Abstract

Symptomsofanxiety,avoidanceandarousal(?AAA?)cansignificantly,andnegatively,impactonone?sday- to-dayfunctioningandqualityoflife.Thisisespeciallytrueforgirlsandwomenwhoaremorethantwiceas likelytobediagnosedwithananxietydisorderwhencomparedtomen.Theproposedprojectaddressesthe pathogenesisofAAA,threeofthenegativevalanceRDoCsystems,inthecontextofaspecificgeneticriskfor suchsymptomsingirlswiththeFMR1fullmutation(i.e.fragileXsyndrome,FXS).Itisbroadlyrecognizedthat AAAsymptomsareanimportantandclinicallysignificantproblemforgirlsandwomenwithFXS.Recent surveyreportsindicatethat56%ofgirlswithFXShavereceivedtreatmentforananxietydisorder.Females withFXS,whoareunderrepresentedinresearchstudies,haveamorediverserangeofsymptomsandoverall higherIQthanmaleswithFXS,whichallowsfemalestoplayaparticularlyimportanttranslationalrolein understandingthecomplexitiesoftheAAAphenotype. UsingFXSasahumanmodelsystem,criticalgapsinourknowledgebaseregardingAAAsymptomswill beaddressed.Thisprojectwillemployanacceleratedlongitudinaldesigntotracksymptomdevelopmentin60 girlswithFXSfromages8-15years,andlinearmixedmodelingtoestimatechangeassociatedwithage.The developmentofnegativevalenceRDoCsystemswillbetrackedintandemwithkeyneuralsystemswhile consideringgenetic,hormonal,andenvironmentalfactorsthatmaycontributetotheclinicalpresentationof AAAsymptoms.Thismultimodalapproachwillfacilitatecomprehensiveanalysisofgene-brain-behavior interactionsthatunderlieAAAsymptoms.Ourdesignwillallowustotestnovelhypothesesregardingthe courseofAAAsymptomsandexaminemediatingfactorssuchasHPAaxisregulation.Combiningtraditional functionalandstructuralmetricsofbrainconnectivitywillallowusprobetheprefrontal-limbiccircuitryknownto haveakeyroleinAAAsymptoms.Utilizingflexible,opticalneuroimaging(functionalnearinfrared spectroscopy,fNIRS),wewillexamineprefrontalcorticalresponsestoanxietyduringnaturalisticsocial interactionstoyieldecologicallyvalidassessmentsofrealtimeanxietyresponseinvivo. Theprojectproposedherebuildsonsubstantialresearchinthepastgrantperiodfocusedongene- environment-brain-behaviorassociationsinfemaleswithFXS.ThecombinationofnewknowledgeaboutFXS thathasbecomeavailableinthepastseveralyearsandnewmethodsforinterrogatingtheseassociations providesanidealfoundationfromwhichnewhypothesescanbetestedinthenewgrantperiod.Plottingthe trajectoryofAAAsymptomdevelopmentandexaminingkeylinkageswithneurobiology,physiology,hormones, genesandenvironmentwilladvancethescientificknowledgebaseregardingthepathogenesisofAAAinFXS. Theseresultswilladvanceclinicalpracticebyidentifyingcriticalwindowswheninterventionsandpreventative strategieswillbemosteffectiveandhelptoadvanceaprecisionmedicineapproachwithinFXS. 1

Public Health Relevance

Anxiety can be a pervasive and challenging symptom for many people, particularly women, interfering with educational and vocational success and personal relationships. Girls with a common genetic disorder called fragileXsyndromeareatgreatlyincreasedriskofanxietysymptomsduetotheeffectsofthisconditiononbrain developmentandfunction.InthisresearchwehopetolearnmuchmoreaboutwhygirlswithfragileXsyndrome are at risk for significant anxiety symptoms and how factors related to the brain, family and stress hormone systeminfluencetheiroutcome.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH050047-23
Application #
9961659
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Gilotty, Lisa
Project Start
1993-07-01
Project End
2022-02-28
Budget Start
2020-03-01
Budget End
2021-02-28
Support Year
23
Fiscal Year
2020
Total Cost
Indirect Cost

  Institution

Name
Stanford University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305

  Publications

Sandoval, Gisela M; Shim, Sehoon; Hong, David S et al. (2018) Neuroanatomical abnormalities in fragile X syndrome during the adolescent and young adult years. J Psychiatr Res 107:138-144
Fung, Lawrence K; Reiss, Allan L (2016) Moving Toward Integrative, Multidimensional Research in Modern Psychiatry: Lessons Learned From Fragile X Syndrome. Biol Psychiatry 80:100-111
Saggar, Manish; Vrticka, Pascal; Reiss, Allan L (2016) Understanding the influence of personality on dynamic social gesture processing: An fMRI study. Neuropsychologia 80:71-78
Quintin, Eve-Marie; Jo, Booil; Hall, Scott S et al. (2016) The cognitive developmental profile associated with fragile X syndrome: A longitudinal investigation of cognitive strengths and weaknesses through childhood and adolescence. Dev Psychopathol 28:1457-1469
Martin, Arianna; Quintin, Eve-Marie; Hall, Scott S et al. (2016) The Role of Executive Function in Independent Living Skills in Female Adolescents and Young Adults With Fragile X Syndrome. Am J Intellect Dev Disabil 121:448-60
Saggar, Manish; Hosseini, S M Hadi; Bruno, Jennifer L et al. (2015) Estimating individual contribution from group-based structural correlation networks. Neuroimage 120:274-84
Hustyi, Kristin M; Hall, Scott S; Quintin, Eve-Marie et al. (2015) The relationship between autistic symptomatology and independent living skills in adolescents and young adults with fragile X syndrome. J Autism Dev Disord 45:1836-44
Hall, Scott S; Frank, Michael C; Pusiol, Guido T et al. (2015) Quantifying naturalistic social gaze in fragile X syndrome using a novel eye tracking paradigm. Am J Med Genet B Neuropsychiatr Genet 168:564-72
Green, Tamar; Barnea-Goraly, Naama; Raman, Mira et al. (2015) Specific effect of the fragile-X mental retardation-1 gene (FMR1) on white matter microstructure. Br J Psychiatry 207:143-8
Peng, Daniel X; Kelley, Ryan G; Quintin, Eve-Marie et al. (2014) Cognitive and behavioral correlates of caudate subregion shape variation in fragile X syndrome. Hum Brain Mapp 35:2861-8

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