PI: HEINEN, STEPHEN J Title: Cortical Planning and Control ... filePI: HEINEN, STEPHEN J Title:...

PI: HEINEN, STEPHEN J Title: Cortical Planning and Control of Smooth Pursuit

Received: 07/05/2007 FOA: PA07-070 Council: 01/2008

Competition ID: FOA Title: RESEARCH PROJECT GRANT (PARENT R01)

2 R01 EY011720-11A1 Dual: Accession Number: 3012478

IPF: 1842901 Organization: SMITH-KETTLEWELL EYE RESEARCH INSTITUTE

Former Number: Department: NONE

IRG/SRG: CVP AIDS: N Expedited: N

Subtotal Direct Costs

(excludes consortium F&A)

Year 11: 250,000

Year 12: 250,000

Year 13: 250,000

Year 14: 250,000

Year 15: 250,000

Animals: Y

Humans: N

Clinical Trial: N

Exemption: 10

HESC: N

New Investigator: N

Senior/Key Personnel: Organization: Role Category:

Stephen Heinen PhD The Smith-Kettlewell Eye Research

Institute

PD/PI

--------------------------- ---------------------- Consultant

Appendices

1135_1997heinenliu, 1136_1999watamaniukheinen, 1134_sjhappendixlist

APPLICATION FOR FEDERAL ASSISTANCE

SF 424 (R&R)2. DATE SUBMITTED

07/05/2007Applicant Identifier

6-014

3. DATE RECEIVED BY STATE State Application Identifier1. * TYPE OF SUBMISSION

❍ Pre-application ● Application❍ Changed/Corrected Application

4. Federal IdentifierEY011720

5. APPLICANT INFORMATION * Organizational DUNS:073121105* Legal Name: The Smith-Kettlewell Eye Research InstituteDepartment: NONE Division: None* Street1: 2318 Fillmore Street Street2:

* City: San Francisco County: San Francisco * State: CA: California

Province: * Country: USA: UNITED STATES * ZIP / Postal Code: 94115

Person to be contacted on matters involving this applicationPrefix: * First Name: Middle Name: * Last Name: Suffix:Ms. Beatriz St. John* Phone Number: 415-345-2035 Fax Number: 415-345-8455 Email: [email protected]

6. * EMPLOYER IDENTIFICATION NUMBER (EIN) or (TIN):--------------------

7. * TYPE OF APPLICANTM: Nonprofit with 501C3 IRS Status (Other than Institution of Higher Education)

Other (Specify):Small Business Organization Type

❍ Women Owned ❍ Socially and Economically Disadvantaged

8. * TYPE OF APPLICATION: ❍ New

● Resubmission ❍ Renewal ❍ Continuation ❍ Revision

If Revision, mark appropriate box(es).

❍ A. Increase Award ❍ B. Decrease Award ❍ C. Increase Duration❍ D. Decrease Duration❍ E. Other (specify):

9. * NAME OF FEDERAL AGENCY:NIH

10. CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER:TITLE: Research Project Grant (Parent R01)

* Is this application being submitted to other agencies? ❍ Yes ● NoWhat other Agencies?

11. * DESCRIPTIVE TITLE OF APPLICANT'S PROJECT:Cortical Planning and Control of Smooth Pursuit

12. * AREAS AFFECTED BY PROJECT (cities, counties, states, etc.)N/A

13. PROPOSED PROJECT:* Start Date * Ending Date04/01/2008 03/31/2013

14. CONGRESSIONAL DISTRICTS OF:a. * Applicant b. * Project08 CA-008

15. PROJECT DIRECTOR/PRINCIPAL INVESTIGATOR CONTACT INFORMATIONPrefix: * First Name: Middle Name: * Last Name: Suffix:Dr. Stephen J Heinen PhDPosition/Title: Senior Scientist * Organization Name: The Smith-Kettlewell Eye Research InstituteDepartment: NONE Division: None* Street1: 2318 Fillmore Street Street2:



* Phone Number: 415-345-2101 Fax Number: 415-345-8455 * Email: [email protected]

Tracking Number: Funding Opportunity Number: Received Date: Time Zone: GMT-5 OMB Number: 4040-0001Expiration Date: 04/30/2008

SF 424 (R&R) APPLICATION FOR FEDERAL ASSISTANCE Page 216. ESTIMATED PROJECT FUNDING 17. * IS APPLICATION SUBJECT TO REVIEW BY STATE EXECUTIVE ORDER 12372 PRO-

CESS?a. YES ❍ THIS PREAPPLICATION/APPLICATION WAS MADE AVAILABLE TO THE

STATE EXECUTIVE ORDER 12372 PROCESS FOR REVIEW ON:DATE:

b. NO ● PROGRAM IS NOT COVERED BY E.O. 12372; OR

❍ PROGRAM HAS NOT BEEN SELECTED BY STATE FOR REVIEW

a. * Total Estimated Project Funding $2,083,162.00b. * Total Federal & Non-Federal Funds $2,083,162.00c. * Estimated Program Income $0.00

18. By signing this application, I certify (1) to the statements contained in the list of certifications* and (2) that the statements herein are true, completeand accurate to the best of my knowledge. I also provide the required assurances * and agree to comply with any resulting terms if I accept anaward. I am aware that any false, fictitious, or fraudulent statements or claims may subject me to criminal, civil, or administrative penalties. (U.S.Code, Title 18, Section 1001)

● * I agree* The list of certifications and assurances, or an Internet site where you may obtain this list, is contained in the announcement or agency specific instructions.

19. Authorized RepresentativePrefix: * First Name: Middle Name: * Last Name: Suffix:Ms. Ruth Poole* Position/Title: Chief Operating Officer * Organization Name: The Smith-Kettlewell Eye Research InstituteDepartment: None Division: None* Street1: 2318 Fillmore Street Street2:



* Phone Number: 415-345-2043 Fax Number: 415-345-8455 * Email: [email protected]

* Signature of Authorized Representative

Ruth Poole

* Date Signed

07/02/2007

20. Pre-application File Name: Mime Type:

21. Attach an additional list of Project Congressional Districts if needed.

File Name: Mime Type:

Tracking Number: Funding Opportunity Number: Received Date: Time Zone: GMT-5 OMB Number: 4040-0001Expiration Date: 04/30/2008

424 R&R and PHS-398 SpecificTable Of Contents Page Numbers

SF 424 R&R Face Page------------------------------------------------------------------------------------------ 1

Table of Contents--------------------------------------------------------------------------------------------- 3

Performance Sites--------------------------------------------------------------------------------------------- 4

Research & Related Other Project Information------------------------------------------------------------------ 5

Project Summary/Abstract (Description)---------------------------------------- 6

Public Health Relevance Statement (Narrative attachment)---------------------------------------- 7

Facilities & Other Resources---------------------------------------- 8

Equipment---------------------------------------- 9

Research & Related Senior/Key Person-------------------------------------------------------------------------- 10

Biographical Sketches for each listed Senior/Key Person---------------------------------------- 12

PHS 398 Specific Cover Page Supplement------------------------------------------------------------------------ 20

PHS 398 Specific Modular Budget------------------------------------------------------------------------------- 22

Personnel Justification---------------------------------------- 26

Consortium Justification---------------------------------------- 27

Additional Narrative Justification---------------------------------------- 28

PHS 398 Specific Research Plan-------------------------------------------------------------------------------- 29

Introduction to Revised/Supplemental Application---------------------------------------- 32

Specific Aims---------------------------------------- 35

Significance and Related R&D---------------------------------------- 36

Preliminary Studies/Phase I Final Report---------------------------------------- 41

Experimental/Research Design and Methods---------------------------------------- 50

Inclusion Enrollment Report---------------------------------------- 60

Progress Report Publication List---------------------------------------- 62

Vertebrate Animals---------------------------------------- 64

Select Agent Research---------------------------------------- 66

Multiple PI Leadership Plan---------------------------------------- 67

Bibliography & References Cited---------------------------------------- 68

Consortium/Contractual Arrangements---------------------------------------- 76

Letters of Support---------------------------------------- 77

Resource Sharing Plan (Data Sharing and Model Organism Sharing)---------------------------------------- 78

PHS 398 Checklist--------------------------------------------------------------------------------------------- 79

Appendix

Number of Attachments in Appendix: 3

Table of Contents Page 3

Principal Investigator/Program Director (Last, first, middle): Heinen, Stephen, J

RESEARCH & RELATED Project/Performance Site Location(s)

Project/Performance Site Primary Location

Organization Name: The Smith-Kettlewell Eye Research Institute

* Street1: 2318 Fillmore Street Street2:


Province: * Country: USA: UNITEDSTATES * Zip / Postal Code: 94115

File Name Mime Type

Additional Location(s)

Tracking Number: OMB Number: 4040-0001Expiration Date: 04/30/2008

Performance Sites Page 4


RESEARCH & RELATED Other Project Information

1. * Are Human Subjects Involved? ❍ Yes ● No

1.a. If YES to Human Subjects

Is the IRB review Pending? ❍ Yes ❍ No

IRB Approval Date:

Exemption Number: 1 2 3 4 5 6

Human Subject Assurance Number

2. * Are Vertebrate Animals Used? ● Yes ❍ No

2.a. If YES to Vertebrate Animals

Is the IACUC review Pending? ❍ Yes ● No

IACUC Approval Date: 06-14-2007

Animal Welfare Assurance Number A4375-01

3. * Is proprietary/privileged information

included in the application?

❍ Yes ● No

4.a. * Does this project have an actual or potential impact on

the environment?

❍ Yes ● No

4.b. If yes, please explain:

4.c. If this project has an actual or potential impact on the environment, has an exemption been authorized or an environmental assessment (EA) or

environmental impact statement (EIS) been performed? ❍ Yes ❍ No

4.d. If yes, please explain:

5.a. * Does this project involve activities outside the U.S. or

partnership with International Collaborators?

❍ Yes ● No

5.b. If yes, identify countries:

5.c. Optional Explanation:

6. * Project Summary/Abstract 1167_SJHProjectSummary.pdf Mime Type: application/pdf

7. * Project Narrative 1168_SJHProjectNarrative.pdf Mime Type: application/pdf

8. Bibliography & References Cited 1186_SJHRefs.pdf Mime Type: application/pdf

9. Facilities & Other Resources 1068_SJHresources.pdf Mime Type: application/pdf

10. Equipment 1069_SJHequipment.pdf Mime Type: application/pdf


Other Information Page 5


Our goal is to understand how frontal cortex controls smooth pursuit eye movements.

Previous work has elucidated other regions involved in reflexive pursuit. However, whencognition intervenes, frontal lobe circuitry likely participates. We have developed a

pursuit go/nogo paradigm that exploits cognitive functions often deficient in patients with

frontal lobe damage, such as rule encoding, set shifting and decision making, in an effort

to differentiate functions of frontal structures in pursuit control. Both the supplementaryeye field (SEF) and frontal eye field (FEF) are differentially active during the paradigm,

and our fMRI results in humans and preliminary single-unit data in monkey suggest that

ventrolateral prefrontal cortex (VLPFC) is also. We propose to determine how theseregions interact in the decision to execute or withhold a pursuit movement in the context

of a rule. Aims are:

1) Characterize SEF and FEF encoding of a rule-based oculomotor “if” decision

2) Investigate SEF and FEF involvement in the evolution of a rule-based “when” signal

3) Determine the role of the VLPFC in mental set-switching

Project Description Page 6


Our research will provide insight into the neuronal pathways that underlie cognitive

oculomotor function in the normal oculomotor system, to allow diagnosis of frontalcortical damage in patients who have cognitive disorders. We have also done fMRI work

to provide a linkage between monkey and human brain regions. This work should aid in

translating our stimuli towards use in the diagnosis process.

Public Health Relevance Statement Page 7


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. If research involving Select Agent(s) will occur at any performancesite(s), the biocontainment resources available at each site should be described. 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:

The PI has a laboratory in the -- -- -- -- ---- -- -- -- - building. In this building the PI shares an ensemble of

spaces with three other investigators. The space includes 4 specially shielded (for magnetic and electric

fields) rooms for alert primate experiments. Each of these spaces is equipped with a Chase, 3-foot magnetic

field coil system for measuring eye movements in monkeys. Each system has the coil-lift feature that allows

easy access for primate chairs to the center of the coils. Each space has an attached room for computer and

electronic instrument access to the experimental room. There are in addition in the shared space, 2 prep

rooms, a small instrument tool room and a computation and analysis space. The primate experiment room is

also equipped with a micro-stimulator, a multiple-channel amplifier system, and a micro-drive for

microinjection that will provide the necessary equipment for conducting the proposed experiments.

Clinical:

N/A.

Animal:

The monkeys are housed -- - - --- - --- ---- -- - - ---- - - - -- - ---- -- --- --- - --- -- -- The facility is

operated by the animal care manager and staff under the supervision of consulting veterinarians. The

manager and staff provide daily care, cleaning, observations, and enrichment. Social interaction is a part of

enrichment and occurs with compatible pairs unless otherwise stated in a protocol. Compatible animals are

housed together for a couple of hours a day. The housing consists of 2 cages and a larger play cage. Non-

compatible animals have access to the larger play cage for a couple of hours a day as well.

Computer:

The PI’s lab has a dedicated computer with LabView and MatLab for real time data collection and behavioral

control. A second Mac computer is used for stimulus display. There are also three general purpose

computers for offline data analysis and reporting.

Office:

Dedicated office space is available for all personnel associated with this project.

Other:

A shared central printer/workstation computing facility is available to all projects, that includes one Apple and

one Intel workstation connected to two flatbed scanners, an HP 4000TN laser printer and an HP8550 color

printer. A medical photographer, medical illustrator, and machinist are available as core facilities to all active

projects at Smith-Kettlewell, as well as a superb research support group for computer hardware, electronic,

and computer software assistance on a limited shared basis. Photocopying, word processing and secretarial

service is also available.

Facilities Page 8


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

The major equipment available in my laboratory includes a C-N-C electromagnetic field eye movement

measurement system, multi-channel neural recording amplifiers, stimulus isolators, waveform generators, a

29-inch monitor, and a number of storage and digital oscilloscopes.

Equipment Page 9


RESEARCH & RELATED Senior/Key Person Profile (Expanded)

PROFILE - Project Director/Principal Investigator

Prefix * First Name Middle Name * Last Name Suffix

Dr. Stephen J Heinen PhD

Position/Title: Senior Scientist Department: NONE

Organization Name: The Smith-Kettlewell Eye Research Institute Division: None

* Street1: 2318 Fillmore Street Street2:

* City: San Francisco County: San Francisco * State: CA: California Province:

* Country: USA: UNITED STATES * Zip / Postal Code: 94115

*Phone Number Fax Number * E-Mail

415-345-2101 415-345-8455 [email protected]

Credential, e.g., agency login: --------------

* Project Role: PD/PI Other Project Role Category:

File Name Mime Type*Attach Biographical Sketch 1137_SJHbio.pdf application/pdf

Attach Current & Pending Support

PROFILE - Senior/Key Person

Prefix * First Name Middle Name * Last Name Suffix

------------- ------- PhD

Position/Title: Assistant Professor Department: College of Optometry

Organization Name: -------- ------------- Division:

* Street1: ------ ---------- ------ Street2:

* City: -------- -------- County: --------------- * State: ----- ---------- Province:

* Country: USA: UNITED STATES * Zip / Postal Code: --------

*Phone Number Fax Number * E-Mail

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

Credential, e.g., agency login: -----------------------

* Project Role: Consultant Other Project Role Category:

File Name Mime Type*Attach Biographical Sketch ------------------------- application/pdf

Attach Current & Pending Support


Key Personnel Page 10


Filename

MimeType

ADDITIONAL SENIOR/KEYPERSON PROFILE(S)

Filename

MimeType

Additional BiographicalSketch(es) (Senior/Key Person)

Filename

MimeType

Additional Current andPending Support(s)

1) Please attach Attachment 1




When submitting senior/key persons in excess of 8 individuals, please attach additional senior/key person forms here. Each additional form at-tached here, will provide you with the ability to identify another 8 individuals, up to a maximum of 4 attachments (32 people).

The means to obtain a supplementary form is provided here on this form, by the button below. In order to extract, fill, and attach each additionalform, simply follow these steps:

••

••

•••

Important:

Select the "Select to Extract the R&R Additional Senior/Key Person Form" button, which appears below.

Save the file using a descriptive name, that will help you remember the content of the supplemental form that you are creating. When as-signing a name to the file, please remember to give it the extension ".xfd" (for example, "My_Senior_Key.xfd"). If you do not name your filewith the ".xfd" extension you will be unable to open it later, using your PureEdge viewer software.

Using the "Open Form" tool on your PureEdge viewer, open the new form that you have just saved.

Enter your additional Senior/Key Person information in this supplemental form. It is essentially the same as the Senior/Key person form thatyou see in the main body of your application.

When you have completed entering information in the supplemental form, save it and close it.

Return to this "Additional Senior/Key Person Form Attachments" page.

Attach the saved supplemental form, that you just filled in, to one of the blocks provided on this "attachments" form.

Please attach additional Senior/Key Person forms, using the blocks below. Please remember that the files you attach must be Senior/Key Person Pure Edge forms, which were previously extracted using the process outlined above. Attaching any other type of file mayresult in the inability to submit your application to Grants.gov.

RESEARCH & RELATED Senior/Key Person Profile (Expanded)

Additional Senior/Key Person Form Attachments


Key Personnel Page 11


8 pages redacted--biosketches omitted as requested

OMB Number: 0925-0001Expiration Date: 9/30/2007

Stephen

J

Heinen

PhD

Beatriz

St. John

415-345-8455

[email protected]

415-345-2035

Administrative Assistant

2318 Fillmore Street

San Francisco

San Francisco

94115

PHS 398 Cover Page Supplement

1. Project Director / Principal Investigator (PD/PI)

* Title:

* Street1:

* City:

* Zip / Postal Code:

Street2:

County:

* State:

Province:

* Country:

Prefix: * First Name:

Middle Name:

* Last Name:

Suffix:

2. Human Subjects

* New Investigator? No

Degrees:

Yes

Clinical Trial? No Yes

* Agency-Defined Phase III Clinical Trial? No Yes

* First Name:

Middle Name:

* Last Name:

Suffix:

3. Applicant Organization Contact

Person to be contacted on matters involving this application

Prefix:

* Phone Number: Fax Number:

Email:

● ❍

● ❍

❍ ❍

Dr.

PhD

Ms.

CA: California

USA:

Tracking Number:Clinical Trial & HESC Page 20


PHS 398 Cover Page Supplement

OMB Number: 0925-0001Expiration Date: 9/30/2007

4. Human Embryonic Stem Cells

* Does the proposed project involve human embryonic stem cells? No Yes

If the proposed project involves human embryonic stem cells, list below the registration number of thespecific cell line(s) from the following list: http://stemcells.nih.gov/registry/index.asp . Or, if a specificstem cell line cannot be referenced at this time, please check the box indicating that one from the registry will be used:

Cell Line(s): Specific stem cell line cannot be referenced at this time. One from the registry will be used.

● ❍

❏

Tracking Number:Clinical Trial & HESC Page 21


04/01/2008 03/31/2009

0.00

250,000.00

Salary, wage and benefit base 76.30 194,567.00 148,454.00

DHHS

07/18/2006 148,454.00

398,454.00

04/01/2009 03/31/2010

0.00

250,000.00

Salary, wages and benefits base 76.30 200,403.00 152,907.00

DHHS

07/18/2006 152,907.00

402,907.00

PHS 398 Modular Budget, Periods 1 and 2OMB Number: 0925-0001

1.

Expiration Date: 9/30/2007

Start Date: End Date:Budget Period: 1

* Direct Cost less Consortium F&A

A. Direct Costs

B. Indirect Costs

Consortium F&A

* Total Direct Costs

Indirect Cost TypeIndirect CostRate (%)

Indirect CostBase ($) * Funds Requested ($)

Cognizant Agency (Agency Name, POC Name and Phone Number)

Indirect Cost Rate Agreement Date Total Indirect Costs

Funds Requested ($)C. Total Direct and Indirect Costs (A + B)

2.

3.

4.

1.

Start Date: End Date:

Budget Period: 2


A. Direct Costs

B. Indirect Costs

Consortium F&A







2.

3.

4.

Funds Requested ($)

Funds Requested ($)

250,000.00

250,000.00

Tracking Number:Modular Budget Page 22


04/01/2010 03/31/2011

0.00

250,000.00

Salary, wages and benefits base 76.30 206,416.00 157,495.00

DHHS

07/18/2006 157,495.00

407,495.00

04/01/2011 03/31/2012

0.00

250,000.00

Salary, wages and benefit base 76.30 212,609.00 162,220.00

DHHS

07/18/2006 162,220.00

412,220.00

OMB Number: 0925-0001

1.




A. Direct Costs

B. Indirect Costs

Consortium F&A







2.

3.

4.

1.

Start Date: End Date:

Budget Period: 4

* Direct Cost less Consortium F&AA. Direct Costs

B. Indirect Costs

Consortium F&A







2.

3.

4.

PHS 398 Modular Budget, Periods 3 and 4

Funds Requested ($)

Funds Requested ($)

250,000.00

250,000.00



1,250,000.00

0.00

1,250,000.00

788,162.00

2,038,162.00

04/01/2012 03/31/2013

0.00

250,000.00

Salary, wages, and benefits base 76.30 218,986.00 167,086.00

DHHS

07/18/2006 167,086.00

417,086.00

1115_SJHPersonnelJustification.pdf

1072_ConsortiumJustificationNA.pdf

1073_AddtNarrativeJustifciationNA.pdf

* Section A, Total Direct Cost less Consortium F&A for Entire Project Period $

Section A, Total Consortium F&A for Entire Project Period $

* Section A, Total Direct Costs for Entire Project Period

* Section B, Total Indirect Costs for Entire Project Period

* Section C, Total Direct and Indirect Costs (A+B) for Entire Project Period

Personnel Justification

Consortium Justification

Additional Narrative Justification

1.



A. Direct Costs

B. Indirect Costs

Consortium F&A







2.

3.

4.

Cumulative Budget Information

1. Total Costs, Entire Project Period

2. Budget Justifications

PHS 398 Modular Budget, Period 5 and CumulativeOMB Number: 0925-0001Expiration Date: 9/30/2007

$

$

$

Funds Requested ($)

250,000.00



Attachments

PersonnelJustification_attDataGroup0File Name Mime Type1115_SJHPersonnelJustification.pdf application/pdf

ConsortiumJustification_attDataGroup0File Name Mime Type1072_ConsortiumJustificationNA.pdf application/pdf

AdditionalNarrativeJustification_attDataGroup0File Name Mime Type1073_AddtNarrativeJustifciationNA.pdf application/pdf



Personnel:

Dr. Heinen oversees all of the projects in the laboratory, and is the head of the surgical

team. He designs the experiments, reviews all of the data collected, and does the

majority of the writeup of the experimental results. He also participates in running the

experiments. He writes grant proposals and progress reports, and protocols for the

animal projects, and assists fellows in writing grants in their attempts to obtain external

funding. Dr. Heinen attends and presents his work at at least two conferences a year.

He fulfills external and internal citizenship requirements (reviewing papers, grants,

serving on committees, managing non-research personnel, etc.) Dr. Heinen works - - --

time (-- - calendar months) on this project.

-- ---- - -- -- - --- is a recent graduate from the Bioengineering Program at the University of

San Diego. She does the bulk of the programming and data analysis for the laboratory.

She uses Matlab and LabView to write stimulus presentation, real time data-acquisition

code and data analysis code for both the physiology and human eye movement projects.

She also makes intellectual contributions to the science that we are doing. -- - - - works

--- -- time (-- - calendar months) on this project.

- - - - -- - -- - is a recent graduate from Vassar’s Neuroscience and Behavior program.

Monkey research is exceptionally work intensive. There are many aspects to it that

- - - - -- - participates in, such as preparing for and conducting surgeries, daily preparation

of the animals for experiments, training, and participating in running experimental

sessions. Since we often run experiments on two monkeys daily, these duties in and of

themselves take up most of - - - - -- - - time. However, she still manages to do a good

deal of clerical work, such as ordering supplies, and revising and adding amendments to

protocols. - --- - - - works - - -- time (- calendar months) on this project.

Unpaid Consultant:

--- ---- - - - --- ---- Ph.D. will provide consultation to Dr. Heinen on the theory and

computational modeling of the cortical processes underlying the cognitive control of

pursuit eye movements. The two have worked on these issues during Dr. --- ---- -

fellowship with Dr. Heinen.

Personnel Justification Page 26


Consortium Justification – N/A

Consortium Justification Page 27


Additional Narrative Justification – N/A

Additional Justification Page 28


1180_SJHIntro.pdf

1181_SJHSpecAims.pdf

1182_SJHBackSig.pdf

1214_SJHProgRpt.pdf

1199_SJHResMeth.pdf

1061_SJHenrollmentreport.pdf

1185_SJHProgRptPubs.pdf

1212_SJHVertAnim.pdf

946_SelectAgentResearchNA.pdf

947_MultiplePILeadershipPlanNA.pdf

948_ConsortContracArrangeNA.pdf

1114_SJHLetterSupport.pdf

950_ResourceSharingPlanNA.pdf

PHS 398 Research Plan

1. Application Type:From SF 424 (R&R) Cover Page and PHS398 Checklist. The responses provided on these pages, regarding the type of application be-ing submitted, are repeated for your reference, as you attach the appropriate sections of the research plan.

*Type of Application:

ResubmissionNew Renewal Continuation Revision



2. Specific Aims

3. Background and Significance

4. Preliminary Studies / Progress Report

5. Research Design and Methods

6. Inclusion Enrollment Report

7. Progress Report Publication List

8. Protection of Human Subjects

9. Inclusion of Women and Minorities

10. Targeted/Planned Enrollment Table

11. Inclusion of Children

12. Vertebrate Animals

13. Select Agent Research

14. Multiple PI Leadership

15. Consortium/Contractual Arrangements

16. Letters of Support

17. Resource Sharing Plan(s)

18. Appendix

1. Introduction to Application(for RESUBMISSION or REVISION only)

Attachments 8-11 apply only when you have answered "yes" to the question "are human subjects involved" on the R&R Other Project InformationForm. In this case, attachments 8-11 may be required, and you are encouraged to consult the Application guide instructions and/or the specificFunding Opportunity Announcement to determine which sections must be submitted with this application.

Human Subjects Sections

Other Research Plan Sections

2. Research Plan Attachments:Please attach applicable sections of the research plan, below.

❍ ● ❍ ❍ ❍

Tracking Number:List of Research Plan Attachments Page 29


Attachments

IntroductionToApplication_attDataGroup0File Name Mime Type1180_SJHIntro.pdf application/pdf

SpecificAims_attDataGroup0File Name Mime Type1181_SJHSpecAims.pdf application/pdf

BackgroundSignificance_attDataGroup0File Name Mime Type1182_SJHBackSig.pdf application/pdf

ProgressReport_attDataGroup0File Name Mime Type1214_SJHProgRpt.pdf application/pdf

ResearchDesignMethods_attDataGroup0File Name Mime Type1199_SJHResMeth.pdf application/pdf

InclusionEnrollmentReport_attDataGroup0File Name Mime Type1061_SJHenrollmentreport.pdf application/pdf

ProgressReportPublicationList_attDataGroup0File Name Mime Type1185_SJHProgRptPubs.pdf application/pdf

ProtectionOfHumanSubjects_attDataGroup0File Name Mime Type

InclusionOfWomenAndMinorities_attDataGroup0File Name Mime Type

TargetedPlannedEnrollmentTable_attDataGroup0File Name Mime Type

InclusionOfChildren_attDataGroup0File Name Mime Type

VertebrateAnimals_attDataGroup0File Name Mime Type1212_SJHVertAnim.pdf application/pdf

SelectAgentResearch_attDataGroup0File Name Mime Type946_SelectAgentResearchNA.pdf application/pdf

MultiplePILeadershipPlan_attDataGroup0File Name Mime Type947_MultiplePILeadershipPlanNA.pdf application/pdf

ConsortiumContractualArrangements_attDataGroup0File Name Mime Type948_ConsortContracArrangeNA.pdf application/pdf

LettersOfSupport_attDataGroup0



File Name Mime Type1114_SJHLetterSupport.pdf application/pdf

ResourceSharingPlans_attDataGroup0File Name Mime Type950_ResourceSharingPlanNA.pdf application/pdf

AppendixFile Name Mime Type1134_SJHAppendixList.pdf application/pdf1135_1997HeinenLiu.pdf application/pdf1136_1999WatamaniukHeinen.pdf application/pdf



3 pages redacted--reviewer critiques

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Figure 1. Neuron and animal behavior before and after a decision boundary shift. A) An MT neuron (and the animal), discriminate whether the motion angle is clockwise or counterclockwise of the decision boundary. An SEF neuron (and animal) signals an oculomotor decision boundary similarly. B) When the boundary is shifted out of the MT neuron’s range, it

continues to respond as before. The neurometric function of an SEF neuron instead shifts following a boundary change.�

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C. Progress Report/Preliminary DataWe use a go-nogo oculomotor decision task called “ocular baseball” (Figure 4). In it, the

observer evaluates the motion of a target in the context of a rule, and decides whether or not to pursue it. In the basic version of the task, the rule dictates that the observer pursue the target if its trajectory intersects the “strike zone”, an illuminated square on the monitor, and maintains fixation otherwise. No eye movements are allowed until the target intersects the strike zone, providing a delay period that allows decoupling of the neuronal evaluation from movement-related activity. Additionally, the different target motion directions allow us to decouple the

evaluation from the visual encoding of the target.

Figure 4. The ocular baseball task (standard version). A. Temporal schematic. Monkeys fixate until the target intercepts the strike zone. B. Spatial layout. Target trajectory and strike zone determine whether the target is a “strike” or a “ball.” In a strike trial, the target crosses the zone, and the animal must pursue it. In a ball trial, the target bypasses strike zone, and the animal must maintain fixation. The

monkey may only pursue the target during the movement period. In ball trials, the delay period ends when the target intersects the extended edge of the zone (dashed vertical lines).

The activity of SEF neurons during the delay period of ocular baseball predicts the trajectory of the target in the context of the task rule while animals perform the task (Figure 5). Interestingly, two complementary populations of neurons do this, one that signals with increased activity to pursue (a “strike”), and one that signals with increased activity to maintain fixation (a “ball”).

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Figure 5. SEF neurons and pursuit behavior during ocular baseball. A) A “strike neuron” signals with increased activity that the target should be pursued. B) A “ball neuron” signals with increased activity to maintain fixation. C) Cartesian eye position traces for strike and ball trials D) Horizontal eye velocity recorded during pursuit (top) and fixation (bottom) in the baseball task. Dashed lines represent when the target appeared, and green and red lines represent when it crossed the leading edge of the strike zone in strike and ball trials respectively. Vertical down-pointing arrows indicate separation time, when the neuron significantly determines strike or ball.

Abstract rule representation by the SEF SEF activity during the delay period in ocular baseball might simply reflect visual

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Preliminary Studies/Progress Page 41


motion. This is unlikely, given that receptive fields of motion neurons usually are tuned to a single direction (e.g. Albright, 1984), and the “receptive fields” of baseball-related neurons are not tuned to any specific direction, but reflect either strikes or balls (Figure 6). In fact, most SEF

strike and ball neurons are not tuned to a single motion direction (Kim et al., 2005). Figure 6. Tuning functions of SEF neurons active during ocular baseball. A) Mean activity during the delay period of a cell that preferred strike trajectories. Note overall higher activity for strikes, regardless of target approach angle. Strike angles are shaded in green and ball angles in red. B) A neuron that preferred ball angles.

However, these could still be sensory neurons with complex receptive fields. If so, their activity should remain constant for a given motion trajectory regardless of whether the trajectory was a strike or a ball. To test this, we recorded SEF neurons using a two-plate, two-angle (2P2T) version of our task in which plate-size and the strike/ball trajectories were co-varied (Figure 7). Note that the strike neuron shown in Figure 7b was more active for the large than the small plate in Interval 1, suggesting that it was responding to plate size. This makes sense, because the probability of a strike with the large plate is 1.0. In Interval 2, the activity discriminated ball and strike trajectories for the small plate, and was similar for both 10 and 20 deg trajectories for the large plate. Figures 7c-e summarizes these results. Note however, that most neurons were more active for the 10 than 20 deg trajectory despite that both were strikes (Figure 7C). Again, the neurons appeared to code relative probability since the 10 deg trajectory was always a strike.

Figure 7. Two-plate two trajectory experiment. A) Stimulus configuration. B) An SEF neuron signals plate size early, and later signals strike or ball. Activity was analyzed in Intervals 1 or 2. Traces compared for summary plots are correspondingly labeled c-e. C) Interval 1 difference in activity between the two plates. D) Interval 2 difference in activity for the small plate. E) Interval 2 activity for the large plate.

Previous work has shown that neurons in lateral intraparietal cortex (LIP) encode the

probability that a stimulus set instructs a rewarded response (Yang & Shadlen, 2001). Our 2P2T result suggests that SEF activity reflects the probability of different trajectory/plate combinations, and therefore may reflect a cognitive expectation about the current stimulus set.

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Alternatively, a low-level memory of whether the target was a strike or a ball on the previous trial could explain this result (Kowler, 1990, Fecteau & Munoz, 2003; Heinen et al., 2005). Our preliminary data suggest that these cells (and the animal) are susceptible to recent trial history (Figure 8). Here, activity accompanying a 20 deg angle and a large plate was higher (and pursuit latency shorter) when preceded by 10 deg strikes than by 10 deg balls. Experiments will vary trial sequence to test cognitive strategy and low-level memory hypotheses.

Figure 8. Trial sequence affects pursuit latency (A) and an SEF neuron (B).

The activity of SEF neurons appears to specify the abstract rule of ocular baseball. To determine if the neuron adjusted to a new decision boundary (see

Figure 1), we computed psychometric functions for the animal’s behavior in the task, and neurometric functions for the cells (Figure 9) (see Methods). This data were taken from experiments where additional 20 deg (strike) and 30 deg (ball) trials were used. To obtain the psychometric function, the response of the animal was plotted as the percentage of ball responses (fixations). For 40 deg trajectories, the animal fixates on almost 100% of the trials, and on 10 deg trials it (correctly) almost never fixates, and pursues instead. For the more difficult trials (20 and 30 deg), performance lies between. Neurometric functions were computed by obtaining the probability that the neuronal activity signaled a strike or ball from Z-scores (see Methods).

Psycho- and neurometric functions were also computed with the small plate data from the 2P2T experiment. While the recording duration for a neuron limited the number of different trajectories we used, scaled-down functions could still be computed. Figure 9A compares the 2P2T psychometric and neurometric functions and those obtained with standard baseball for the same neuron. Both functions shifted in the 2P2T experiment, indicating that both the monkey and cell adjusted their responses to the new decision boundary (15 deg). This data is summarized as distributions of the angles where each function crossed the 50% level. This is in

contrast to what occurs for MT neurons (Britten et al., 1996) (see Figure 1).

Figure 9. Comparing neuronal and pursuit performance in standard baseball and 2P2T baseball. A) Psychometric and neurometric functions. B) Population data.

A strong test of whether a neuron encodes

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a sensory stimulus or a rule is to determine if it still codes the rule when it changes and the stimulus remains identical. In inverted baseball, the rule is inverted on the same stimulus so that the animal must pursue in trials that were previously balls and vice versa. In preliminary data, the animal performed well on the task, and CP and RP for an SEF neuron, while initially

lower during the inversion, appeared to recover in subsequent blocks of trials. (Figure 10).

Figure 10. SEF CP and RP with rule inversion. Note that with the inverted rule, CP and RP are initially low, but rise above chance, suggesting that the neuron eventually encodes the rule change.

SEF and FEF involvement in an oculomotor decision SEF neurons showed rule-related activity during ocular baseball. To assess their

involvement in making the pursuit go/nogo decision, we computed choice probability (CP) for individual neurons (Figure 11), as has been done in the past (Britten et al., 1996, Purushothaman and Bradley, 2005). CP is based on signal detection theory (Green and Swets, 1966), and characterizes the difference between two distributions of neuronal activity observed for two different responses. To compute CP for a neuron, we constructed a distribution of firing rate for the animal’s strike decisions, and a second for ball decisions. From these distributions, an ROC curve was obtained, and the area under it was computed to obtain the CP (see Methods). The mean significant CP of SEF neurons was .66, suggesting significant involvement in the decision. Next, we computed a “rule probability” (RP) index by constructing histograms of neuronal activity with respect to whether the trajectory was a strike or a ball. Interestingly, the RP was similar to the CP, but slightly higher (.68).

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The higher RP suggested that SEF neurons better predicted the rule than the behavior. To test this, we analyzed neuronal activity when the animal made errors, and found that it continued to signal the rule, and not the decision (Figure 12).



Figure 12. SEF activity during error trials. A) An example SEF strike neuron. The activity when the animal errs and withholds a movement is similar to that in strike-success trials. Green and red vertical lines indicate plate crossing for strike and ball trials respectively. B.) Error activity (normalized by activity for strike success

– ball success) for SEF neurons. Bars indicate differences in neural activity (left-pointing: strike success > strike error; right-pointing: strike error > ball success).

If the SEF does not make the decision, what structure does? The FEF appears closer to the motor output than the SEF (Schall, 1991A; Tehovnik & Sommer, 1997), and therefore might be more linked to the oculomotor decision. We first located the frontal pursuit area (FPA) of the FEF just posterior to the genu of the arcuate sulcus (Gottlieb et al., 1993; Tanaka & Lisberger, 2002; Stanton et al., 2005) by evoking smooth eye movements with low-current microstimulation (< 50 μA). Fixation neurons are adjacent to this area, so our chamber location allowed us to record them as well (Sommer & Wurtz, 2000).

Not surprisingly, FEF pursuit and fixation neurons are active during ocular baseball (Figure 13). Our preliminary data suggest that as is the case for saccades (Schall, 1991A), pursuit neurons are more movement-related here than in the SEF. The pursuit cell in Figure 13A was more directionally tuned during ocular baseball (Figure 13B) than the SEF strike neuron in Figure 6, as quantified by a vector-average computed direction index (DI)(Kim et al., 2005) (FEF neuron, DI= 1.1 vs. SEF neuron, DI= 0.3), consistent with the population (Population: FEF DI= 1.3; SEF DI =0.8).

To determine the extent that these neurons were involved in the decision process, we computed their CP (Figure 13). The mean CP of FEF neurons (0.72) was higher than of SEF neurons (0.66). Also when compared to SEF neurons, the CP and RP rankings were equal (CP = 0.72; RP= 0.72). However when task difficulty was increased by adding target trajectories close to the plate corners (22 and 25 deg), the CP and RP reversed in the FEF (CP = 0.70; RP=0.63). Furthermore, the error activity of FEF neurons predicted the decision of the animal (Figure 13D). While these data suggest that the activity of neurons in the FEF, but not the SEF reflect the decision, this does not prove that the FEF itself makes the decision and the SEF is not involved. Experiments will use ambiguous strike/ball stimuli to determine CP independent of rule contamination. A structure that solely reflects rule interpretation should have chance CP whereas a structure that reflects the decisions should have a CP that is greater than chance.

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Further evidence of involvement of the SEF and FEF in decision making will be obtained from evaluating CP, RP and error activity of neurons during rule inversion. A timing signal for rule-guided pursuit initiation

The prominent RACE model (Hanes et al., 1998) states that two independent go and stop signals determine movement initiation (see Figure 3A). In the model, movement is initiated if the go signal reaches threshold before the stop signal, and withheld if the opposite occurs. The activity of SEF strike and ball cells at first glance resembles go and stop signals respectively (Figure 14). However, when considering only strike trials, the activity of ball cells decreases and reaches a minimum preceding movement initiation at the same time strike activity peaks. This result is inconsistent with the RACE model, and suggests that strike and ball activity is dependent, and possibly coupled by mutual inhibition, similar to how units that govern anticipatory pursuit have been modeled (Badler & Heinen, 2006).

Figure 14 Individual SEF strike and ball cells (A) and population during strike trials only (B).

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plate crossing, or it could be related to target appearance. We used a two-speed target paradigm that provided two different plate intersection times to tease apart these factors (Figure 26). Here, the peak activity of SEF strike neurons occurs suggest they are timing the plate intersection, since it aligns better with this event than target onset (Figure 15A). However, on trials where pursuit is initiated too early, the peak (and trough) activity reflects the animal’s timing decision suggesting both populations work together to time movement onset (Figure 15B).

Figure 15. SEF activity during two-speed target motion. Here, all angles are 30 deg strikes, and the target can move at either 13 or

17 deg/sec. The animal must acquire the target within 200 msec of plate intersection.

The neuronal results suggest the SEF does not make the “if decision, but is involved in the “when” decision. It is possible that the if decision is made by pooling a subset of neurons (Purushothaman and Bradley, 2005) from the SEF, not all of which convey the correct response. Alternatively, the SEF merely reflects strike and ball information for some other purpose, such as timing the movement. Our preliminary muscimol inactivation data suggest that the SEF is involved in both if and when decisions. Inactivation lead to more errors in ocular baseball. Pre-inactivation error rate 21.1% , and after inactivation, the error rate increased to 28.0%. Furthermore, the latency in strike trials was decreased (p=0.0016), although simple pursuit was not affected (Figure 11). A smaller latency change was observed for saccades (pre: 197.4 msec, SE=9.5, inact: 182.0 msec, SE=10.7).

Figure 16 Muscimol inactivation. A) Latency decreases in ocular baseball. B) Simple pursuit latency is unaffected. Note longer simple pursuit latencies than normal reflects a general delay of pursuit initiation typical for monkeys trained on ocular baseball. Asterisk indicates significant difference.

To assess whether the SEF generally delays pursuit initiation, or if it is can assess target motion to time it, we also tested the animal in 2-speed ocular

baseball after inactivation. The inactivation shortened the latency on slow trials, and increased early errors. This resulted in more similar pursuit latency distributions for the fast and slow targets, suggesting that the SEF timing signal is specific for target speed.

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Figure 17 Inactivation results from 2-speed ocular baseball. A) Eye velocity (all directions). B) Latency summary. Note that eye movements begin earlier for the slow target after inactivation.

The SEF has strong reciprocal connections to the FEF (Barbas & Pandya, 1991) and these areas might work together to generate pursuit and fixation during ocular baseball. Our preliminary data suggest that the SEF conveys rule and timing information to the FEF. SEF activity peaks earlier than FEF activity (SEF: 131 msec before movement; FEF: 83 msec after), and CP in the delay period is higher for the SEF than the FEF (see Figure 2). Furthermore, FEF cells responded differently during ocular baseball than during passive pursuit or fixation, in that directional tuning of FEF pursuit neurons was reduced, and fixation activity was higher (Figure 18). This latter result might reflect the task constraint that the animal postpone pursuit during the delay period. The delay period activity was not visual when we tested fixation cells with moving visual stimuli outside of ocular baseball (Figure 18B) (2/3 fixation neurons showed this, p < .05). This result is consistent with our fMRI data showing greater BOLD activation in human FEF in “decided nogo” (ball trials) than during passive fixation with identical motion and behavior (Figure 18C).

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Other preliminary data more directly link the SEF and FEF. When we inactivated the SEF, the delay period activity in the FEF fixation neurons decreased in both strike and ball trials (Figure 19). FEF fixation cells normally show a large burst of activity during the delay period when the target starts to move. Following inactivation, the fixation cell shown here did not



exhibit this feature. This was true for all three ball cells recorded in this condition (Figure 19C).

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Rule-based processing beyond the cortical eye fields Undoubtedly, other structures in the brain are active in pursuit go/nogo decision

processes besides the SEF and FEF. We investigated this by conducting an fMRI study where activation during ocular baseball was compared with that during simple pursuit and fixation. We found that the SEF, the FEF and another frontal area, the ventrolateral prefrontal cortex (VLPFC) were differentially active during the baseball task (Figure 20AB). That the VLPFC was active is not surprising, since this area, while not previously implicated in decision making, plays a role in rule-encoding and retrieval in humans (Bunge, 2004).

The VLPFC also participates in cognitive set-switching in humans and monkeys (Monchi et al. 2001; Nakahara et al., 2002). Our preliminary data suggest that the activity of neurons in the VLPFC during errors in ocular baseball signals the animal’s decision, as do FEF neurons (see Figure 13D). However, VLPFC neurons are even more active during error trials than success trials (Figure 20D). In set-switching, errors must be monitored to detect when the task has changed, and since it signaled errors in our preliminary data, the VLPFC might perform this function. Experiments will be done in which activity is recorded here during standard ocular baseball, and after a covert rule switch to inverted baseball to assess their role in set-switching. CP and RP will also be characterized during standard ocular baseball to compare VLPFC decision making involvement with that of other structures.

Figure 20. Activation of the VLPFC during ocular baseball. A) fMRI results showing VLPFC activity. B) fMRI summary showing higher activity for ocular baseball than control pursuit and fixation for six observers. C) Activity of a monkey VLPFC neuron in the task and during error trials. Note higher activity when the animal pursued in error trials than correct trials. C) Higher error activity for five neurons recorded from VLPFC to date.



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Inclusion Enrollment Report

Study Title: Cortical Planning and Control of Smooth Pursuit

Total Enrollment: 6 Protocol Number:

Grant Number: EY011720

PART A. TOTAL ENROLLMENT REPORT: Number of Subjects Enrolled to Date (Cumulative)

by Ethnicity and Race

Sex/Gender

Ethnic Category Females Males

Unknown or

Not Reported Total

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Not Hispanic or Latino 3 3 6

Unknown (individuals not reporting ethnicity)

Ethnic Category: Total of All Subjects* 3 3 6 *

Racial Categories

American Indian/Alaska Native

Asian 1 1 2

Native Hawaiian or Other Pacific Islander

Black or African American

White 2 2 4

More Than One Race

Unknown or Not Reported

Racial Categories: Total of All Subjects* 3 3 6 *

PART B. HISPANIC ENROLLMENT REPORT: Number of Hispanics or Latinos Enrolled to Date (Cumulative)

Racial Categories Females Males

Unknown or

Not Reported Total

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Asian

Native Hawaiian or Other Pacific Islander

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White

More Than One Race

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Racial Categories: Total of Hispanics or

Latinos**

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* These totals must agree.** These totals must agree.

Inclusion Enrollment Report Page 60


Inclusion Enrollment Report Page 61


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F. VERTEBRATE ANIMALS Monkeys (Macaca mulatta) will be used for these experiments. A total of about 6 male juvenile monkeys will be used over the five-year period of the project. Because the project goals are to provide data and test hypotheses about the neuronal organization serving ocular motility that can eventually be used to develop better diagnostic tests in humans and to better understand human visual and oculomotor disorders, it is essential to use animals that possess a repertoire of eye movements as similar to that of humans as possible. This limits the choice of animal for these studies to the monkey. In this project major emphasis is placed on studies involving the pursuit and saccadic systems. As far as we have been able to determine from our past work and from that of other laboratories, these systems in the monkey are very similar to that of humans. We will be able to utilize all the information gathered in our past work in this species in order to locate recording/stimulating sites in cortex. We have restricted the number of animals used to be the minimum that is consistent with obtaining reliable experimental results. Many tests are to be done in these studies, and all of them cannot be performed in the same animals since repeated cortical recording over an extended period of time results in complications such as dura build-up, implant deterioration and even cortical damage. Therefore, two animals will be used for SEF and FEF recording and inactivation pilot data, two will be used for inactivation of SEF and FEF, and two for VLPFC recording. The monkeys for this project will be housed within the animal facilit--- -- -- - - --- - - -- - ll. This facility has a consultant veterinarian, -- - ------ - -- - -- --- -- whose services are readily available when needed, and he is also responsible for frequent inspections of the facility. Smith-Kettlewell maintains an animal research committee which reviews and monitors all animal research projects to assure compliance with the NIH "Guide for the Care and Use of Laboratory Animals" and to assure that the facility meets USDA certification requirements. Monkeys are prepared for these chronic experiments by injection of atropine sulfate (.08 mg/kg, i.m..) followed by an injection of the anesthetic ketamine hydrochloride (12 mg/ kg, i.m.). Monkeys will be endotracheally intubated and anesthetized with gas (Isofluorane) to effect. Depth of anesthesia and condition of the animal will be monitored throughout the surgery by a dedicated anesthesia technician. An intravenous catheter will be inserted in a leg vein and A continuous slow-rate IV drip of lactated Ringer's solution will be given, at a baseline level of 10 ml/kg/hr, adjusted to compensate for additional fluid loss, if necessary. A prophylactic antibiotic dose will be given approximately 30 min prior to the first skin incision, and at least once intraoperatively. All surgeries are carried out under sterile conditions in the - - - - -- - small animal surgery facility. A cardiac monitor is attached to the animal and heart rate is displayed throughout the surgery. Rectal temperature is maintained at 37oC using a heating pad. At the end of surgery the animal is placed on warm bedding in the recovery room. When it can sit up and support itself, it is returned to its home cage in the animal facility. . During the period of post-surgical recovery, the animal is monitored closely and analgesics are used according to the recommendations of the consulting veterinarian (typically buprenex, 0.01-0.02 mg/kg, I.M. for 2-4 days, or longer if signs of pain or distress are observed). Systemic antibiotics are administered routinely during the week following surgery and thereafter when prescribed by the consultant veterinarian.

Vertebrate Animals Page 64


The animal is allowed to fully recover from the effects of this surgery before the training and recording sessions begin. For these daily sessions, the animal comes voluntarily into a comfortable primate chair from its home cage. Its head is restrained painlessly through the use of the implanted device on its skull for the duration of the recording session (about 3-4 hours). It is then returned to its home cage. At the conclusion of the experiments the animal will be anesthetized with ketamine hydrochloride (12 mg/kg, i.m.) and then deeply anesthetized with a lethal overdose of Nembutal (~100 mg/kg, i.v.). Total lack of a corneal reflex is taken as an indication that an adequate level of anesthesia has been obtained to proceed with cardiac perfusion. The animal is perfused through the left ventricle with a formalin fixative solution. This method of euthanasia is consistent with recommendations of the Panel on Euthanasia of the American Veterinary Medical Association.

Vertebrate Animals Page 65


Select Agent Research – N/A

Select Agent Research Page 66


Multiple PI Leadership Plan – N/A

Multiple PI Leadership Plan Page 67


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Consortium/Contractual Arrangements – N/A

Consortium/Contractual Page 76


June 26, 2007

Dr. Steve Heinen

The Smith-Kettlewell Eye Research Institute

2318 Fillmore Street

San Francisco, CA 94115

Dear Steve,

I am very interested in your project, “Cortical Planning and Control of Smooth Pursuit,”

which you are submitting to NEI as an R01 grant proposal. I would be happy to provide

consultation on issues such as the theory and computational modeling of cortical

processes underlying the cognitive intervention of pursuit eye movements.

Your proposal is very relevant to my work in the modeling of eye movements based on

cognitive suppression, and the parametric control of eye movement initiation times

depending on higher-cortical modulation. Should your proposal be funded, I would be

very happy to travel to San Francisco and consult on the project.

Sincerely,

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

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Letters of Support Page 77


Resource Sharing Plan (s) – N/A

Sharing-Data and Model Organism Page 78


❍

❏

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EY011720

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❍

❍ ●

❍

❍ ❍

1. Application Type:

2. Change of Investigator / Change of Institution Questions

* Type of Application:

Middle Name:

* First Name:

* Previously Reported:

* Name of former institution:

* Last Name:

From SF 424 (R&R) Cover Page. The responses provided on the R&R cover page are repeated here for your reference, as you answerthe questions that are specific to the PHS398.

Federal Identifier:

Name of former principal investigator / program director:

* Inventions and Patents:

If the answer is "Yes" then please answer the following:

3. Inventions and Patents (For renewal applications only)

Change of principal investigator / program director

Change of Grantee Institution

New

Prefix:

Suffix:

Resubmission

Yes

Yes

Renewal

No

No

PHS 398 Checklist

Continuation Revision



Tracking Number:Checklist Page 79


❍ ●

4. * Program Income

5. Assurances/Certifications (see instructions)

*Budget Period

If you checked "yes" above (indicating that program income is anticipated), then use the format below to reflect the amount andsource(s). Otherwise, leave this section blank.

Is program income anticipated during the periods for which the grant support is requested?

In agreeing to the assurances/certification section 18 on the SF424 (R&R) form, the authorized organizational representative agrees tocomply with the policies, assurances and/or certifications listed in the agency's application guide, when applicable. Descriptions ofindividual assurances/certifications are provided at: http://grants.nih.gov/grants/funding/424

If unable to certify compliance

Explanation:

Yes

*Anticipated Amount ($)

, where applicable, provide an explanation and attach below.

No

*Source(s)


OMB Number. 0925-0001



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