diencephalic mechanisms of visuomotor integration · 2008-07-18 · departmentofhealth and human...
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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 ($)
$225,000
Wake Forest University Health SciencesMedical Center Boulevard
Winston-Salem, NC 27157
Institutional Profile File Number (if known) 9021205
12. ADMINISTRATIVE OFFICIAL TO BE NOTIFIED IF AWARD IS MADE
Name
Title
Address
MAILING ADDRESS (Street, city, state, zip code)
Wake Forest University Health SciencesMedical Center Boulevard
Winston-Salem, NC 27157
E-MAIL ADDRESS:
stanford@wlubmc.edu
5. VERTEBRATE ANIMALS [] No [] Yes
5a. If "Yes," IACUC approval Date 5b. Animal welfare assurance no
07-15-03 A3391-01
8. COSTS REQUESTED FOR PROPOSED
PERIOD OFSUPPORT
7b. Total Costs ($) 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
Wake Forest University Health SciencesMedical Center Boulevard
Winston-Salem, NC 27157
Tel (336) 716-2406
E-Mail nihawards@wfubmc.edu
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 svrana@wfubmc.edu
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 Page 1 •
• 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.
Winston-Salem, NC 27157
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) Page 2 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) Page 3 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 ) Page 4 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) Page 5 Biographical Sketch Format Page •
• Principal Investigator/Program Director (Last, first, middle): Stanford, Terrence R.
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) Page 6Number pages consecutively at the bottom throughout the application. Do not use suffixes such as 3a, 3b.
Biographical Sketch Format Page •
• Principal Investigator/Program Director (Last, first, middle): Stanford, Terrence R.
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) Page 7Number pages consecutively at the bottom throughout the application. Do not use suffixes such as 3a, 3b.
Biographical Sketch Format Page •
• Principal Investigator/Program Director (Last, first, middle): Stanford, Terrence R.
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) Page 8 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
• Continuation Page Principal Investigator/Program Director
(Last, first, middle) Stanford, Terrence, R.
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.
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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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Motor Output Motor Output Motor Output
_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,
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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,
(_ _1 _-_
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OcTh neurons maintained task-relevant spatial information throughout an instructed delay period. These data
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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-
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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
:._'G.'/!_:.'::'+:.,':U::_9_%:i:::.'il.:::i!_i:Yil)i:i.i(.:'i'i_+_='i.i.:: : :+ :'
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& l....... J_*'" "........ adaJ II I, .... ,,*5/3
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
Tithe (ins)
200 400
180]
°°t /270 0 90 180 9'O
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
A. visual B. motor
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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
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& 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
A. A,P. 7 N_26
B. A.P. 7.5 N-52
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[] md • 3-4units
,_ vi/nni • 5-6 units
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NTvd/mi
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
A. slimuE on cue Or'go' stimuli off
1.0 N_ 7
befo_ue after-cue I
_:, , i memory ........
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time (ms) /
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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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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
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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
oContinuationPage Principal Investigator/Program Director
(Last, first, middle) Stanford, Terrence, R.
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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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
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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
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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
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(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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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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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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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 • •
Surgery II (recording) •
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Recording • • • • • •
Data analysis • • • • •
Writing •
Stanford, Terrence, R.
Aim 3 (2-3 animals)
Surgery I (coil) •
Oculomotor training • •
Surgery II (recording) •
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.
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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.
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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.
PHS 398/2590 (Rev. 5/01) Page _34 Continuation Format PaQe
,Continuation Page Principal Investigator/Program Director
(Last, first, middle) Stanford, Terrence, R.
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PHS 398/2590 (Rev. 5/01) Page _38 Continuation Format PaQe
oContinuation Page
Stanford, Terrence, R.Principal Investigator/Program Director
(Last, first, middle)
PHS 398/2590 (Rev. 5/01) Page _39 Continuation Format Paqe
Principal InvestigatodProgram Director (last, First, Middle): Stanford, Terrence R.
CHECKLISTTYPE OF APPLICATION (Check all that apply.)
--'7 NEW application. (This application is being submitted to the PHS for the first time.)
[_ SBIR Phase I D SBIR Phase I1: SBIR Phase I Grant No.
D STTR Phase I [_] STTR Phase I1: STTR Phase I Grant No.
[_ REVISION of application number: EY012389-05(This application replaces a prior unfunded version of a new, competing continuation, or supplemental application.)
E_ COMPETING CONTINUATION of grant number:
(This application is to extend a funded grant beyond its current project period.)
[_ SUPPLEMENT to grant number:
(This application is for additional funds to supplement a currently funded grant.)
E_] CHANGE of principal investigator/program director.
Name of former principal investigator/program director:
[_ FOREIGN application or significant foreign component.
D SBIR Fast Track
r_ STTR Fast Track
INVENTIONS AND PATENTS(Competing continuation appl. and Phase II only)
[] No [] Previously reported
[] Yes. If"Yes," _- [] Not previously reported
1. PROGRAM INCOME (See instructions.)All applications must indicate whether program income is anticipated during the period(s) for which grant support is request. If program income isanticipated, use the format below to reflect the amount and source(s).
Budget Period Anticipated Amount Source(s)
2. ASSURANCES/CERTIFICATIONS (See instructions.)The following assurances/certifications are made and verified by thesignature of the Official Signing for Applicant Organization on the FacePage of the application. Descriptions of individual assurances/certifications are provided in Section II1. If unable to certify compliance,where applicable, provide an explanation and place it after this page.
•Human Subjects; ,Research Using Human Embryonic Stem Cells.•Research on Transplantation of Human Fetal Tissue .Women and
•Debarment and Suspension; "Drug- Free Workplace (applicable to new[Type 1] or revised [Type 1] applications only); ,Lobbying; -Non-Delinquency on Federal Debt; .Research Misconduct; .Civil Rights(Form HHS 441 or HHS 690); ,Handicapped Individuals (Form HHS 641or HHS 690); ,Sex Discrimination (Form HHS 639-A or HHS 690); ,AgeDiscrimination (Form HHS 680 or HHS 690); .Recombinant DNA andHuman Gene Transfer Research; .Financial Conflict of Interest (exceptPhase I SBIR/STTR) ,STTR ONLY: Certification of Research Institution
Minority Inclusion Policy ,Inclusion of Children Policy, Vertebrate Animals, Participation.
3. FACILITIES AND ADMINSTRATIVE COSTS (F&A)I INDIRECT COSTS. See specific instructions.
[_ DHHS Agreement dated: 1/1 0/02 D No Facilities And Administrative Costs Requested.
D DHHS Agreement being negotiated with Regional Office.
r'_No DHHS Agreement, but rate established with Date
CALCULATION* (The entire grant application, including the Checklist, will be reproduced and orcvided to peer reviewers as confidential information.)
a. Initial budget period: Amount of base $ 215,000 x Rate applied 43.5 % = F&A costs
b. 02 year Amount of base $ 220,000 x Rate applied 43.5 %= F&A costs
c. 03 year Amount of base $ 225,000 x Rate applied 43.5 % = F&A costs
d. 04 year Amount of base $ 225,000 x Rate applied 43.5 %= F&A costs
e. 05 year Amount of base $ 225,000 x Rate applied 43.5 % = F&A costs
TOTAL F&A Costs
*Check appropriate box(es):
D Salary and wages base [_ Modified total direct cost base
[] Off-site, other speciat rate, or more than one rate involved (Explain)
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['-7 Other base (Explain)
$ 93,525
$ 97,700
$ 97,875
$ 97,875
$ 97,875
$ I 482,850 I
4. SMOKE-FREE WORKPLACE [] Yes [] No (The response to this question has no impact on the review or funding of this application.)
PHS 398 (Rev. 05/01 ) Page 39 Checklist Form Page
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