that is different. In this case, the distinguishing

characteristic is color and the "oddball" is considered to be a color singleton. Studies in visual psychophysics

have demonstrated that feature singletons seem to "pop out" of the visual scene, a form of automatic

"attentional capture" (Paschler, 1988; Theeuwes, 1991; See Egeth & Yantis 1997 for review). Indeed, many

studies have examined the behavioral consequences of placing irrelevant popout stimuli in conflict with the

goals of the task. Using this principle, this experiment compares top-down (reward expectation) and bottom-

up (popout) influences. In this case, however, the feature singleton is the relevant stimulus. A neural correlate

of popout has been observed in FEF where neurons signal the presence of oddball stimuli in their RFs (Bichot& Schall, 1996; 1999). Here we examine how reward ....................

expectation influences the time course of oddball detection in

the activity of OcTh neurons.

Figure 15. Feature search saccade task with location-reward bias. Panel 1:

Bar height is symbolic of the reward magnitude associated with a correct

saccade to a given location. Reward magnitude-location associations are

varied across blocks. Depicted is a block in which the high-reward

location is left and a trial for which the "oddball" target (green) is right.

Dotted circle: location of hypothetical response field. See text for details.

D

@

@

Reward + LocationAssociationFeatureSearchExperimental design This experiment combines the

reward contingency task described above (Aim 2, Exp. 1)

with a visual search task (Fig. 15). Monkeys will perform a speeded visual search task in which they are

required to make a saccade to an oddball target defined bv color. Each trial begins with a central fixation spot.

After a variable fixation interval, the fixation light is extinguished and an array of four eccentric stimuli

appears (90 degrees of separation with rotation and eccentricity based on the neuron's RF). The monkey must

make a saccade to the stimulus that is of a different color within 500 ms to obtain reward. On any given trial,

the target will be either red or green; the remaining distracter stimuli will be an alternate color. As above for

Experiment 1, the 4 possible target locations will be differentially rewarded, and this association will be

learned during blocks of 200-400 trials. Blocks with reward-location bias will be interleaved with control

blocks in which all potential target locations have equal reward value.

In this task, the target location is not correlated with the highly rewarded location. Within a given

block of trials, there will be trials in which the location of the oddball and that of high reward agree (p - 0.25)

and those for which thev will not (p - 0.75). Combining across reward-location blocks and considered from

the perspective of the neuron's response field, there are essentially 4 conditions: 1) the target is in the response

field and the response field location correspond to high reward (TH), 2) the target is in the response field and

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(Last, first, middle) Stanford. Terrence. R.

the response field location corresponds to low reward (TL), 3) a distracter is in the response field and the

response field location corresponds to high reward (DH), and 4) a distracter is in the response field and the

response field location corresponds to low reward (DL).

Data Analysis As in previous experiments, we will measure the magnitude and timing of activity

modulation for the purpose of comparisons across conditions. Analysis methods will be as described for

previous experiments. Neural discrimination functions will be generated using the methods described above

(see Aim 1, Experiment 1) for all target/distracter combinations with high/low reward contingencies.

Possible outcomes In general, this is a speeded reaction time task in which a perceptual discrimination

must be made and a saccade executed to a low reward location on most trials. The results of Kawagoe et al.,

(1998) and Platt and Glimcher (1999) suggest that, all things being equal, there is a decision bias toward

locations that are associated with higher reward and that this bias is reflected in the activity of visuomotor

neurons. As such, we expect that in the context of this experiment, we will observe differential effects on both

neural activitv and reaction time. Specifically, we would expect activity to be greatest and rise most rapidly

for the TH condition (when the target and high-reward location coincide within the neuron's response field),

and least for the DL condition {when the target appears outside the response field and the location of the

neuron's response field corresponds to low-reward). Intermediate levels of response will be obtained for the

TL and DH conditions. Reaction time, whether toward or away from the neuron's response field, should be

shortest for trials in which target location corresponds to high reward, and it is quite possible the time courseof neural discrimh_ation will be correlated with RT on correct trials.

Aim 2: Experiment 3: Interaction between expected reward and visual feature detection: reward+colorassociation.

Specific rationale Experiment 2 (above) evaluates the interaction between competing bottom-up (color-

singleton) and top-down (location of expected reward) on activity related to perceptual discrimination and

motor planning. In this experiment, we evaluate the effect of feature-reward magnitude associations on neural

activity and behavioral performance by associating reward magnitude with the color of the visual search

target. Unlike the previous experiment, in which the high-rewarded location is most often in conflict with location of

the target, in this experiment the influence of reward c

magnitude can either favor or compete with the goal of the c

target search.

Figure 16. Feature search saccade task with color-reward bias. Panel 1:

Bar height is symbolic of the reward magnitude associated with a

correct saccade to a given target by color. Reward magnitude-color

associations are varied across blocks, Depicted are two trials from a

block in which the high-reward color is green. Upper : green target;

Lower: red target. Dotted circle: location of hypothetical response field

See text for details.

c

Q

@ Reward = FeatureAssociationFeatureSearch

,C @

o c

c

GExperimental desigt7 The search task shown in Fig.

16 is identical to that described for Experiment 2, requiring

rapid detection and saccadic orientation to either a red or green oddball target presented among 3 yellow

distracters. However, in this case, reward magnitude is not tied to a location; rather it is associated with either

the color red or green. Again, trials are run in blocks of 200-400 trials during which the monkey learns the

color/reward value association. From the perspective of the neuron's response field, there are 4 possibilities:

high-reward target color in response field, low-reward target color in response field, high-reward target

outside response field, low-reward target outside response field. Control blocks in which red and green have

equal reward value will be interleaved.

Data Analysis As in previous experiments, we will measure the magnitude and timing of activity

modulation for the purpose of comparisons across conditions. Analysis methods will be as described for

previous experiments. Neural discrimination functions will be generated as described above (see Aim 1, Exp.1).

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•ContinuationPage PrincipalInvestigator/ProgramDirector(Last.first, middle) Stanford. Tcrrcnce. R.

Possible outcomes Based on the same logic outlined for Exp. 2, we expect response magnitude and

timing to reflect the level of conflict between the reward expectation and target location. In this case, however,

the neural discrimination functions should asymptote sooner and RTs should be shorter for trials in which the

saccade is made to the highly rewarded target color.

AIM 3: REPRESENTATION OF SPATIAL MEMORY

Aim 3: Spatial memory versus motor planning.

Rationale For the same reasons that decision-related signals can be difficult to distinguish from activity

related to motor planning, activity that is sustained during the retention interval of a traditional remembered

saccade task may or may not be a correlate of spatial memory of the target. Consider the fact that once the

stimulus is detected and its location known, a monkey has sufficient information to plan a movement to look

toward that stimulus. In this case, activity during the memory period could represent motor intention rather

than sensory memory (Asaad et al., 1998; see Miller & Cohen, 2001 for review).

Dorsolateral prefrontal cortex, which is known to receive strong input from MD, is generally considered to

be a primary locus of spatial working memory function (See Goldman-Rakic, 1997; Owen, 1997; Miller &Cohen, 2001 for reviews). Given the anatomical association between MD and PFCdl, it seems most likely that

true mnemonic signals will be observed in MD. Using a traditional memory-guided saccade task, we have

previously observed "memory-period" activity in all regions of thalamus, including VA, VL, and the rostral

intralaminar group (Massoglia et al., 2002), however, as noted above, this task fails to differentiate between

sensory memory and motor planning signals. This current experiment employs a task that disrupts the usual

spatial congruence between the locations to be remembered and the movements to be executed. By

decoupling the memory and motor requirements, this task will distinguish between a mnemonic

representation of stimulus location and a motor planning signal for saccade vector. This, in turn, will permit

us to determine if in fact memory ToskCue Stimulus Memory Motor plan $oooade

representations for past events are

plans for future actions are _,×at*ondifferentially distributed amongOcTh nuclei.

Figure 17. Color-location memory tasks.

Top: memory choice (upper panels) and

memory matching (lower panels) tasks

compared for case of same memory

requirement. Bottom: memory choice (upper

panels) and memory matching (lower panels)

tasks compared for case of same motor

requirement. Dotted circle: location of

hypothetical response field. See text for

details.

SAMEMEMORY

SAMEMOTOR

Experimental Design Figure 17

illustrates the task design. Critical to

the experiment is the comparison of activity under conditions that have the same mnemonic requirement but

require different movement vectors to conditions that have different mnemonic requirements but require the

same movement vector. To accomplish this end, we will combine a color-location memory choice task with a

color-location match/nonmatch task. For both tasks, a trial begins with the presentation of a central, yellow

fixation stimulus. Once the monkey acquires fixation, a task cue is provided to tell the monkey which of the

two tasks is ongoing based on a previously learned association. The appearance of two small yellow dots (task

cue: Fig. 17 - top, upper path) indicates to the monkey that it is the memory choice task. After a short delay, a

red and a green circle replace the 2 dots (stimulus period). After a viewing period of 500 ms, the stimuli are

extinguished. After a memory interval, the fixation spot changes color to match that of one of the two

previously presented stimuli (motor plan interval). After a short delay, the fixation spot is extinguished (GO

signal), and the monkey must look to the location where the color-matched stimulus had appeared. The

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matching task is cued by presenting two symbols (task cue: Fig. 17 - top, lower path): a plus sign and a minus

sign (both outside the neuron's response field). After a short delay, the cue stimuh disappear and, as in the

choice task, a red and a green circle are presented and later extinguished to begin the memory interval. After

the memory interval, a single spot reappears at one of the two previous locations followed by the plus and

minus symbols. If both the color and location of the spot match those of the stimulus (sample) period, the

monkey must make a saccade to the plus sign. Otherwise, the monkey must look to the minus sign to indicatea nonmatch.

Careful consideration of the mnemonic and motor requirements of these tasks reveals their logic. In

both cases, correct performance of the task requires memory of both the location and color of the two stimuli.

The primary difference is that, from the outset of the trial, the monkey knows if one of the two stimulus

locations will be the target of a saccade (memory choice task) or not (matching task). In the top panel

(described above), the choice and matching tasks have the same mnemonic requirements, but different motor

requirements. In contrast, the bottom panel compares choice and matching tasks that have different

mnemonic requirements, but the same motor requirement.

Data analysis Critical analyses will focus on comparing the magnitude and time course of activity

during the memory and motor planning phases of the two tasks. As for previously described experiments,

analyses will be performed on measures of average firing frequency across time during the trial as represented

by instantaneous firing frequency histograms or spike density functions.

Possible outcomes As discussed above, this experiment attempts to determine if neurons in OcTh code

the locations of remembered stimuli, or if this information is coded only in the context of a motor plan to look

at the remembered location. The basic predictions are straightforward. Memory period activity for neurons

that code for the location of previously presented stimuli should respond similarly for all cases of a stimulus

having occurred within the response field and independent of whether or not a saccade to this location will be

required (Fig. 17: top panel - Same Memory). The same neuron should respond quite differently for trials in

which the stimuli are presented in different spatial locations, even if the impending saccades are identical (Fig.

17: bottom panel - Same Motor). In contrast, a neuron most closely allied with motor planning will respond

similarly when the planned saccades have the same vector, independent of the remembered stimulus

locations. Also, the task has the potential for dissociating memory-related and motor-planning activity in

time. While the activity related to sensory memory will be evident during the memory period (when both

stimulus locations must be remembered), motor planning activity should only reach its full expression during

the motor plan phase of the task, after the monkey has enough information to rule out one of the potential

targets.

SummaryThe experiments proposed in Aims 1-3 represent a systematic approach to investigating the role of

OcTh in the context-dependent control of visually-guided behavior. Along with providing a test for the

existence of functionally segregated information processing channels, considered in the context of similar

experiments in anatomically-related visuomotor areas, these data will provide insights into how information is

transformed as a result of processing intrinsic to thalamus. Beyond visuomotor control, these data may have

more far-reaching implications for models of subcortical-cortical interaction.

Timeline for completion of Proposed Studies

year 1 2 3 4 5

quarter 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3

Aim 1 (2-3 animals)Personnel recruitment • • •

Surgery I (coil) •

Oculomotor training] •

Surgery II (recording) •

Recording • • • • •

Data analysis • • • • •

Writing • •

Aim 2 (2-3 animals)Surgery I (coil)

Oculomotor training • •


PHS 398/2590 (Rov. 5/01) Page 31 Continuation Format Pacle



Recording • • • • • •

Data analysis • • • • •

Writing •

Stanford, Terrence, R.

Aim 3 (2-3 animals)

Surgery I (coil) •

Oculomotor training • •


Recording ° • • • • •

Data analysis • ° ° • •

Wnting • •

Future Directions

The proposed recording studies are designed to examine correlations between neural activity and

behavioral events. Dual recording techniques could be applied to further define the distinct roles of different

thalamic regions; recording in thalamus in combination with orthodromic or antidromic stimulation to reveal

afferent and efferent connections will be of great value to understanding this system. Further, recording in

oculomotor thalamus while reversibly deactivating its cortical or subcortical inputs, and the reverse

experiment, recording in thalamic targets while deactivating thalamus are experiments that could provide

potent insights into the functional relationships of these sensorimotor domains. Finally, studies of the

relationships between neural activity and behavioral context are in a nascent stage. Future experiments have

the potential to be much more sophisticated and to contribute greatly our understanding of the neural basis ofbehavior.

General methods

Awake, Behaving Preparation

Initial training period: Rhesus monkeys (Macaca mulatta) will be used in all experiments. During the initial

training period, animals are acclimated to a restraining chair that has been designed for their comfort. Trained

animals readily climb into the chair using the "pole and collar" technique. Time in the chair is typically 2-3 hours

during which they are receiving food rewards and are interacting in the experimental setting. Once acclimated to

the restraint and experimental setting the animals will be surgically prepared (See below - eye coil and head

restraint) for behavioral training on the specific behavioral tasks.

Task training: Training on the behavioral tasks proceeds according to standard procedures widely in use for

rhesus monkeys. Successive approximations (i.e., "shaping") will be used in animals working for liquid rewards.Fluid control will follow the recommendations set forth by the NIH Guide for the Care and Use of Laboratory

Animals and by an NIH workshop report on the use of higher mammals in neuroscience research (Van

Sluyters & Oberdorfer, 1991). During training the animal is seated in the primate chair with its head restrained.

Visual stimuli are presented and saccade eye movements monitored. Once trained to criterion (typically several

weeks depending on task difficulty), animals will be surgically prepared for electrophysiological recording by

implanting a recording cylinder through which an electrode can be advanced to oculomotor thalamus.

Surgical Procedures

Eye coil and head restraint: Animals are deprived of food for 12 hrs before surgery. Prior to preoperative

anesthesia, animals receive injections of Atropine (0.04-0.06 mg/kg, ira) to control secretions. Surgical sites are

shaved and scrubbed before the animal is moved to the operating room. The animal is placed on inhalant

anesthesia (isoflurane 1.5-3.0%). End-tidal CO2 is monitored and kept between 3.8 and 4.5, heart rate is

monitored, and normal temperature is maintained with a circulating hot water pad.

The animal is placed in a stereotaxic apparatus and the field prepared. Skin is incised along the midline and

retracted to expose the skull. A post is attached to the skull by titanium surgical screws for the purpose of

restraining the head during experiments. The post and screws are bonded together with sterile orthopedic bone

cement. Once the posts are secured, the animal is removed from the stereotaxic holder, placed on its back, and a

new sterile field prepared around the eyes (note: the surgeon(s) rescrub, regown and reglove if necessary). The

eyelids are retracted and the conjunctiva circumsected around the cornea. A pre-formed sterile loop of insulated

wire (eye coil) is placed onto the sclera surrounding the cornea. The eye coil is sutured to the sclera in 3-4

locations around the globe using absorbable suture (typically 6.0 vicryl). A small pouch is created in the

connective tissue at the lateral edge of the eye by making a small incision and blunt dissection of lower layers.




The two free ends of the eye coil are brought into the pouch and a strain relief loop is formed. A suture needle is

used to carry the ends of the wire subcutaneously to a small incision at the lateral edge of the bony orbit and a

small loop of wire is attached to the underlying muscle. The two ends of the wire are then run subcutaneously to

the wound margin surrounding the head post implant. The free wires of the eye coil are soldered to a small

electrical connector, which is then secured to the head post implant with additional bone cement. All incisionsare closed.

Recording cylinder: The recording cylinder is placed in a separate surgical procedure after the monkey has been

trained on the behavioral tasks. Preoperative procedures and anesthesia are the same as above. The anesthetized

animal is placed in a stereotaxic instrument and a circular region of scalp is removed to expose the skull. The

periosteum is removed and a circular region of bone is removed using a sterile drill. Placement of the crardotomy

is guided by MRI images for optimal access to oculomotor thalamus. A recording cylinder is placed over the

craniotomy and secured using orthopedic bone cement and anchored to 2-6 sterile stainless steel screws that have

been threaded into skull. The interior of the cylinder is washed with sterile saline, filled with antibiotic solution,

and closed with a sterile cap that threads into the cylinder opening.

Postoperative Procedures: Animals will be monitored and records maintained according to NIH guidelines,

USDA regulations and Wake Forest University policy. Analgesics and antibiotics will be administered as

required and recommended by the veterinary staff. Surgical sites will be examined daily and, if necessary,

topical antibiotics and/or anesthetics will be applied. Inflammation of the eye may be controlled by topical

administration of antibiotic ointment and topical ophthalmic steroid solution.

Measurement of eye movements The search coil method of monitoring eye position is based on theprinciple of magnetic induction (Robinson, 1963; Fuchs & Robinson, 1966). Briefly, the monkey will be

positioned so that its head is centered within 2 magnetic fields that are in spatial (horizontal and vertical) and

phase quadrature. The magnetic fields induce current to flow within an eye coil that is surgically attached the

globe of one eye (See eye coil surgical procedure). The amount of induced current is proportional to angular

relationships between the eye coil and the horizontal and vertical magnetic fields. Analog signals proportional

to horizontal and vertical eye position will be sampled and digitized at 500 Hz. Using gain and offset controls,

eye position will be calibrated so that voltages correspond to specific points of ocular fixation.

Recording procedures At the beginning of each experimental session, the recording chamber will be

opened and the electrode positioned using a X-Y translation stage. MRI will guide placement of the electrode

within the cylinder as well as provide estimates of appropriate electrode depth. Once positioned at an X-Y

coordinate, the dura will be pierced with a 21 gauge hypodermic needle and a parylene-coated tungsten

microelectrode advanced through the needle and down to the oculomotor thalamus using a hydraulic

microdrive. Amplified and filtered (300 Hz to 4 kHz) neural activity will be monitored using an oscilloscope

and an audio monitor. Estimates of electrode location will be determined by listening for activity related to

visual stimuli and/or saccadic eye movements.

Data collection For each experimental trial, several events are digitized and stored for off-line analysis.

Horizontal and vertical eye position are sampled every 2 msec (500 Hz). Target positions, onset and offsettimes, and the onset and offset times of stimulation train are stored with a resolution of 2 msec. Action

potentials are timed at a resolution of 10 microseconds and spike times are referenced to task-related events

during off-line analysis.

Eye movement analysis Velocity criteria are used to define the onset ( > 30 °/sec) and offset ( < 30 °/sec)

of visually-gtdded or stimulation-induced saccades. Once defined, horizontal and vertical component

durations and amplitudes can be derived. Component velocities will be obtained by differentiation of the eye

position signals. Values obtained for the horizontal and vertical components will then be used to compute

vectorial amplitude and velocity.

Histology At the conclusion of an experimental sequence, electrolytic marking lesions willbe made by

passing DC current through the recording electrode. Animals will be given a lethal dose of pentobarbital and

then perfused intracardially with 0.9% saline followed by either 10% formalin or 2% paraformaldehyde and

0.2% glutaraldehyde. Brains will be cut in the coronal or parasagittal plane on a freezing microtome, and

sections mounted and stained for Nissl substance to assess the placement of recording tracks and marker

lesions. Camera lucida drawings and computer-assisted reconstruction will be used to localize recording sites.

PHS 398/2590 (Rev. 5/01 ) Page _33 Continuation Format Paqe



e=

fo

1)

2)

3)

4)

5)

Human Subjects

Not applicable

Vertebrate Animals

Eight adult, male or female, macaque monkeys (Macaca mulatta), weighing approx. 5-7 kg. will be used.

During the initial training period, animals are acclimated to a restraining chair that has been designed for

their comfort. Trained animals readily climb into the chair using the "pole and collar" technique. Time in

the chair is typically 2-3 hours during which they are receiving food rewards and are interacting in the

experimental setting. Once acclimated to the restraint and experimental setting the animals will be

surgically prepared for behavioral training on the specific behavioral tasks. During training, the animal is

seated in the primate chair with its head restrained. Visual stimuli are presented and saccade eye

movements monitored. Training on the behavioral tasks proceeds according to standard procedures

widely in use for rhesus monkey. Successive approximations (i.e., "shaping") will be used in animals

working for liquid rewards. Fluid control will follow the recommendations set forth by the NIH Guide for

the Care and Use of Laboratory Animals and by an NIH workshop report on the use of higher mammals in

neuroscience research (Van Sluyters & Oberdorfer, 1991). Ideally, a well-trained animal will work to

satiety during an experimental session and, in doing so, obtain its minimum daily water requirement. In

the event that the animal does not obtain its minimum fluid intake during a session, fluid will be

supplemented to the appropriate level when the animal is returned to its home cage. Once trained to

criterion (typically several weeks depending on task difficulty), animals will be surgically prepared for

electrophysiological recording by implanting a recording cylinder through which an electrode can be

advanced to oculomotor thalamus. Typically animals participate in experiments for 5 days each week

(usually Mon-Fri) and receive water ad libitum on the remaining two days.

The awake behaving primate preparation, using rhesus monkeys, is the model of choice for studying issues

in sensorimotor integration. Because of the relatively advanced cognitive capacity of these animals, they

readily learn the complex behavioral tasks necessary to investigate issues that are most readily applied to

the human condition. There is no suitable alternative for the experiments proposed. The number of

monkeys requested in this proposal is based on the guideline that a given experiment must be replicated in

at least one monkey. The number requested is based on the P.I.'s experience with this preparation.

All animals our housed and maintained in an AAALAC accredited facility managed by the Animal

Resources Program of the Wake Forest University School of Medicine. The facility is directed by Dr.

Jeanne Wallace, who is certified by the American College of Laboratory Animal Medicine. Veterinary care

and assistance is readily available.

The P.I. is highly experienced (12 yrs.) in the training of macaque monkeys and is dedicated to ensuring

their health and well being. Several methods are used to minimize stress and discomfort. A pole and

collar technique is used to manipulate animals when transported from cage to the primate chair.

Minimizing direct physical contact greatly reduces the stress of this procedure. The restraining apparatus

is a purpose-built chair designed specifically to maximize comfort. Animals are in the chair no more than

2-4 hours on any given day and they are removed from the chair and returned to the home cage if

demonstrating signs of discomfort. Post-operative procedures require administration of narcotic

analgesics, followed by daily treatment with Tylenol as needed. Throughout the duration of an individual

animal's participation in experimental protocols, fluid intake, weight, and a variety of other physiologicaland behavioral measures (see below) will be recorded to assure the animal's continued health and well-

being. Daily inspections by laboratory personal and animal care staff ensure early detection of anypotential problems.

Animals will by euthanized by exsanguination while under deep barbiturate anesthesia (100 mg/kg, i.v.).

This method conforms to recommendations of the Panel on Euthanasia of the American Veterinary

Medical Association. Standard perfusion techniques are used whereby the thoracic cavity is opened and

perfusate injected into an opening made in the left ventricle and exits via an opening in the right atrium.

The perfusate is heparinized saline followed by a mixture of aldehyde fixatives. The brain is removed from

the cranium and processed for histology.


,Continuation Page Principal Investigator/Program Director


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Principal InvestigatodProgram Director (last, First, Middle): Stanford, Terrence R.

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