u of wm tom yin grant documents part 3

8/7/2019 U of WM Tom Yin Grant Documents Part 3

1/67

Notice of AwardRESEARCH Issue Date: 03/16/2009Department of Health and Human ServicesNational Institutes of HealthNATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS

Grant Number: 5R01DC003693-06 REVISEDPrlnclpallnvestlgator(s):LUIS C POPULlN, PHDProject Title: Multisensory Processing in the Behaving Preparation

Award e-malled to : [email protected] Period: 12/01/2008 - 11/30/2009Project Period: 09/01/1999 - 11/30/2010Dear Business Official:The National Institutes of Health hereby revises this award to reflect an increase in the amount of$31,237 (see "Award Calculation" in Section I and "Terms and Conditions" In Secllon III) toUNIVERSITY OF WISCONSIN MADISON in support of the above referenced project. This awardis pursuant to the authority of 42 USC 241 42 CFR 52 and is subject to the requirements of thisstatute and regulation and of other referenced, incorporated or attached terms and conditions.Acceptance of this award including the "Terms and Condillons" is acknowledged by the granteewhen funds are drawn down or otherwise obtained from the grant payment system.Each publication, press release or other document that cites results from NIH grant-supportedresearch must Include an acknowledgment of NIH grant support and disclaimer such as "Theproject'described was supported by Award Number R01DC003693 from the Nallonallnstitute OnDeafness And Other Communication Disorders. The content is solely the responsibilityof theauthors and does not necessarily represent the official views of the National Institute On DeafnessAnd Other Communication Disorders or the Nationallnstltutes of Health."Award recipients are required to comply with the NIH Public Access Policy. This inciudessubmission to PubMed Central (PMC), upon acceptance for publication, an electronic version of afinal peer-reviewed, manuscript resulting from research supported in whole or in part, with directcosts from National Institutes of Health. The author's final peer-reviewed manuscript is defined as'the final version accepted fo r journal publication, and includes all modifications from the publishingpeer review process. For additional information, please visit http://publicaccess.nih.gov/.Award recipients musfpromote objectivity in research by establishing standards to ensure that thedesign, conduct and reporting of research funded under NIH-funded awards are not biased by aconflicting financial interest of an Investigator. Investigator is defined as the Principal Investigatorand any other person who is responsible for the design, conduct, or reporting of NIH-fundedresearch or proposed research, including the Investigator's spouse and dependent children.Awardees must have a written administrative process to identify and manage financial conmct ofinterest and must inform Investigators of the conflict of nterest policy and of the Investigators'responsibilities. Prior to expenditure of these awarded funds, the Awardee must report to the NIHAwarding Component the existence of a conflicting interest and within 60 days of any newconflicting interests identified after the initial report. Awardees must comply with these and all otheraspects of 42 CFR Part 50, Subpart F. These requirements also apply to subgrantees, contractors,or collaborators engaged by the Awardee under this award. The NIH websitehttp://grants.nih.gov/grantsfpolicvlcoifindex,htm provides additional information.

, Page-I+ - ~ * ~ 1 ~ ~ 4 2011-04-22 000167


2/67

If you have any questions about this award, please contact the individual(s) referenced in SectionIV.Sincerely yours,

Sherry DabneyGrants Management OfficerNATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERSAdditional information follows

Page-2

2011-04-22 000168


3/67

SECTION 1- AWARD DATA - 5R01DC00369306 REVISEDAward Calculation (U.S. Dollars )Federal Direct CostsFederal F&A CostsApproved BudgetFederal ShareTOTAL FEDERAL AWARD AMOUNTAMOUNT OF THIS ACTION (FEDERAL SHARE)

SUMMARY TOTALS FOR ALL YEARSYR THIS AWARD CUMULATIVE TOTALS

$212,500$99,875$312,375$312,375.. $312,375

$31,237

6 $312,375 $312,3757 $312,375 $312,375..Recommended future year total cosl support, subject to the availability of funds and satisfactoryprogress of the project

fEIN:Fiscal Information:gEDANu:er :

ocumen umber:Fiscal Year:

ICC

: ~ 7 3 ROCUO 3B

2009CAN 2009 2010472510 312,375 312,375

Recommended future year total cost support, subject to the availability of funds and satisfactoryprogress of the projectNIH Administrative Data:PCC: HR61 1OC: 414E 1Processed: SDENNISON 03/13/2009SECTION 11- PAYMENT/HOTLINE INFORMATION - 5R01DC00369306 REVISEDFor payment and HHS Office of Inspector General Hotline information, see the NIH Home Page athtip:lIgranls.nih.gov/grants/poHcy/awardconditions.htmSECTION /11- TERMS AND CONDITIONS - 5R01DC00369306 REVISEDThis award is based on the application submitted to, and as approved by, NiH on the abovetltledproject and is subject 10 the terms and conditions incorporated either directly or by reference in thefollowing:

a. The grant program legislation and program regulation cited in this Notice of Award.b. Conditions on activities and expenditure of funds in other statutory requirements, such asthose included in appropriations acts.c. 45 CFR Part 74 or 45 CFR Part 92 as applicable.d. The NIH Grants Policy Statement, including addenda in effect as of the beginning date ofthe budget period.e. This award notice, INCLUDING THE TERMS AND CONDITIONS CITED BELOW.

(See NIH Home Page at 'http://grants.nih.gov/grants/policy/awardconditions.htm' for certainreferences cited above.)This institution is a signatory to the Federal Demonstration Partnership (FOP) Phase V Agreementwhich requires active institutional participation in new or ongoing FOP demonstrations and pilots.An unobligated balance may be calTled over into the next budget period without GrantsManagement Officer prior approval.This grant is subject to Streamlined Noncompeting Award Procedures (SNAP).

Page3

2011-04-22 000169


4/67

In accordance with P.L. 110-161, compliance with the NIH Public Access Policy is now mandatory.For more Information, see NOT-OD-08-033 and the Public Access website:http://publicaccess,nilhgov/.

Treatment of Program Income:Additional CostsSECTION IV - DC Special Terms and Conditions - 5R01 DC00369306 REVISEDThis revised award Increases the total costs authorized consistent with the NIH and NIDCD fiscalpolicies for FY2009.STAFF CONTACTSThe Grants Management Specialist is responsible for the negotiation, award and administration ofthis project and for interpretat ion of Grants Administrat ion pOlicies and provisions. The ProgramOfficial is responsible for the scientific, programmatic and technical aspects of this project. Theseindividuals work together in overall project administration. Prior approval requests (signed by anAuthorized Organizational Representative) should be submit led in writing to the GrantsManagement Specialist. Requests may be made via e-mail.Grants Management Specialis t: Hoai DoanEmail: [email protected]: (301) 435-1404 Fax: (301) 402-1758Program Official: Christopher PlattEmail: [email protected]: (301)496-1804 Fax: (301)402-6251

SPREADSHEET SUMMARYGRANT NUMBER: 5R01DC00369306 REVISEDINSTITUTION: UNIVERSITY OF WISCONSIN MADISON

Facilities and Administrative Year 6 Year 7Costs

&A Cost Rate 1 147% 7%F&A Cost Base 1 $212,500 212,500&A Costs 1 $99,875 99,875

Page-4

2011-04-22 000170


5/67

THE UNIVERSITYWISCO---N-SI-N

M AD IS O N 03/25/2009To Whom I tMay Concern:

. the following grant application submitted to NIHis named on an animal care and use protocol approved on 02111/2009 (3-year approval).

Most Recent Committee Re-review: 02111/2009.

Name of Principal Investigator: Populln, Luis C.

Address: Medical Sciences Ctr., 1300 University Ave., 8385

Title of Grant Application: Multisensory processing In the behavingpreparationGrant #: pendingName of Animal Care and Use Committee: SMPH

Name of Chairperson: Dr. Amy Moser

The University of Wisconsin-Madison has an animal welfare assurance on file with the Office forProtection from Research Risks. The assurance number is A3368-01.

Significant modifications required prior to committee approval of a protocol which was alreadysubmitted to the funding agency are as follows: NONE

Chairperson's Signature:__FOAM IIM01498011-08

Research Animal Resources Center396 Enzyme Institute University of Wisconsin-Madison 1710 University Avenue

6081262-1238 Fax: 608/265-2698 Email: [email protected]

Madison, Wisconsin 53726-4087http://www.rarc.wisc.edu

2011-04-22 000171


6/67

PI: POPULIN, LUIS C Title: Multisensory Processing in the Behaving PreparationReceived: 03/05/2007 FOA: PA07-070 Council: 10/2007Competition 10: FOA Title: RESEARCH PROJECT GRANT (PARENT R01)2 R01 DCOO3693-0SA1 Dual: NS Accession Number: 2978361IPF: 578503 Organization: UNIVERSITY OF WISCONSIN MADISONFormer Number: Department: ANATOMY-GENIRG/SRG: SMI AIDS:N Expedited: NSubtotal Direct Costs Animals: Y New Investigator: N(excludes consortium F&A) Humans: N Early Stage Investigator: NYear 5: 250,000 Clinical Trial: NYear 6: 250,000 Current HS Code: 10Year 7: 250,000 HESC: NYear 8: 250,000Year 9: 250,000

SeniorlKey Personnel: Organization: Role Category:LUIS POPULIN The Board of Regents of the University PO/PI

of Wisconsin System

2011-04-22 000172


7/67

APPLICATION FO R FEDERAL ASSISTANCE 2. DATE SUBMITTED Applicant I d e n t ~ f i e r SF 424 (R&R) 02/14/2007 358213. DATE RECEIVED BY STATE State Application Identifier1 . ' TYPE OF SUBMISSIONo Pre-application Application 4. Federal Identifi ero Changed/Corrected Application DC0036935. APPLICANT INFORMATION .. Organizational DUNS:161202122.. Legal Name: The Board of Regents of the University ofWisconsin SystemDepartment: Division:.. Street1: 21 N. Park Street Street2: Suite 6401.. City: Madison County: Dane * State: WI: WisconsinProvince: Counlry: USA: UNITED STATES ZIP I Postal Code:53715-1218Person to be contacted on m atters involving this applicationPrefix: .. First Name: Middle Name: .. Last Name: Suffix:Ms. JENNIFER RODIS Phone Number: 608262-4990 Fax Number: 608-262-5111 Email: [email protected],edu6.' EMPLOYER IDENTIFICATION NUMBER (EIN) or (TIN): 7 TYPE OF APPLICANTH: PublicJState Controlled Institution of Higher EdUcation8.' TYPE OF APPLICATION: o New Other (Specify): Small Business Organization Type Resubmission o Renewal o Continuation QRevision o Women Owned o Socially and Economically DisadvantagedIf Revision, mark appropriate box(es). 9. NAME OF FEDERAL AGENCY:o A. Increase Award o B. Decrease Award o C. Increase Duration National Institutes of Healtho D. Decrease DurationQ E. Other (specify): 10. CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER:TITLE: Research Project. Grant (Parent R01)"" Is this application being submitted to other agencies? U Yes NoWhat other Agencies? . .11.' DESCRIPTIVE TITLE OF APPLICANT'S PROJECT:Multisensory Processing In the Behaving Preparation12 AREAS' AFFECTED BY PROJECT (cities, counties, states, etc.)NfA13. PROPOSED PROJECT: 14. CONGRESSIONAL DISTRICTS OF:"" Start Date "" Ending Date a. "" Applicant b. "" Project09/01/2007 08/31/2012 02 00215. PROJECT DIRECTOR/PRINCIPAL INVESTIGATOR CONTACT INFORMATIONPrefix: "" First Name: Middle Name: "" Last Name: Sullix:Dr. LUIS C POPULINPosilionml le: ASSISTANT PROFESSOR "" Organization Name: The Board of Regents of the University of Wisconsin SystemDepartmenl: ANATOMY-GEN Division: S ~ e e t 1 : 1300 UNIVERSITY AVE S ~ e e l 2 : 8385 MEDICAL SCIENCES CTR City: MADISON County: * State: WI: WisconsinProvince: Country: USA: UNITED STATES ZIP I Postal Code:53706-1509 Phone Number: (608) 265-6451 Fax Number: (608) 262-7306 Email: [email protected]

Tracking Number: Funding Opportunity Number: Reeefved Dale: Time Zone: GMTS OMe Number: 4040.0001Expiration Dale: 04l30{2008

2011-04-22 000173


8/67

SF 424 (R&R) APPLICATION FOR FEDERAL ASSISTANCE Page 216. ESTIMATED PROJECT FUNDING 17. 'I S APPLICATION SUBJECT TO REVIEW BY STATE EXECUTIVE ORDER 12372 PROCESS?a. YES 0 THIS PREAPPLICATION/APPLICATION WAS MADE AVAILABLE TO THEa. ,. Total Estimated Project Funding $1,837,500.00 STATE EXECUTIVE ORDER 12372 PROCESS FOR REVIEW ON:b. Total Federal & NonFederal Funds $1,837,500.00 DATE:C. * Estimaled Program Income $0.00 b. NO

PROGRAM IS NOT COVERED BY E.O. 12372; OR

0 PROGRAM HAS NOT BEEN SELECTED BY STATE FOR REVIEW18. 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 01 certifications andasSUflIn


9/67

Principal Investigator/Program Director (Last, first, middle): POPULlN, LUIS, C

424 R&R and PHS39B SpecificTable Of Contents

SF 424 R&R Face Page ................................................................Table of Contents u ........................................................................................................................Research & Related ProjecUPerformance Site Location(s).. ... . . . ............... .Research & Related Other Project Inform atlon- . .......................................

Project Summary/Abstract (Description)- ..... ~ .......................Public Health Relevance Statement (Narrative attachment) . u ............................ .Facilities & Other Resources. . . ~ .. . ..................Eq uip ment . . . ........

Research & Related Senior/Key Person . .................... ................ .......Biographical Sketches for each listed Senior/Key Person _ . . . .

PHS 398 Specific Cover Page Supplementoao a . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .PHS 398 Specific Modular Budg et . ....................................................

Personnel Justific ation .................PHS 398 Specific Research Pian .............................._ ....................

Introduction to Revised/Supplemental Application ... . .........Specific Aims .......Significance and Related R & D ~ .. . --- ..Experimental/Research Design and Methods . _ ao Vertebrate Animals . ..... ........Bibliography & References Citedto ........................................

PHS 398 Checklist ............

Table of Contents Page 3

Page Numbers

345678

10121416202124272834454752

2011-04-22 000175


10/67

Principallnvestigator/Program Director (Last, first, middle): POPULlN, LUIS, C

RESEARCH & RELATED Project/Performance Site Location(s)

ProjecVPerformance Site Primary LocationOrganization Name: The Board of Regents of the University of Wisconsin System*Street1: 1300 University Ave Street2:* City: MadisonProvince:

Additional Location(s)

Trm:klng Number:

County: Dane Counl!y: USA: UNITEDSTATES

* State: WI: Wisconsin* Zip I Postal Code:

File Name

Performance Sites

Mime Type

Page 4

,

OMB Number: 4040..()001EXpiration Dale: 0413012008

2011-04-22 000176


11/67

Principallnvesti gator/Program Director (Last, first, middle): POPULlN, LUIS, C

RESEARCH & RELATED Other Project Informat ion1. * Are HUman Subjects Involved? 0 Ves No1.a. If YES to Human Subjects

Is the IRS review Pending? o Ves o NoIRB Approval Date:Exemption Number: _1 _ 2 _ 3 _4 _5 _6Human Subject Assurance Number

* Are Vertebrate Animals Used? Ves 0 No2.a. If YES to Vertebrate Animals

Is the IACUC review Pending? o Ves NoIACUC Approval Date: 0307-2006Animal Welfare Assurance Number A336801

* Is proprietary/privileged information 0 Ves NoIncluded in the application?

.B. * Does this project have an actual or potential Impact on 0 Ves Nothe environment?.b. If yes, please expJaln:.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? 0 Ves o No.d. If yes, please explain:~ . a . * Does this p roject involve activities outside the U.S. or o Ves No

partnership with International Collaborators?.b. If yes, Identify countries;.c. Optional Explanation:

* Project Summary/Abstract Abslrac11001742443.pdf Mime Type: application/pdf* Project Narrative ProJeclNarrativel0017q2534.pdf Mime Type: application/pdfBibliography & References Cited Bibliography1001742444.pdf Mime Type: application/pdfFacilities & Other Resources Facililles1001742434.pdf Mime Type: application/pdf10. Equipment Equipmen11001742440.pdf Mime Type: application/pdf

Tracking Number: Other Information Page 5 OMB Number: 4040.{l001ExplraUon Date: 04130/2008

2011-04-22 000177


12/67

Principallnvesligator/Program Director (Last, first, middle): POPUlIN, LUIS, C

ABSTRACTThe goal of this project is to extend our knowledge of the neural mechanisms that underlie the integrationof information from different sensory modalities and their transformation into motor commands to generategaze shifts. Specifically, we will seek to establish the relationship between the magnitude and timing ofsensory responses, associated motor discharges, and resulting gaze shifts.

The proposed experiments, to be carried out in a newly developed head-unrestrained monkeypreparation, are a natural continuation of those carried out in the behaving, head-restrained cat during theprevious funding period. The change from the cat to. the monkey preparation was dictated by the questionsthat arose from our previous work, which cannot be adequately addressed in the cat. The experimentalapproach will be to record from single units in the intermediate layers of the superior colliculus (SCi) ofmonkeys (1) during the presentation of acoustic, visual, and bimodal stimuli, and (2) while they orient to thesources of those stimuli.The proposed work comprises four specific aims: AIM 1 will test the. hypothesis that facilitation ofbehavioral responses to bimodal stimuli in primates is mediated by integrative mechanisms that obey linear(or sub-additive), not super-additive processes. AIM 2 will test the alternative hypothesis that enhancedbimodal responses are observed in single SC units, but under conditions of high behavioral significance tothe subject. AIM 3 will test the hypothesis that the SC operates in two distinct modes: a detection mode,characterized by large neuronal responses that increase the likelihood of orienting movements directed to thesource of the stimUli, and an attention-driven mode, characterized by smaller, transient neuronal responsesthat provide for fine behavioral control, e.g., stopping the response if changing conditions so require. AIM 4will test the motor error hypothesis (Sparks, 1986) in the head-unrestrained monkey.

Project Description Page 6

2011-04-22 000178


13/67

Principallnvestigator/Program Director (last, first, middle): POPULlN, lUIS, C

PROJECT NARRATIVEThis project is concerned with two of the most fundamental questions facing systems neuroscience: how isi n f o r m ~ t i o n from different sensory modalities integrated into a unique and single representation of thesurrounding space, and how is such information used to generate and control movement - specifically, gazeshifts (coordinated movements of the eyes and head). Furthering our understanding of how nature hasimplemented neural solutions to these basic questions will result in the design of better computer-braininterface devices, prostheses, smart robots, automatic system recognition devices, and ultimately helpneurology/otolaryngology in devising electronic and pharmacological solutions for patients affects withsensory and sensorimotor integration diseases.

Public Health Relevance Statement Page 7

2011-04-22 000179


14/67

Principal Investigator/Program Director (last, first, middle): POPUUN, lUIS, C

FACILITIESLaboratory. The PI's l a b o r a t o ~ -4- . . pf the University of WisconsinMedical School. It comprises -15 0 square reet, and It IS eqUippea wlln three complete experimental setupsfor audio-oculomotor behavioral and physiological experiments. .Offir The offices of PI Pit-doctoral fellows, computer proarammers, technician, and students arelocated__ _ . . . . --.- J .Anira,. The animals are housed in the animal care facility of the University of Wisconsin-Madison Medical

School_ *' _ )rhe facility is operated by experienced staffunder the supervision of a Dr. iiiVeierinary Medicine.Other. Access to the Medical Electronics Lab and The Physics Dept Instrument Shop is available for anhourly fee. The services provided by these facilities are essential to build, maintain, and adapt ourexperimental equipment as needed.

Facilities Page 8

2011-04-22 000180


15/67


EQUIPMENTThe PI's laboratory is completely equipped to carry out the proposed work. It consists of threeexperimental setups. Each setup consists of a double-walled (3.2 X 3 X 2) m sound proof chamber (AcousticSystems, Austin, TX), a phase angle magnetic search coil system (CNC Engineering) with three phasesensitive detectors, and Tucker Davis Technologies System 3 hardware to present acoustic stimuli. Dataacquisition and stimulus presentation systems are controlled with PCs running custom'software. The array ofelectrophysiological equipment for each setup includes: amplifier (BAK Electronics), window discriminator(Tucker Davis Technologies), audio monitor, analog filters (Krohn Hite, Co), real-time spike sorting system(Alpha Omega, Nazareth IlIit, Israel), two oscilloscopes (Tektronix), and Narishige microdrives for chronicrecordings.The computers in the PI's lab include 17 PCs, 2 Macintosh, and a Dell PowerEdge 4040 two-processorLinux server that runs an Oracle database containing all eye movement and physiological data collected inthe lab. All computers are linked by an intranet served by a windows 2003 server that handles mail, databackup, and printing services. In addition the PI's lab is equipped with a Lexmark laser printer, an Epsoncolor printer, and a Hewlett-Packard scanner.

Equipment Page 9

2011-04-22 000181


16/67

Principal Investigator/Program Director (Last, first, middle): POPUUN, LUIS, C

RESEARCH & RELATED Senior/Key Person Profile (Expanded)PROFILE - Project Director/Principal Investigator

Prefix * First Name Middle Name. * Last Name SuffixDr. LUIS C POPULIN

Positionmtle: ASSISTANT PROFESSOR Department: ANATOMY-GENOrganization Name: The Board of Regents of the University of Wisconsin Division:System Slreet1: 1300 UNIVERSITY AVE Slreel2: 63B5 MEDICAL SCIENCES CTR City: MADISON County: * State: WI: Wisconsin Province: Counlry: USA: UNITED STATES Zip I Poslal Code: 53706-1509

*Phone Number Fax Number E-Mail(60B) 265-6451 (60B) 262-7306 LPOPULlN@WISC. EDU

Credential, e.g., agency login:* Project Role: PO/PI

*Attach Biographical SketchAttach CUrrent & Pending Support

Tracking Humber: Key Personnel

Other Project Role Category:File NameLuls_Popuiln1001742437.pdf

Page 10

Mime Typeapplication/pdf

OMS Number: ~ ~ . ( I O O 1 expiration Dale: 0.413012008

2011-04-22 000182


17/67

Principal Investigator/Program Director (last, first, middle): POPUUN , lUIS, C

RESEARCH & RELATED Senior/Key Person Profile (Expanded)Additional Senior /Key Person Form Attachments

When submitting seniorlkey persons in excess of 8 individuals, please attach additional seniorlkey person forms here. Each additional form attached 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 ad ditionalform, simply follow these steps: Select the "Select to Extract the R&R Additional SeniorlKey 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 assigning a name to the file, please remember to give it the extensi on ".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 Pure Edge viewer software. Using the Open Form" tool on your PureEdge viewer, open the new form that you have just saved. Enter your additional Senio r/KeyPerson information in this supplemental fonn. It is essentially the same as the Senior/Key person fonn 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 SeniorlKey Person Form Attachments" page. Attach the saved supplemental form, that you just filled in, to one of the blocks provided on this "attachments" form.

Important: Please attach additional SenlorlKey Person forms, using th e blocks below. Please remember that the files you aUach 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.

1) Please attach Attachment 12) Please aUach Attachment 23) Please attach Attachment 34) Please attach Attachment 4

ADDITIONAL SENIOR/KEYPERSON PROFILE(S)

Additional BiographicalSketch(es) (Senior/Key P e r ~ o n )

Additional Current andPending Support(s)

Filename

MlmeType

Filename

MimeType

Filename

MlmeType

Tracking Number: Key Personnel Page 11 OMB Number: 40OW-0001EXpiration Date: 0413012008

2011-04-22 000183


18/67

PrincipallnvestigatorJProgram Director (Last, first, middle): POPULlN, LUIS, C

BIOGRAPHICAL SKETCHNAMELuis C Populin

EDUCATIONITRAININGIPEF, C6rdoba, ArgentinaOregon State UniversityUniversity of Wisconsin-MadisonUniversity of Wisconsin-MadisonPOSITIONS AND HONORS

POSITION TITLEAssistant Professor

DEGREEBSMSPhDPost Doc

YEAR1978198819961996

FIELD OF STUDYPhysical EducationMotor BehaviorNeuroscience and KinesiologyAnatomy

1988-1990 Project Assistant, Motor Behavior Laboratory, Dept. of Kinesiology, University of Wisconsin1990-1996 Research Assistant, Dept. of Neurophysiology, University of Wisconsin with Dr. Tom Yin1996-199" Research Associate, Dept. of Anatomy, University of Wisconsin with Dr. John Harting1997-2003 Assistant Scientist, Dept. of Anatomy, University ofWisconsin, Madison2003- Assistant Professor, Dept. of Anatomy, University of Wisconsin, Madison1996 Sigma Xi Graduate Research Award1997 Fifteen Jerzy E. Rose Neuroscience AwardPUBLICATIONSPopulin LC, Rose DJ, Heath KE (1990) The role of attention in one-handed catching. J Motor Behav 22:149-158.Stelmach GE, Populin LC, MUlier F (1990) Postural muscle onset and voluntary movement in the elderly.Neurosci Lett 117:188-193.Populin LC, and Yin TCT (1995) Topographical organization of the motoneuron pools that innervate themuscles of the pinna of the cat. J Comp Neurol 363:600-614.Yin TCT, Populin LC (1997) Sound localization and pinna movements in the behaving cat. In: AcousticalSignal Processing in the Central Auditory System (Syka J, ed), pp 399-405. New York: Plenum Press.Populin LC, Yin TCT (1998) Sensitivity of auditory cells in the superior colliculus to eye position in the

behaving cat. In: Psychological and Physiological Advances in Hearing (Palmer AR, Rees A, SummerfieldAQ, Meddis R, eds), pp 441-448. London: Whurr Publishers.Yin TCT, Populin LC (1998) Behavioral and physiological studies of sound localization in the cat. In: CentralAuditory Processing and Neural Modeling (Brugge J and Poon P, eds). New York: Plenum Press.Populin LC, Yin TCT (1998) Behavioral studies of sound localization in the cat. J Neurosci 18: 2147-2160.Populin LC, Yin TCT (1998) Pinna movements of the cat during sound localization. J Neurosci 18: 4233-4243.Populin LC, Yin TCT (1999) Kinematics of eye movements of cats to broadband acoustic targets. JNeurophysiol 82:955-962.Smith PH, Populin LC (2001) Fundamental differences between the thalamocortical recipient layers of the catauditory and visual cortices. J Comp NeuroI436:508-519.Populin LC, Tollin DJ, Weinstein JM (2002) Human gaze shifts to acoustic and visual targets. Ann N Y AcadSci 956:468-473.Populin LC Yin TCT (2002) Bimodal interactions in the superior colliculus of the behaving cat. J Neurosci22:2826-2834.Populin LC, Tollin DJT, Yin TCT (2004) Effect of eye position on saccades and neuronal responses toacoustic stimuli in the superior colliculus of the behaving cat. J NeurophysioI92:2151-2167.Tollin DJ, Populin LC, Yin TCT (2004) Neural correlates of the precedence effect in the inferior colliculus ofbehaving cats. J NeurophysioI92:3286-3297.Tollin OJ, Populin LC, Moore JM, Ruhland JL, Yin TCT (2005) Sound localization performance in the cat: Theeffect of training the head. J Neurophysiol 93:1223-1234.

Biosketches Page 12

2011-04-22 000184


19/67

Principallnvestigator/Program Director (Last, firsl, middle): POPULlN, LUIS, C

Populin LC (2005) Anesthetics change the excitation/inhibition balance that governs sensory processing inthe cat superior colliculus. J Neurosci 25:5903-5914.Populin LC (2006) Monkey sound localization: head-restrained versus head-unrestrained orienting. JNeurosci 26:9820-9832.

Biosketches Page 13

2011-04-22 000185


20/67

Principallnvestigalor/Program Director (last, first. middle): POPUlIN, lUIS, C

PHS 398 Cover Page Supplement

1. Project Director / Principal Investigator (PO/PI)Prefix: IDr- I * First Name:llUISMiddle Namej C I* last Name: IpOPULli'ISuffix: I I

* New Investigator? eNo OYe.Degrees: IPhD I I I

2. Human SubjectsClinical Trial? eN o OYe.

* AgencyDefined Phase III Clinical Trial? eNo OYe.

3. Applicant Organization ContactPerson to be contacted on matters involving this applicationPrefix: 10 I "* First Name:11 i i \Middle Namej I* Last Name: ' I '110 }Suffix: I I

* Phone Numberr, ' . - ~ ) I Fax Number1 JEmail:r, .."" J

* Title: .G 4- J* Street1: lStreet2: 't :J;J City: : ~ ) ICounty: I* State: C ... ==' IProvince: I I* Country: J * Zip I Postal Code: I>*=--J

I

I

OMS Number: 0925-0001Expiration Dale: 9/30/2007

II

I

II

II

II

I

"* ' 1 \ ~ , o D ~ / ~ ConY \ m ~ , r r n ~ ~ V . Ctinical Trial & HESC Page 1Tracking Number:2011-04-22 000186


21/67

PrincipallnvestigalorlProgram Director (Last, first, middle): POPUlIN, LUIS, C

Tracking Number;

PHS 398 Cover Page Supplement

4. Human Embryonic Stem Cells., Does the proposed project involve hUman embryonic stem cells? OYes

If the proposed project involves human embryonic stem cells, list below t h ~ registration number of thespecific cellline{s) from the following list: http:{{stemcells.nih.govlregistryfindex.asp . Or, if a specificstem cell line cannot be referenced al this time, please check the box indicating that one from the registry will be used:

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

Clinical Trial & HESC Page 15

OMS Number: 09250001Expiration Date: 913012007

2011-04-22 000187


22/67

Principallnvestigator/Program Director (last, first, middle): POPULJN, LUIS, CPHS 398 Modular Budget, Periods 1 and 2

Budget Period: 1 Start Date: ~ 9 / 0 1 / 2 0 0 7 IA. Direct Costs

B. Indirect CostsIndirect Cost Type

1. IMDTC On-campus2. I3. I4. I

End Date: ~ 8 / 3 1 / 2 0 0 8 I

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

Funds Requested ($)* Direct Cost less Consortium F&A I 2 5 0 . 0 0 0 . 0 ~ Consortium F&A I I

* Talai Direct Costs I 2 5 0 . 0 0 0 . 0 ~ Indirect Cost Indirect CostRate (%) Base ($) Funds Requested ($)

I 2 5 0 . 0 0 0 . 0 ~ I 1 1 7 . 5 0 0 . 0 ~ I c::J I II II c::J I II II c::J I II I

Cognizant Agency (Agency Name, POC Name and Phone Number) fDHHS, Henry Williams, 214-767-3261 I

Indirect Cost Rate Agreement Date ~ 8 / 0 9 / 2 0 0 6 I Total Indirect Costs I 1 1 7 . 5 0 0 . 0 ~ C. Total Direct and Indirect Costs (A + B) Funds Requested ($) I 3 6 7 . 5 0 0 . 0 ~

Budget Period: 2Start Date: ~ 9 / 0 1 / 2 0 0 8 I End Date: 128/31/2009 I

A. Direct Costs Funds Requested ($)Direct Cost less Consortium F&A I 2 5 0 . 0 0 0 . 0 ~

Consortium F&A I ITotal Direct Costs I 2 5 0 . 0 0 0 . 0 ~

B. Indirect Costs Indirect Cost Indirect CostIndirect Cost Type Rate (%) Base ($) Funds Requested ($)

1. IMDTC On-campus II 47.001 I 2 5 0 . 0 0 0 . 0 ~ I 1 1 7 . 5 0 0 . 0 ~ 2. I I c::J I II I3. I I c::J I II I4. I I c::J I II ICognizant Agency (Agency Name, POC Name and Phone Number) IOHHS, Henry Williams, 214-767-3261 I


TrackIng Number: Modular Budget Page 16

2011-04-22 000188


23/67

Principallnvestigator/Program Director (last, first, middle): POPUlIN, lUIS, CPHS 398 Modular Budget, Periods 3 and 4

Budget Period: 3 Start Date: ~ 9 / 0 1 / 2 0 0 9 IP". u,reCt ,-OStS

B. Indirect CostsIndirect Cost Type

1. IMDTC On-campus2. I3. I4. I

End Date: ~ 8 / 3 1 1 2 0 1 0 I

* Direct Cost less Consortium F&AConsortium F&A


Funds Requested ($)I 2 5 0 . 0 0 0 . 0 ~ I I

* Total Direct Costs I 2 5 0 . 0 0 0 . 0 ~ Indirect Cost Indirect CostRate (%) Base ($) Funds Requested ($)I I 2 5 0 . 0 0 0 _ 0 ~ 1 1 1 7 . 5 0 0 . 0 ~ I 0 I II II c=J I II II c=J I II I

Cognizant Agency (Agency Name, poe Name and Phone Number) IOHHS, Henry Williams, 2 1 4 - 7 6 7 ~ 3 2 6 1 I

Indirect Cost Rate Agreement Date ~ 8 / 0 9 / 2 0 0 6 I Tolallndirect Costs I 1 1 7 . 5 0 0 . 0 ~ C. Total Direct and Indirect Costs (A + B) Funds Requested ($) I 3 6 7 . 5 0 0 . 0 ~

Budget Period: 4Start Date: ~ 9 / 0 1 l 2 0 1 0 I End Date: 108/3112011 I

A. Direct Costs Funds Requested ($)* Direct Cost less Consortium F&A I 2 5 0 . 0 0 0 . 0 ~

Consortium F&A I I* Total Direct Costs I 2 5 0 . 0 0 0 . 0 ~

B. Indirect Costs Indirect Cost Indirect CostIndirect Cost Type Rate (%) Base ($) * Funds Requested ($)

1. IMDTC On-campus I 2 5 0 . 0 0 0 . 0 ~ I 1 1 7 . 5 0 0 . 0 ~ 2. I 1c=J I II I3. I I c=J I II I4. I I c=J I II ICognizant Agency (Agency Name, POC Name and Phone Number) IDHHS, Henry Williams, 214-767-3261 I


Tracking Number: Modular Budget Page 17

2011-04-22 000189


24/67

Principallnvesti gator/Program Director (Last, first, middle): POPUlIN, LUIS, CPHS 398 Modular Budget, Period 5and Cumulative

Budget Period: 5


Start Date: 109101/2011 I End Date: ~ 8 / 3 1 / 2 0 1 2 IA. Direct Costs Funds Requested ($)

* Qirect Cost less Consortium F&A I 2 5 0 . 0 0 0 . 0 ~ Consortium F&A I I* Total Direct Costs I 2 5 0 . 0 0 0 . 0 ~

B. Indirect CostsIndirect Cost Indirect Cost

Indirect Cost Type Rate (%) Base ($) Funds Requested ($)1. ~ D T C Oncampus I 2 5 0 . 0 0 0 . 0 ~ I 1 1 7 . 5 0 0 . 0 ~ 2. I I c::J I II I3. I I c::J I II I4. I I c::J I II ICognizant Agency (Agency Name. POC Name and Phone Number) jDHHS, HenlY Williams, 214-767-3261 I

IndirectCost Rate Agreement Date ~ 8 / 0 9 / 2 0 0 6 I Totallndirect Costs I 1 1 7 . 5 0 0 . 0 ~ C. Total Direct and Indirect Costs (A+ B) Funds Requested ($) I 3 6 7 . 5 0 0 . 0 ~

I umulative Budget Information I1. Total Costs, Entire Project Period* Section A. Total Direct Cost less Consortium F&A for Entire Project Period $1 1 . 2 5 0 . 0 0 0 . 0 ~ Section A, Total Consortium F&A for Entire Project Period $1 I* Section A, Total Direct Costs for Entire Project Period $1 1 . 2 5 0 . 0 0 0 . 0 ~ * Section S, Total Indirect Costs for Entire Project Period $1 5 8 7 . 5 0 0 . 0 ~ * Section C, Tolal Direct and Indirect Costs (A+S) for Entire Project Period $1 1 . 8 3 7 . 5 0 0 . 0 ~

2. Budget JustificationsPersonnel Justification EersonnelJustification1001742439.pdf IConsortium Justification I IAdditional Narrative Justification I I

Tracking Number: Modular Budget Page 18

2011-04-22 000190


25/67


PersonnelJustification_altDataGroupOFile NamePerson nelJustification100 1742439.pdfConsorliumJustification_altDataGroupOFile NameAdditionalNarrativeJustification_atlDataGroupOFile Name

TrackIng Number: Modular Budget

AttachmentsMime Typeapplication/pdf

Mime Type

Mime Type

Page 19

2011-04-22 000191


26/67

Principal Investigator/Program Director (last, first, middle): POPUUN, lUIS, C

BUDGET JUSTIFICATIONAll categories are projected to increase by 3% each year. Fringe benefits are at theprojected University of Wisconsin rates.Luis C Populin, P.h.D. F I ~ PI, will devot 7.,{(.;t f his time to the project. /;fe will trainersonneldesign and supervise e raining of the mon eys, perform surgical procedures toimplant eye coils and recording cylinders, perform the physiological recordings, analyzethe data and prepare manuscripts.( *. El:HlJAssociate Research Specialist, will d e v o t e i ; ! . I f f . ' + ~ f her timeto the project.l. ]Sin charge of managing the primate colony of the PI's lab,actively participates in the training of the monkeys, assists in the surgical procedures,takes part in data analysis, and manages the overall functioning of the lab.

~ , ~ Programmer Analyst.) ''''Ji;


27/67

Principallnvesti gator/Program Director (Last, first, middle): POPULlN, LUIS, C

PHS 398 Research Plan1. Application Type:

OMS Number: 0925-0001ExpIration Dale 913012007

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:ONew Resubmission o Renewal o Continuation o Revision

2. Research Plan Attachments:Please attach applicable sections of the research plah, below.1. Introduction to Application(for RESUBMISSION,of REVISION only)

IlntroductionToApplication1001742536.pdf I2. Specific Aims ~ p e c i f i c A i m s l 0017 42441.pdf J3. Background and Significance ~ a c k g r o u n d A n d S i g n i f i c a n c e 1 0 0 1 7 4 2 4 3 6 . p d f 4. Preliminary Studies I Progress Report I5. Research Design and Methods EesearchDesignAndMethodsl001742442.pdf6. Inclusion Enrollment Report I7. Progress Report Publication List Ifj!.!man Subjects S!1!;cljQ[l:Attachments 8-11 apply only when you have answered "yes" to the question "are human subjects involved" on the R&R Olher Project InformationForm. In this case, attachments 8-11 may be required, and you are encouraged to consult the Application guide instructions andlor the specificFunding Opportunity Announcement to determine which sections must be submitted w i ~ h this application.8. Protection of Human Subjects9. Inclusion of Women and Minorities10. Targeted/Planned Enrollment Table11. Inclusion of Children

Other Researcb plan Sections

12. Vertebrate Animals ~ e r t e b r a t e A n i m a l s 1 0 0 1 7 4 2 4 3 5 . p d f 13. Select Agent Research14. Multiple PI Leadership15. Consortium/Contractual Arrangemenls16. Letters of Support17. Resource Sharing Plan(s)

18. Appendix

Tracking N u ~ b e r : List of Research Plan Attachments Page 21

2011-04-22 000193


28/67

Principal Investigator/Program Director (Last, first, middle): POPULlN, LUIS, C

Introduction T oApplication_ attDataGroupOFile NameInlroduclionToApp/icalion1 001742536.pdf

SpecificAims_attOataGroupOFile NameSpecificAims1001742441.pdf

8ackgroundSignificance_attOataGroupOFileNameBackgroundAndSignificance1001742436.pdf

ProgressReport_attOataGroupOFile Name

ResearchOesignMethods_attOataGroupOFile NameResearchDesignAlldMethods1001742442.pdf

InclusionEnrollmentReport_attOataGroupOFile NameProgressReportPublicationList_attOataGroupOFile Name

ProtectionOfHumanSubjects_attOataGroupOFileName

InclusionOfWomenAndMinorities_attOataGroupOFileName

TargetedPlannedEnrolimentTable_attOataGroupOFileName

InciuslonOfChiidren_attDataGroupOFileName

VertebrateAnlmals_attOataGroupOFileNameVertebraleAnimals1 001742435.pdf

SelectAgentResearch_attOataGroupOFile Name

MultiplePILeadershipPlan_attOataGroupOFile Name

ConsortiumContractualArrangements_attDataGroupOFile Name

LettersOfSupport_attOataGroupOFile Name

ResourceSharingPlans_attOataGroupOFile Name

List of Research Plan AttachmentsTracking Number:

AttachmentsMime Typeapplication/pdf



Mime Type

M l m e T y p ~ application/pdf

Mime Type

Mime Type

Mime Type

Mime Type

Mime Type

Mime Type


Mime Type

Mime Type

Mime Type

Mime Type

Mime TypePage 22

2011-04-22 000194


29/67


30/67

\

2011-04-22 000196


31/67

Principallnvesligator/Program Director (last, first, middle): POPULIN, LUIS, C

A. SPECIFIC AIMSThe goal of this project is to extend our knowledge oHhe neural mechanisms that underlie the integration of information from different sensory modali ties and their transformation into motor commands to generate gaze shifts. The experimental approach will be to record from single units in the intermediate layers of thesuperior colliculus (SCi) of the head unrestrained (HU) monkey. Specifically, we will seek to define the relationship between the magnitude and timing of sensory responses, motor discharges, and resulting gaze shifts.Psychophysical studies have established that interactions among different sensory modalities have profound influences upon perception and behavior. By comparison, much less is known about the neural mechanisms underlying such interactions, which have been primarily studied in anesthetized animals. Much attentionhas been focused on a process of non-linear summation of sensory responses called "bimodal enhancement"that is readily observed in the SCi of anesthetized preparations. Bimodal enhancement is routinely cited in theliterature as the physiological explanation for behavioral facilitation.Recent studies of bimodal integration in behaving animals have challenged the notion of bimodal enhancement as a mechanism underlying behavioral facilitation because large, enhanced interactions are notObserved in behaving preparations (Populin and Yin, 2002; Bell et aI., 2001, 2005). Thus there is a large voidin our understanding of the neural mechanisms underlying the integration of sensory information from differentmodalities and the behaviors they facilitate. The proposed experiments arose from the results of those carriedout in the behaving, head-restrained (HR) cat during the previous funding period, which cannot be adequatelyaddressed in the cat. The following four specific aims will guide the proposed work:

Specific Aim 1 will test the hypothesis that facilitation of behavioral responses to bimodal stimuli is mediated by integrative mechanisms that obey linear (or sub-additive), not super-additive processes. Specifically,this aim will investigatej- . -1Y . . ]'C 0 -Specific Aim 2 will test the hypothesis that enhanced bimodal responses are observed in single SCi umts,but under conditions of high behavioral significance to the subject. Specifically.,,! {

[ ? 7f=-Specific Aim 3 will test the hypotheSiS that the SC operates in two distinct modes: a detection mode,characterized by large neuronal responses that increase the likelihood of orienting movements directed to thesource of the stimUli, and an attention-driven mode, characterized by smaller, transient neuronal responsesthat provide for further behavioral control- e.g., stopping the response if changing conditions so require. Thishypothesis arose from observations that showed that

Specifically, it is hypothesized that

Specific Aim 4 will test the motor error hypothesiS (Sparks, 1986) in the HU monkey. It is well establishedthat the representation of auditory space in the SC shifts as a function of eye position, but in HR preparationsthe I I : , Accordingly,the motor error hypotheSis will be tested in the HU monkey using behavioral m a n e u v e r ~ l JI 1B. BACKGROUND AND SIGNIFICANCEInteractions between different sensory modalities influence our perceptions and behaviors. They may affectshifts of attention (Driver and Spence, 1998), sensory discrimination (Butter etal., 1989; Farahetal., 1989), andreaction times (Frens etal., 1995; Taylor etal., 1999; Schrogerand Widman, 1998; Colonius and Arndt, 2001). Agreat body of behavioral literature documents the psychophysics of this phenomenon, but relatively little is knownabout the underlying physiological mechanisms. Thus, there is a large void in our understanding of the neuralmechanisms that govern behavior in normal, everyday multisensory settings. In fact most of what is known hasbeen learned from the superior colliculus (SC) of anesthetized preparations.The SC has served as the model for the study of multisensory interactions. It receives ascending and de-

Specific Aims Page 27

2011-04-22 000197


32/67

Principallnvestigator/Program Director (Last. first, middle): POPULlN, lUIS, C

scending sensory inputs (Huerta and Halting, 1984) where they form representations of visual (Stein et aI., 1976;Finlayetal., 1978) and auditory (Gordon, 1973; King and Palmer, 1983; Wise and Irvine, 1983; Middlebrooksand Knudsen, 1984; Hirsch et aI., 1985) space, and body surface (Cynader and Berman, 1972; Meredith et aI.,1991), The SC is also the site of various motor maps that underlie eye movements (Robinson, 1972; Schiller andStryker, 1972; Guillon etal., 1980) and pinna movements (Stein and Clamann, 1981).In anesthetized animals, the various maps are in spatial register (Gordon, 1973; Stein et aI., 1976; King andPalmer, 1983,1985; Meredith and Stein, 1986a,b), a phenomenon thought to be a manifestation of a fundamental aspect of SC organization and function (Stein and Meredith, 1993). In behaving animals that move their eyesrelative to their heads, the maps can be brought out of register (Poppel, 1973), Thus the alignment is thoughtto be actively maintained to compensate for eye movements (Jay and Sparks, 1987b; Populin et al., 2004). Ourunderstanding of the principles that govern multisensory interactions under such dynamic conditions, and thetransformations that lead to behavioral facilitation, is rudimentary at best. Thus, a fundamental goal of the proposed experiments is to contribute to our understanding of this area.

Bimodal interactions in the intermediate layers of the superior colliculusStudies by Stein and colleagues in anesthetized animals have shown that information from different sensorymodalities is integrated non-linearly by neurons in the SCi, which results in bimodal enhancement (or suppression) of sensory responses (Meredith and Stein, 1983; King and Palmer, 1985). Bimodal enhancement is thoughtto be a mechanism that facilitates the detection of biologically relevant stimuli and the subsequent orientationto the sources (Meredith and Stein, 1983; 1986a,b; Newman and Hartline, 1981; King and Palmer, 1985; Steinand Meredith, 1993). It is is frequently cited in the psychophysical and functional imaging literature as the physiological explanation for the well-documented facilitation of behavioral responses to bimodal stimuli (Calvert,2001; Calvert et aI., 2000, 2001; Driver and Spence, 1998). Interestingly, summation of sensory responses ofthe magnitude reported in anesthetized animals, which can reach up to 300% in the anesthetized cat (Meredithand Stein, 1986b) and 452% in the anesthetized guinea pig (King and Palmer, 1985), has not been observed inbehaving animals (Populin and Yin, 2002; see also the data by Bell et aI., 2001; 2005).Populin and Yin (2002) tested for the presence of non-linear interactions of sensory responses in the SCi ofbehaving cats trained on audiooculomotor tasks. They hypothesized that if bimodal enhancement, which is soprominently observed in anesthetized animals were a mechanism underlying behavioral facilitation, it should bereadily observed in a behaving preparation that actually shows behavioral facilitation to bimodal stimuli.The responses to bimodal stimuli recorded in the SCi of the behaving cat were larger than the responses toeither single modality stimulus but were ,slightly smaller than their sum, in many Visual. t h' I' ddt' saccade latency: saccadelaten.95.4)(Populin and Yin, 2002). Fig, 1 illustrates 0 !rpA L = : I ; ~ L an example from the population studied :!!! 8. 20 [7:.:J .by Populin and Yin (2002). The saccadic :"0" 12 1' . 'J',""""""""."' . ".. 1 . If""'"'' "Y ... ',',eye movements executed by the cat to i" 2.5 . ,11;;.... ..... ) & ( : < : ; ' . I , ) i i , ( ; \ ~ " ~ bimodal targets during those recordings E1) I I I Iwere more stereotyped and consistent 'g. 00 . WIi", ." , . c-_-!,"''' .....O J I . ~ . w j I ' ' ' ' ....,/U.'''" ...than those to visual and acoustic targets, ',500 0 500 1,000

Auditory Bimodal

and most importantly, they had a shorter Time (ms)latency: that is, they were facilitated, The Fig 1. Bimodal neuron in the SC of the cat recorded with fixationsingle unit responded to both visual and task. Top, vertical component of eye movements to targets at (0,-acoustic stimuli. The bimodal responses 23) deg. The visual stimulus was a red LED, the acoustic stimuluswere 7.5% larger than the sum of the two was broadband noise, and the bimodal stimulus was a combinedunimodal responses, indicating that they v i s u a / ~ a c o u s t i c presented s i m ~ l t a n e o u ~ / y f ~ o m the s ~ " ! l e location.were not enhanced. These bimodal data, BehaVIOral responses to the bimodal stimuli were facilitated.which are in stark contrast with those from the SC of anesthetized cats, are representative of the integration processes in the SC of the behaving cat (Populin and Yin, 2002). Note: similar results, albeit interpreted differently,have been published by Bell et al. (2001).Bell et al. (2001) hypothesized that the lack of large bimodal enhancement in their recordings was perhapsdue to the fact that the RFs of most of the neurons they studied covered the central portion of space. They suggested that bimodal enhancement might be more relevant and important for processing stimuli located fartheraway from the fovea, as suggested by Anastasio et al. (2000). The argument is that in more peripheral areas of

Background & Significance Page 29

2011-04-22 000198


33/67

Principallnvestigator/Program Director (last, first, middle): POPUlIN, lUIS, C

space, where latencies to visual stimuli are longer and thresholds for detection higher, there is room for auditorystimuli to contribute, resulting in facilitation of behavioral responses. Thus, behavioral facilitationjnJhe_perinhF!rvJs attributed to bimodal enhancement. Gaze latencv data from our laboratorv. however suggest'

YJ:. . . . ..

1978), thus it is assumed thatlranger latenCies are Indicative of Increased tasK dlTTICU IV l r osner,

Studies of bimodal inte ration in monke s Bell et aI., 2UU'I, LUUO; Frens and Van 0y ( pstal, 1998) and humans(e.g., Colonius and Arndt, 2003) have required subjects to orient to the visual component of the stimuli and toignore the acoustic. Under these conditions the acoustic stimulus is used as either a distractor or an attractor,depending on the degree of spatial congruency. Thus, is i t really important to require subjects to treat the sourcesof acoustic stimuli as targets for saccadic eye movements? Is it relevant and why?We believe that the answer to these questions is yes because primates can actually orient to the sources ofacoustic stimuli (Populin, 2006) - there is no reason to assume that primates do not treat acoustic stimuli as targets for saccades. Therefore, considering the acoustic component of bimodal stimuli, as well as acoustic stimulias non-tar ets should lead to an incorrect model of bimodal inte ration.*is POSSI e a me 0 0 ogical dl icu ties may have contribu e to t e approac 0 not requiring subjectsto treat sources of acoustic stimuli as targets for saccadic eye movements because measuring gaze shifts toacoustic targets is not a straight forward process, neither in humans nor monkeys. In addition, it has been reported that monkeys are difficult (if not impossible) to train to perform saccadic eye movements to acoustic targets(Grunewald et aI., 1999; Linden et aI., 1999). The experiments proposed in Aim 1 will not be constrained by thislimitation because monkeys are able to orient to acoustic targets (Populin, 2006).It is our contention that the kev to understanding how facilitation of behavioral responses to bimodal stimlllLis brought about resides iriJ

t:.TTeCtS OJ higher order variables on ;:'1,; JunctionBimodal integration has been defined by temporal and spatial interactions between ascending and descending sensory inputs (Meredith and Stein, 1986a; Meredith etal.,1987; Stein and Meredith, 1993; Wallace andStein, 1994). As discussed above, there are large discrepancies in the magnitude of bimodal integration indicesbetween anesthetized and behaving preparations. Studies in anesthetized animals report increases in the mag-Background & Significance Page 30

2011-04-22 000199


34/67

Principallnvestigalor/Program Director (Last, firs!, middle): POPULlN, LUIS, C

nitude of responses to bimodal stimuli as large as 300% (Meredith and Stein, 1983), and in some cases up toinfinity (Meredith and Stein, 1986b). On the other hand, studies in behaving animals that used the same indexto quantify bimodal responses report changes that ranged between 25-66% (Bell et aI., 2001). Differences justas large were reported by King and Palmer (1985) from anesthetized guinea pigs and by Populin and Yin (2002)frombehaving cats that used the same metric to quantify bimodal interactions.

However, Bell et al. (2003) have suggested that higher order variables, not just the intensity, spatial, andtemporal properties of the stimuli, might be responsible for the differences in the magnitude of the integrationindexes observed between the anesthetized and behaving preparations (see Corneil and Munoz, 1996; Munozand Corneil, 1995). With the exception of Bell et al.'s (2003) findings in the monkey that the act of fixation, notjust the mere presence of a fixation light, can influence sensory responsiveness and bimodal integration, we arenot aware of any other physiological s!udy in which higher order variables, representing cognitive aspects of anexperimental task, have been included in the design of the experiments. The SC of cat (Harting et al., 1992) andmonkey (Huerta and Harting, 1984) receives numerous descending inputs from the cerebral cortex that couldconvey signals representing the hypothesized higher order variables to the SC.Tests of the effects of instructions on bimodal integration, e.g., maintain fixation versus make a saccade, orhigher order variables pertaining to the significance of the stimuli, e.g., the size of the reward, must be carried{Jut on the same neurons of the same animal using identical sensory stimulation. Accordingly, Aim 2 will test thehvpothesis thall

Monkeys are very sensitive to these types or mampUialions Wiatt and Glimcher, 1999).In addition, the experiments proposed in Aim 2 will provide an important control for the experiments proposed under Aim 1. A common problem encountered in experiments with behaving animals is that subjects donot respond in trials in which stimuli are presented at near threshold levels (Frens and Van Opstal, 1998), whichis paradoxical because bimodal integration mechanisms, according to the law of inverse effectiveness (Stein andMeredith, 1993), are expected to compensate for the poor effectiveness of low intensity stimuli by non-linearlyenhancing the magnitude of the In "".,.,.,.,


35/67

Principallnvestigator/Program Director (last, first, middle): POPULIN, LUIS. C

'\S' 'I__ Iml ar 0 serva-

/

':l Ions nave been made by Bell et al. (2003) in the monkey andby Rizzolatti et al. (1974) in the paralYZe.d c.at using visual~ ~ m u l i . Figure 3C s h o ~ I r

I\ \ Thelmplementation of this hypothetical

~ e c h a n L s m in he SCi coulp rely on c= _~ _ _ _ _ _ i .. - ~ ~ . . J I - . ~ ___ ~ - " , { k , , - - __ l This type of mechanism, i.e., I - hasbeen demonstrated in the superficial gray layer (Pasternack et aI., (1999).In summary, while it is very clear that responses to stimuli presented within a un.it's best area are SignifiCantly]?hanged, it remains to _ ~ e determined ifRFs are a f f e c t e ~ a?d how. S _ . _h-LE!1e experimental work proposed under Specific Aim 3 is designed to answer this question.\=-- . -

1 J predict that ! . '0 be carried outAim 3 will support our hypothesis tnat) - /;[ - .ISuppressiv.e interactions: basis fo r implementation of motor error \

,- and eye head coordination . \It is well established that SCi neurons respond maximally to a stimulus >---------......__ -. Jpresented within their RFs in the absence of other stimUli or behavioral Fig 4. Hypothesized forms ofconstraints. The mere presence of a second stimulus anywhere in the ip- receptive field mOdulation.silateral or contralateral hemifield (Populin and Yin, 2002; Rizzolatti et aI.,1974), or the act of fixation (Bell et aI., 2003), invariably reduce the magnitude of responses to sensory stimuli(see Fig. 3). The large difference in the type of responses to identical stimuli led us to hypothesize that the SCoperates in two distinct modes: detection and attention (Specif ic Aim 3).Invariably, modulation of sensory responses in the SCi takes the form of a reduction of the lar er res onsesrecorded in the detection mode. Thus, the evidence from behaving preparations suggests tha.!l-\ . : : : ~

Acute experiments in the SC revealed that sensory stimuli of different modalities presented from a givenarea of space activated the same part of the SC, suggesting that the various maps are in spatial register.The alignment of the maps, therefore, was thought to provide the neural substrate for sensorimotor integrationBackground & Significance

""k ~ r O r ( + ~ i O - t l V Y > ~ Page 32

2011-04-22 000201


36/67

I

Principallnvestigator/Program Director (last, first, middle); POPUlIN, LUIS, C

(Gaither and Stein, 1979; Gordon, 1973; Harris et aI., 1980; Stein and Meredith, 1993). However, as pOintedout by Poppel (1973), because the coordinate systems for vision and audition are different, with the visual mapoculocentric and the auditory map head-centered, the alignment hypothesis holds only when the two representations are in register, i.e., when the eyes and the head point in the same direction (Gordon, 1973; King andPalmer, 1983; Meredith and Stein, 1985; Middlebrooks and Knudsen, 1984; Stein and Clamann, 1981; Steinand Meredith, 1993). Thus in behaving subjects whose eyes are free to move, one would expect the maps tobecome misaligned whenever the eyes are not at the straight ahead position. For primates, who move their eyes-3 times per second (Albano et aI., 1982; Schiller et aI., 1980), misalignment of the maps should be practicallythe constant condition.

..?enavlo ral tests indicate that this is clearly not the case. Regardless'roinre'l'irr7io:Flrsr;,mflin;:;;atf'ri'


37/67

Principallnvesligator/Program Director (last, first, middle): POPUUN, LUIS, C

The results of Bizzi et al. (1972) demonstrate that behavioral context has a significant effect on eye-head co -ordination. In that study, when monkevs could not predict the time of onset of a visual tamet, gaze shifts startedwill1 the eves followed bvJhe headJ . !*L - - = - = - z = : : - : : n c . : - ; = - = : - : ' ~ J t h e gremesl senslllvllY Tor OIscnmmalion is in the area of frontal space (Blauer, 1983)- as defined by the interaural axis.I }measured a"in Freed an tioarKS (1997a).j

D. RESEARCH DESIGN AND METHODSThe proposed work makes use of a new HU monkey preparation (Populin, 2006). The rationale for changingfrom the HR cat to the HU monkey is the following: 1) The studyof how motor commands are generated based onsensory inputs requires a preparation in which sensory and motor-related neural activity can be readily recorded.While the se of the HR cat is a fruitful substrate for the study of sensory responses (Populin, 2005; Populin andYin, 2002; Populin et aI., 2004), motor activity is difficult to find - we have found eye movement related activityin -5% of the hundreds of neurons we have studied in the Sei of the HR cat. In the se of the monkey, on theother hand, sensory and motor responses are readily found; this is essential for Aims 1 and 4. 2) The monkeyis capable of performing complex tasks with a high degree of cognitive content, which is necessary for Aims2 and 3. 3) The study of the mechanisms in the se that generate gaze shifts will be facilitated in the monkeybecause movements of the eyes and head are much more independent than in the cat; this is vital for Aim 4. Inaddition, the cat has a very limited oculomotor range, thus under HR conditions the best areas of many auditory

Research Design & Methods Page 34- \ ? r o p r ~ ~ { o r n Y \ ~

2011-04-22 000203


38/67

PrincipallnvesUgator/Program Director (Last, first, middle): POPULlN, LUIS, C

neurons are beyond the reach of eye movements; thus no functional relat ion can be established between neuralresponses and behavior. 4) Among the available preparations for studies of this type, the monkey is the closestto humans, including the psychophysics and kinematics of orienting.Subjects and preparation. The subjects will be 12 male rhesus monkeys. Each monkey will undergo one sur-'" gery to implant a head post, eye coils, and a recording chamber; additional surgeries may be needed to replacebroken eye coils. The head post will be used to restrain the head to care for the wound-edge around the implant'i1" and during the initial training, and to hold the spouts used to deliver liquid rewards in the HU condition. The. :: ' periosteum inside the recording chamber will be removed and the bone covered with acrylic. Eye coils, made of

I:::.. I lvire (Cooner Wire Co, Chatsworth, CAl will be implanted as described Judge et al. (1980). The head coil,( of similar construction to those used for the eyes, will be implanted in the head cap.Experimental sessions. A typical experimental session provides 2-4 hours of recording time, during which thesubject performs -3500 trials, with occasional sessions of up to 5 hours, producing> 5000 trials. The large number of trials we obtain from our monkeys is essential for the proposed experiments, particularly those under Aim3, which require extensive RF mapping. In the HR cat, where we succeeded in mapping auditory RFs (Populinet aI., 2004), we were able to obtain only -500 trials or less per recording session.Experimental setup and stimuli presentation. The experiments will be done in a 3x3.7x2 m double walledsound chamber (Acoustic Systems, Austin, TX); the interior of the chamber and all major pieces of eqUipment init are covered with reticulated foam (ilibrook, Minneapolis, MN) to attenuate acoustic reflections. Acoust ic stimuliwill be generated with Tucker Davis Technologies System 3 (Alachua, FL) hardware and presented through anyof 32 speakers (MDT-20, 28 mm, Morel Acoustics, Brookline, MA) that can be positioned anywhere around thesubject, 84 cm from the center of the head. Visual stimuli will be LEOs attached to the front of the speakers.Eye/head movement recordings. Eye and head movements will be measured with the search coil technique(Robinson, 1963) using a phase angle system (CNC Engineering, Seattle, WA), the horizontal output of whichis linear over a 270 deg range. The eye coils will be calibrated with a behavioral procedure that relies on theanimal's tendency to look at spots of light presented in a dimly lit or dark environment. To calibrate the head coil alaser pointer will be attached to the head post, and the investigator will manual ly align the laser beam with LEOsat known positions by moving the monkey's head. Linear functions will be fit to the output of the coil system totransform voltage to degrees of visual angle (Populin, 2006). Horizontal and vertical eye and head position signals will be digitally sampled at 500 Hz with an analog-to-dig italconverter (Tucker Davis Technologies, Alachua,FL) after analog low-pass filtering at 250 Hz (Krohn-Hite, Brocton, MA).Physiological Recordings, criteria for SCi recordings, and receptive and motor field mapping. Single unitrecordings will be obtained with 1-2 MOhms tungsten electrodes (MicroProbe, Potomac, MD). Small holes willbe drilled through the acrylic and skull inside the recording chamber to insert electrodes into the brain insideguide tubes with a Narishige MO-95 microdrive (Narishive, International, East Meadow, NY). A grid attached toth(J recording chamber will guide the insertion of the guide tube. We have adopted this approach, for which wereceived extensive guidance from D r s ~ -i= land discontinued the traditional craniotomybecause (1) the dura matter does not arden over time, (2) recording stability is better, and (3) no surgery toimplant the chamber is needed after training when the subject is performing at its best, which imposes a periodof recovery. The neural signals will be amplified (Bak Electronics, Mount Airy, MD) and bandpass filtered (0.3-3KHz; Krohn-Hite Co, Brockton, MA). Pulses generated by a window discriminator (Tucker Davis Technologies,Alachua, FL) when action potentials meet the criteria set by the investigator will be recorded with an event timerwith jJsec accuracy and saved on disk for analysis.The first recordings in each animal will be made with the HR to determining the orientation of the grid used toguide the electrodes into the brain with respect to the visual map in the superficial layers of the SC (Cynader andBegman, 1972). Typically, after 3-4 successful electrode penetrations it is possible to predict the location of theRFs in future electrode penetrations. After the relation between the orientation of the grid.and the visual map ofthe superficial layers is established, the head of the anim I will e sed before lowering the electrode into the

Ci. As the animal e s arious ex erimental tasks P Y " l ' y l ~ 0 fr.-f.o e WI est our pre IC Ions' - : a : : : i b : : - : o ~ u : r t 1It: : : e ~ l - : : : : o c : : : a " ' t ~ 1 :-::::n""o:Ti1t :-:e::-:::ie r . : e - ; : ' c t r : r o ; : ; : r ; e : : - i r : : : n : - i t h h e ; : : - ; : : c o ~ I i 1 t 1 c;;;u""a"'r'"'m"'a"'p;;-.-m"'e ~ W " ' I """'re""yC;-;::o:::n p : ; : : h : - : y s : : : i o : : ; l ; : : : o - : : : g I;:::'::::fa criteria to d eterm i n e if th etip of the electrode has reached the SCi: (1) recording depth relative to the start of the strong visual activi ty of thesuperficial layers (-1-15 mm), (2) the presence of auditory responses, 3) motor discharges associated with eyelgaze movements (Sparks, 1986, Wurtz and Goldberg, 1972). If the pattern of physiological responses does notconform to our expectations we will restrain the head of the animal and re-test; if needed we will reposition the

Research Design & Methods Page 35

2011-04-22 000204


39/67

Principallnvestigator/Program Director (Last, first, middle): POPUlIN, LUIS, C

/

electrode. We will not attempt to isolate single units until we are certain that the tip of electrode is in the SCi.Neuron Classification. Once the decision is made to study a neuron, the first task will be to determine itstype; eventually, as the number of neurons studied grows, we will have to select neurons based on their properties. SCi neurons will be ciassified in three categories: sensory, motor, and sensorimotor neurons. Sensory neu-rons are those that discharge in response to the presentation of visual andlor auditory stimuli, and do not showmotor-related activity, i.e., do not discharge before gaze shifts. Motor neurons are those that do not dischargeto the presentation of sensory stimuli, but discharge before/during gaze shifts. Sensorimotor neurons are thosethat respond to the presentation of sensory stimuli and discharge in relation to gaze shifts. Further sub-classifications may turn out to be necessary to accommodate neurons that may respond to stimuli from only one modalitybut are influenced by the presence of stimuli from another modality that when presented alone does not evokea response (Populin and Yin, 2002; Populin et aI., 2004 .J:i:-

-. JIO objectivelY aetermlne the presence Of motor activity the motor Inaex usea oyFreedman and ~ r k s (1997b) will be used.

- - -- -t"

3-Movement fields, the range of saccade (gaze shifts) directions and amplitudes that are precededlllLa ourst

_ ~ f l l J ; t i v i ! y ' _ ( S p a r k s and M a Y ~ . 1 i l l i l l ) . . w i l l he comouted for eveN neuron that exhibits motor discharaesl . .*:

Tne onset of a burst of activit associated with a gaze shm Will be defined as tne lime at wnlcn me linn rateexceeds 40 s ~ e s / s e c and the offset as the time at which the discharge rate fall below 40 spikes/sec. et aI., 20050 . . . *er e ermlnlng a neuron s ype, I WI e asslgne 0 e mos SUitable experiment in any of the Aims;the exception will be Aim 2, which requires specific training. Sensory neurons will be suited for Alms 1 and 3;those with circumscribed RFs will be best suited for Aim 3. Neurons with motor-related discharges will be idealfor Aims 1 and 4. Our data acquisition software allows us to tailor an experimental session withoutsto the

monke 's work.' ypically, neural thresholds are lower than behavioral thresholds. This may present a

'-=p""ro=e"'m=""o-=-r" ' s t r . - u : : J d i : ' : y r : : i n : : : g : - : n : : - : e : 7 u ~ r o n s at low enough levels to facilitate multisensory interactions because animals tendnot to respond at low levels of stimulation (e.g., Frens and Van Opstal, 1998).Behavioral training: general. Behavioral training is based on positive reinforcement. Monkeys are fit with acollar and taught to accept being handled with a pole and to enter a primate chair before the first surgery. Onceimplanted with eye coils and a head post, the monkey is placed in the recording room to obtain calibration co-efficients for his eye coils. This is accomplished with the visual form of the fixation task with the HR. After thecoefficients are obtained, the auditory version of the fixation task is introduced. We use these tasks to teach oursubjects the basics of our paradigm: orienting to the source of a stimulus leads to a reward (Populin, 2 j 2 Q J , ~ 0 , - , 6 . . l = - . __ ,After the animal has made the connection n orientina and to a tamet an receiving a reward

Research Design & Methods Page 36- 9 r 6 p l " ~ - - : r ; ; ~ O l f 1 ' n ~ 2011-04-22 000205


40/67

Principallnvesligator/Program Director (Last, first, middle): POPULlN, LUIS, C

L ~ ~ ~ ~ ~ * ~ ~ ~ ~ ~ Jistology: electrode tract location. At the end of the recording life of each animal electrolytic lesions (e.g.,30-IJA anodal current for 30-45 sec) will be made in selected locations to help reconstruct electrode tracts. Theplacement of the electrodes will be carried out under the guidance of the grid. We will also have the opportunityto place our monkeys in an MRI located at the Waisman Center of the U of Wisconsin to obtain anatomical infor-mation with the tungsten electrodes in place; we will follow the procedures described in Metzger et al. (2006).Specific Aim 1This Aim will test the hypothesis that behavioral facilitation of responses to bimodal stimuli results from lin(or sub-additive), no!....upper-additive i ~ [ Q t i v e mechanisms. It is further proposed t h a ! i ' - ~ ~ - ~ - - - - - l Ex eriment 1. The roposed wor or 1m IS I us ra e In I 1. 1

Sensory data from the cat provide preliminary support for his A i m i ~ ' : . . . : F i , - " g _ 1 : . . o 3 ~ s " , h - , - , 0 c : . w , - t : ; . ; h c : : e l . -______ = = , ~ latency (unpublished data from three HU cats from this lab) and theaverage magnitude of all sensory responses recorded by Populinand Yin (2002) from the SC of four different HR cats. The behaviordata from Po ulin and Yin 2002

e SIS WI e ana yze using a velocity criterion to determine the onset, offset. peak velocity. and otherkinematics parameters (Populin, 2006) using custom software. The results will be stored in a relational databasefo r f u r t h e r _ a n ~ l y s i s : Physiological data will be analyzed as follows

Research Design & Methods Page 37;k 9 r o r r ~ ~ ~ o r r m ~ 2011-04-22 000206


41/67

Principallnvestigator/Program Director (last, first, middle): POPUUN, lUIS, C

l ~ - - - - - - , ~ - - - - , - - - , - - - - ~ \ f...... Tfie onset of a burst of activity

h ; a ~ s " ' s o " ' c q l a a r . s " " w " l f f n " a " g " ' a = , - " j i ' r l f t - i t M " ' e i 7 f o e " " ' m ; ; ; e ; ; t as the time at which the firingrate exceeds 40 spikes/sec and the offset as the time at which the dischargerate fall below 40 spikes/sec (Takeichi et aI., 2005). Many burst SC neuronsexhibit little spontaneous discharge (Jay and Sparks, 1987a) thus detecting their onseUoffset should not present problems'>k-e mde endent varia Ie will be the t e of stimuli - visual, acoustic'an

between the behavioral and neural variables wll e e he relationregression analysis (,GeneralLinear Model') in SPSS v14.0 (SPSS, In.-",c;-:;C " " h , ! ! i ~ c a ; ! \ g l " o , , - , ...I L . J . ) ' ~ ________ ~ _ - - - - - - __ c- ,Addit ional considerations for anal sis I

' - ] ~ t i m J . V 1 O i n h ~ ~ m n ~ ~ ~ ~ ~ u m ~ ( H a G I T m n n ~ T I T ~ T I n m m ~ r r } . T ~ h A e " S ~ e ~ n ~ s o ~ ~ ~ d ~ a ~ t a ~ r r ~ o ~ n l ~ t ~ h ~ e ~ c v a ~ t ~ s h h ~ o w ~ t ~ h ~ a t ~ esponses are preserved in the bimodal#c-er 0 su Jec s an neurons 0 e num e les as wel las the number of animals used for obtaining them varies considerably (e.g., Freedman and Sparks, 1997; Goldberg and Wurtz, 1972a; Mays and Sparks, 1980). Based on those numbers; which range from -35-380 neuronsfrom 2-7 animals, we estimate having to record from a total of -125-175 neurons, a number that will require 3monkeys. E v e ~ effort will be made to obtain equivalent samples for each of the major types of neurons targeted

( s e n s o ~ , motor, and sensorimotor). We further estimate that completing Aim 1 will require approximately 1.5-2years of experiments. Assuming that we start with na'ive monkeys, the first subject will be ready for recordings inapproximately 6-9 months. Once recordings start, we anticipate recording from each subject for -3 months. Under the PI's supervision the lab technician trains 3 monkeys per day. This is illustrated in the TIMELINE below.Potential Problems and Interpretation of Results, 1) We may encounter 'large differences in the threshold(responsiveness) of s e n s o ~ neurons, which are typically lower in SC neurons than behavioral thresholds. Acommon problem with behaving animals is that subjects do not respond in trials in which stimuli are presentedat near threshold levels (Frens and Van Opstal, 1998), which is paradoxical because bimodal integration mechanisms, according to the law of inverse effectiveness (Stein and Meredith, 1993), are expected to compensate forthe poor effectiveness of low intenSity stimuli by non-linearly enhanCing the magnitude of the s e n s o ~ responsest h < ? ~ \ l ~ t to drive the behavior. Because this Aim will test the hypothesis that t h ~ ~ ~ ' ~ " ' ' - - ' ' - - ' " ' ' ~ ' ' ' ' ' ' ' ' ' " '"

.f!:1,/,'2 We hypothesize tha

Research Design & Methods Page 38c ? r o ( i J ~ ~ - l - 1 \ ~ O I ( ' O ' ) ~

2011-04-22 000207


42/67

Principallnvestigator/ProgramDirector (last, first, middle): POPUUN, lUIS, C~ - - - ~ - - - - - - - - ~ -- -

., ' .

tI ~ u e to tile close associa,iul l u",ween t ~ s = Ical aCllVI!y 0 ne S( ; and orientinq behavior (Sparks,1986), we optimistically anticipate being able to fr-

-- -- - -he major question, therefore, will c o n c e n ~ the validitY of the proposed mode!.1

* ,)NiII call for rejection of the proposed hypothesis and for reconsideration of the entirescheme. The eXisting data, however, suggest that this will not be the case.Specific Aim 2While there is evidence showing that enhancement of sensory signals (large non-linear summat ion) by SCineurons is the result of spurious effects of anesthetics (Populin, 2005), experiments in behaving animals, whichdo not show enhancement, have not considered some potentially important higher order variables. Specifically,such studies have attributed the same behavioral significance to both unimodal and bimodal stimuli: that is, o r i ~ enting to the source of either type of stimuli led to the same reward. This may actually not be the case in nature,where concurrently seeing and hearing information arising from a single event or object leads to improved behavioral performance and, thus, increases the changes of success (e.g., obtaining a meal or avoid becoming ameal). In other words, the process of integration, in the SC mav not necessarily be restricted to sensory signals.Accordingly, this Aim will test the hypothesis that enhanced bimodal responses will be observed in SCi units, but,under conditions of high behavioral significance. The two experiments that compr ise this Aim will require specific'- training. Thus, subjects, two per experiment, will be assigned to only one. The need for the second experimentwill be contingent upon obtaining a positive r e ~ ! J I t , = , f , ! d r o ~ m . : : . . . : t : . : h e : : : . . . : : f i : : : r s : : . : t : . . . ~ - - - - " " " - = = = = " " " ' = - - - - 1 . -__ cE=xcP,eriment 2.1. This experiment will lest!

IWO ti'Jles of control trials are. bUllllnttlis experiment (but aJso see Exp. 2.2 belOW). First, the results ot the will "en'e as contl'Ols, to be compared againstL.,...,=====","":::-iJAllernativeIY, IT expectation IS wnat matters regarOiess OT type or stimUli, me responses to-unlmooal stimuli in the 20% of cued trials should change. SecondL *-..::tc 'he ;m::::a::::g""n"'itu=deC-:o;1f"tt'heh b-":im;;:o;:;d""a:rI';:re"'s"'p"'o""n""se;;-r.ln'"'t'"h:::e::::se:::-trials should approachltre'um of Ille tWO Unimodal responses (Populin and Yin, 2002),[ ---,_ ]we anticipate tha t -6 months of train-

Research Design & Methods Page 39 ( ? f o P t ~ T I \ \ O f ~ 2011-04-22 000208


43/67

Principallnvestigator/Program Director (Last, first, middle): POPUlIN, LUIS, C .

ing will be needed to prepare the monkeys for electrophysiological recordings, which should take -2-3 monthsin each monkey. The start of the training of the monkeys will start with a -3 months separation in order to havethe second monkey ready at the about the electrophysiological recordings in the first are completed. Thus, theexperiment should take about 1-1.25 years to complete.Ex erimental tasks and stimuli. As stated above, the experimental tasks will b { ';K~ - ' - - ' - ' = : : : : l r ___ - ' ~ ~ ____ t:=-='lffittlHor-these-eX\3eFimeRts will be the s ' ; a m ; : ; : ; ; ; e ~ t ; ; o ~ t h h " o s " ; e ; ; ' : _ T l u ~ s e " ' d . r h f o " ' r ' " ' A r o l " m ; - -at is,'> k ---.-Jl'he consid-erations discussed above in terms of level also app y to t ese e x p e r l m e n c : r s ~ . ___Physiological recordings and analysis. This ex eriment will focus 0 Jhe data will be analyzed using Multip e Inear egression enera Inear Mode!') in SPSS

~ V 1 : r 4 ' - - . " 0 7 S " " p n s ~ s - , I { ~ n c . Chicago, IL). In general, the approach for tl:ie-aoolysis will be tile sallie as iR Aim 1 but the .emphasis will be placed onl - 1--'--- f ' n e pas we a ply computed all index to deteFmiR6-if-the-"1m.. , . ::-:.-.nse excee e e sum 0 t e single modality responses (Populin and ';in, 2002). However, suchanalysis did not allow us to take into account the behavioral responses. In this casey *-L The results trom Aim 1 will be used as a oencnmarK. In addilionJ If-.1 .. . /(\

For the controls built in tms expenment, wnlcn Will serve' as 1n00cators a's to whether or notto proceed withExperiment 2.2., comparisons will be made between trialsl

- -_________________________ )tis hypothesized thatl'L,."____JElgleriment 2.2. This is a control for Experiment 2.1. This e x p ~ r i m e n t is aimed at.. ITwomonkeys will be used. Special rewards Will be associated with) -Ie" '

:Jhis experiment will be unnecessary if a negative result is obtalnea in Experiment 2.1.- - - ; A " f t i " : e - r t ; - - h e - s ~ t a - n - . d a r d training has been completed, i.e., monkeys have achieved a 75% success rate withoutspecial rewards, we will start the physiological recordings from one superior colliculus. The goal will be to char-acterize the responses oJl" .7/. ;-.___------------.1

( After the Initial recordings are complete, we will concentrate 011 I - raining the animal for about 2-3 monthsusing the special rewards for either the auditory or visual modalities. The special reward will consist of a largeamount (10-15 times the standard of a leI ra e 'uice' the standard reward is a very small drop of plain water.,The uestion at this oint will' - " = = - : - : - : : : ; ; : : - : : - = - - ; : - : - : - : : : : : ; : - : = : - ; . : : - = - : = ~ = : - : : - = : ; : _ : _ : = = : ; : : : : _ = _ = = _ : : ~ = _ t t ~ a an Glimcher (1999), as well asmany others, have shown that monkeys quickly reco i z e . . a . c h a " n t f g " ' e . . u I D . L . ! ! . " ' e ~ a ~ d O ! . m ' . . ' . i ~ n , " ' i s ' . " t r ' . : a ' . " t i ~ o ~ n . . ' : o " . . f . ' . . : r e ~ w : a ~ r " " d : s - " a ~ n ' : : ' d ~ q ! ' : u ' . " I C : : ' : k ~ l y ~ ad'ust their behavior. Accordin I , we anticipate that

e extended training (-2-3~ ; ; ~ ~ ~ ; ; ; : ; ~ : ~ ~ : ~ ~ : ; : : : : : : : : ~ ~ ~ = ~ ~ ~ ~ ~ ~ ~ _ ; ; ~ us, in to-tal, each of the animals will require an initia peno 0 tralmng 0 a least 6 months, a first (2-3 months) recordingperiod, a -2 months re-training period, followed by a -2-3 months second recording period. Thus, each experiment will last approximately 1.25 years.Experimental tasks and stimuli. Both the experimental tasks and stimuli fflr these control experiments will beidentical to those proposed for Experiment 2.1, with .the only difference t h a ~ L ___ ~ _ " ' I Y _______Data analysIs. I he data ~ I I be analyzed as in Experiment 2.1. ]Potential Problems and Interpretation of Results for Experiments 2.1 and 2.2. The major potential problemwith this Aim would be a negative result in Exp 2.1. That isLL-_______ - . . . : 0 { ' ~ _________

Research Design & Methods )\* G > r ( ' ) f r ~ ~ O C I J \ ' n . J . \ O n Page 402011-04-22 000209


44/67

Principallnvesligalor/Program Oirector (last, first, middle): POPULIN. lUIS, C

this were the case, there will be no need for Exp 2.2; the animals assigned to this experiment, at thatpoint undergoing the basic part of the training, would be assigned to the experiments of another Aim. Although anegative result in this case is neither desired nor antici ated, it would still be considered a si nificant contributionbecause it would rule out , . .A secondpotential problem concerns results of Exp 2.2: it is possible tha _hat is, expecting a large reward after raining wou ave the same effect on, . , - - - - - - - + - : - - - - ....1 gain, although this is not the desired or anticipated result we will consider it acontribution that - erstand the mechanisms of integration in the SC. In both cases ne ative results willbe interpreted a : f - ' ~ = -