social cognition: vulnerable networks involved in ftdmeasuring social cognition: measuring social...

Social Cognition: Vulnerable Social Cognition: Vulnerable Networks Involved in FTDNetworks Involved in FTD

Katherine P. Rankin, Ph.D.Katherine P. Rankin, Ph.D.Assistant Professor, Department of NeurologyAssistant Professor, Department of Neurology

University of California San FranciscoUniversity of California San Francisco

RightRightHemisphereHemisphere

LeftLeftHemisphereHemisphere

BottomBottom

L Ant InsulaL Ant Insula

R Ant InsulaR Ant Insula Ventromedial FrontalVentromedial Frontal

Anterior CingulateAnterior Cingulate

Early FTLDEarly FTLD

00

1515

tt--valuesvalues

(Rosen et al., (Rosen et al., Neurology,Neurology, 2002) 2002)


R Ant InsulaR Ant Insula


Early Frontotemporal DementiaEarly Frontotemporal Dementia(Rosen et al., (Rosen et al., Neurology,Neurology, 2002) 2002)

Dorsolateral frontal atrophy, Dorsolateral frontal atrophy, corresponding to standard corresponding to standard neuropsychological tests of neuropsychological tests of executive functioning, executive functioning, occurs occurs laterlater in the course of FTDin the course of FTD

Ventromedial FrontalVentromedial Frontal


R Ant InsulaR Ant Insula Ventromedial FrontalVentromedial Frontal


Orbital FrontalOrbital Frontal

Early Semantic DementiaEarly Semantic Dementia(Rosen et al., (Rosen et al., Neurology,Neurology, 2002) 2002)

While SD is defined as a While SD is defined as a language disorder, a subset language disorder, a subset of patients initially present of patients initially present with with unilateral right unilateral right temporaltemporal diseasedisease

AmygdalaAmygdala

Left Left Temporal Temporal LobeLobe

RightRightTemporal Temporal LobeLobe

Core Diagnostic Features Core Diagnostic Features –– FTD FTD A.A. Insidious onset and gradual progressionInsidious onset and gradual progressionB.B. Early decline in social interpersonal conductEarly decline in social interpersonal conductC.C. Early impairment in regulation of personal conductEarly impairment in regulation of personal conductD.D. Early emotional bluntingEarly emotional bluntingE.E. Early loss of insightEarly loss of insight

Supportive diagnostic features Supportive diagnostic features –– SDSDB.B. Behavioral disorderBehavioral disorder

1.1. Loss of sympathy or empathyLoss of sympathy or empathy2.2. Narrowed preoccupationsNarrowed preoccupations3.3. Financial parsimonyFinancial parsimony

(Neary et al., 1998)(Neary et al., 1998)

Clinicopathologic CorrelationsClinicopathologic Correlations

•• Many neurodegenerative disease patients show behavioral Many neurodegenerative disease patients show behavioral changes, some of them social and emotionalchanges, some of them social and emotional

•• We need a sophisticated clinical understanding of the various We need a sophisticated clinical understanding of the various profiles associated with all these diseases to improve our profiles associated with all these diseases to improve our diagnostic accuracy in atypical or mixed cases diagnostic accuracy in atypical or mixed cases –– ““personality personality changechange”” is not specific enough to be usefulis not specific enough to be useful

•• These important behavioral symptoms have not been These important behavioral symptoms have not been operationalized yetoperationalized yet

•• Currently assessed qualitatively via clinical interviewsCurrently assessed qualitatively via clinical interviews•• We need tests that are objective, standardized, repeatableWe need tests that are objective, standardized, repeatable

Assessment of social cognition is Assessment of social cognition is essential to early and accurate diagnosisessential to early and accurate diagnosis

Interpersonal Reactivity IndexInterpersonal Reactivity Index (Davis, 1983)(Davis, 1983)

•• Perspective Taking:Perspective Taking:

–– ““The patient believes there are two sides to every The patient believes there are two sides to every question and tries to look at them both.question and tries to look at them both.””

•• Empathic Concern:Empathic Concern:

–– ““If the patient sees someone being taken If the patient sees someone being taken advantage of, they feel protective towards them.advantage of, they feel protective towards them.””

Measuring social cognition:Measuring social cognition: empathyempathy

METHODSMETHODS•• 123 patients123 patients from the UCSF Memory & Aging Center from the UCSF Memory & Aging Center

(30 FTD, 26 SD, 8 PNFA, 38 AD, 15 CBD, 6 PSP)(30 FTD, 26 SD, 8 PNFA, 38 AD, 15 CBD, 6 PSP)•• Caregivers filled out Caregivers filled out IRI questionnaireIRI questionnaire evaluating evaluating

patientspatients’’ current level of empathycurrent level of empathy•• All patients underwent T1All patients underwent T1--weighted MPweighted MP--RAGE MRIRAGE MRI•• VoxelVoxel--based morphometrybased morphometry

–– Brain volumes analyzed using IRI scores as covariate of Brain volumes analyzed using IRI scores as covariate of interest (continuous)interest (continuous)

–– Controlling for age, sex, and total intracranial volumeControlling for age, sex, and total intracranial volume


(Rankin et al., Brain, 2006)(Rankin et al., Brain, 2006)

14

24

34

44

54

64

NC FTD SD PA AD CBD PSPDIAGNOSTIC GROUP

EMPA

THY

SCO

RE

•

•

•••

•

•

Measuring social cognition:Measuring social cognition: eempathympathy


-0.2

-0.15

-0.1

-0.05

0

0.05

0.1

0.15

0.2

10 20 30 40 50 60 70

EMPATHY SCORE

VOXE

L IN

TEN

SITY


Empathy score vs. volume at a sample voxel in the right temporalEmpathy score vs. volume at a sample voxel in the right temporal polepole(58, 10, (58, 10, --33) adjusted for age, sex, and TIV33) adjusted for age, sex, and TIV


Right temporal poleRight temporal pole

Right caudate/Right caudate/Medial OFCMedial OFC

Right insulaRight insula

Right anterior cingulateRight anterior cingulate

x = 7x = 7 z = 0z = 0

Figure threshold: p<0.001 uncorrectedFigure threshold: p<0.001 uncorrected

Regions where empathy score positively Regions where empathy score positively correlates with tissue densitycorrelates with tissue density(Analysis significant after FWE correction at p<0.05)(Analysis significant after FWE correction at p<0.05)


UnthresholdedUnthresholded map:map:2.0 < T < 6.02.0 < T < 6.0

Only the Only the right right hemispherehemisphere appears to appears to mediate empathy mediate empathy change in these change in these patientspatients


•• Right temporal poleRight temporal pole–– ““TransmodalTransmodal association areaassociation area”” ““acts as a gateway for acts as a gateway for

binding. . .associations (such as name, voice, facial binding. . .associations (such as name, voice, facial expression, posture, and private recollections)expression, posture, and private recollections)”” (Mesulam, 1998)(Mesulam, 1998)

–– Multimodal information is synthesized to create Multimodal information is synthesized to create complex, personal symbolic representationscomplex, personal symbolic representations

•• Right Right posteropostero--medial orbitofrontal cortexmedial orbitofrontal cortex–– May aid emotion recognition (May aid emotion recognition (HornakHornak, 1996, 2003), 1996, 2003)–– Encodes reward value of 1Encodes reward value of 1ºº reinforcersreinforcers

((KringelbachKringelbach, 2004), 2004)•• Visceral sensations accompanying emotional experienceVisceral sensations accompanying emotional experience

Structural neuroanatomic correlates of Structural neuroanatomic correlates of empathyempathy

•• Right caudateRight caudate–– Evaluation of reward expectancy from 1Evaluation of reward expectancy from 1ºº reinforcersreinforcers

(Reynolds & (Reynolds & BerridgeBerridge, 2002), 2002)–– Mixed findings re: facial emotion recognition, but is Mixed findings re: facial emotion recognition, but is

involved in emotional voice prosody recognition involved in emotional voice prosody recognition ((CancelliereCancelliere & & KerteszKertesz, 1990), 1990)

•• may interpret stimuli with timing elementmay interpret stimuli with timing element–– Imitating, but not merely observing, emotions (Carr, 2004)Imitating, but not merely observing, emotions (Carr, 2004)

•• Right nucleus Right nucleus accumbensaccumbens (?)(?)–– activity increases with bothactivity increases with both

•• emotional intensity, andemotional intensity, and•• selfself--relatedness (relatedness (PhanPhan, 2005), 2005)

Structural neuroanatomic correlates of Structural neuroanatomic correlates of empathyempathy

Early FTLDEarly FTLD



(Rosen et al., (Rosen et al., Neurology,Neurology, 2002) 2002) AmygdalaAmygdala


InsulaInsula

Right temporal poleRight temporal pole Right caudate/Right caudate/Medial OFCMedial OFC

Right insulaRight insula

Right anterior cingulateRight anterior cingulate

x = 7x = 7 z = 0z = 0

(Rankin et al.,(Rankin et al., BrainBrain, 2006), 2006)

Our studyOur study

The ability to adapt oneThe ability to adapt one’’s behavior based on (usually s behavior based on (usually indirect or implicit) feedback from othersindirect or implicit) feedback from others

The Revised SelfThe Revised Self--Monitoring Scale (RSMS)Monitoring Scale (RSMS)–– ““The patient can usually tell when others consider a joke to The patient can usually tell when others consider a joke to

be in bad taste, even though they may laugh convincingly.be in bad taste, even though they may laugh convincingly.””

–– ““The patient can usually tell when he or she has said The patient can usually tell when he or she has said something inappropriate by reading it in the listenersomething inappropriate by reading it in the listener’’s eyes.s eyes.””

(Lennox & Wolfe, 1984)(Lennox & Wolfe, 1984)

Measuring social cognition:Measuring social cognition:social social selfself--monitoringmonitoring

METHODSMETHODS•• 69 patients69 patients from a neurology clinic specializing in from a neurology clinic specializing in

neurodegenerative diseases (FTD, SD, PNFA, AD, neurodegenerative diseases (FTD, SD, PNFA, AD, CBD, PSP)CBD, PSP)

•• Caregivers filled out Caregivers filled out RSMS questionnaireRSMS questionnaire evaluating evaluating the sensitivity of the patient to social feedback about the sensitivity of the patient to social feedback about his or her behavior his or her behavior

•• All patients underwent T1All patients underwent T1--weighted MPweighted MP--RAGE MRIRAGE MRI•• VoxelVoxel--based morphometrybased morphometry

–– Brain volumes analyzed using RSMS scores as covariate Brain volumes analyzed using RSMS scores as covariate of interest (continuous) controlling for age, sex, & TIVof interest (continuous) controlling for age, sex, & TIV

Measuring social cognition:Measuring social cognition:social social selfself--monitoringmonitoring

6

11

16

21

26

31

36

NC FTD SD PNA AD CBD PSPDIAGNOSTIC GROUP

RSM

S SE

NSI

TIVI

TY T

O E

XPR

ESSI

VE B

EHA

VIO

R S

CO

RE

•

••

• •

• •

* *

* p<0.0001 vs. NCs

p < 0.01 correctedp < 0.01 corrected

R superior R superior frontal gyrusfrontal gyrus

BA 9BA 9

R medial R medial orbitofrontalorbitofrontal

BA 25BA 25

R lateral R lateral orbitofrontalorbitofrontal

BA 47/12BA 47/12

Regions where Regions where social selfsocial self--monitoringmonitoring score positively score positively correlates with tissue densitycorrelates with tissue density

+ monitoring reward value+ monitoring reward value++ punishers leading to change in behaviorpunishers leading to change in behavior

((KringelbachKringelbach & Rolls 2004 meta& Rolls 2004 meta--analysis)analysis)

Social selfSocial self--monitoring:monitoring:medial vs. lateral orbitofrontal cortexmedial vs. lateral orbitofrontal cortex

Our studyOur study

•• Inferring othersInferring others’’ intentionsintentions

•• Imagining othersImagining others’’ knowledge knowledge or feelings (or feelings (DecetyDecety & & Jackson review, 2004)Jackson review, 2004)

Social selfSocial self--monitoring:monitoring:dorsomedial frontal cortexdorsomedial frontal cortex

Our studyOur study

(Gallagher & (Gallagher & FrithFrith review, 2003)review, 2003)

Perspective Taking (social set shifting?):Perspective Taking (social set shifting?):•• separate your perspective/the otherseparate your perspective/the other’’s s

perspective/the facts of the situation, and hold all perspective/the facts of the situation, and hold all three perspectives simultaneously (three perspectives simultaneously (““triadic triadic attentionattention””?; Saxe, 2006)?; Saxe, 2006)

•• keep track of the keep track of the ““ownerowner”” of various mental states of various mental states originating in self and otheroriginating in self and other

•• only understanding othersonly understanding others’’ social intentions, not social intentions, not general (nongeneral (non--social) intentionality (Walter, 2004)social) intentionality (Walter, 2004)

Social selfSocial self--monitoring:monitoring:dorsomedial frontal cortexdorsomedial frontal cortex

KringelbachKringelbach & Rolls, 2003: Social Response Reversal (& Rolls, 2003: Social Response Reversal (fMRIfMRI))

Neuroanatomic correlates of Neuroanatomic correlates of social selfsocial self--monitoringmonitoring

acquisition trialsacquisition trials reversal trialsreversal trials

KringelbachKringelbach & Rolls, 2003: Social Response Reversal (& Rolls, 2003: Social Response Reversal (fMRIfMRI))Areas showing increased activation when subjects change their Areas showing increased activation when subjects change their behavior based on feedback from anotherbehavior based on feedback from another’’s angry facial expressions angry facial expression

Neuroanatomic correlates of Neuroanatomic correlates of social selfsocial self--monitoringmonitoring

Elements of social cognitionElements of social cognition

Warmth/empathyWarmth/empathyComprehension of emotional stimuliComprehension of emotional stimuliComprehension of situational stimuliComprehension of situational stimuliAdherence to social normsAdherence to social normsSocial Social decisionmakingdecisionmakingSocial perspective takingSocial perspective takingDominance/assertivenessDominance/assertivenessSelfSelf--awarenessawareness

Early diagnosis Early diagnosis early treatmentearly treatment





InsulaInsula

•• To measure function in these brain regions, we must use To measure function in these brain regions, we must use social and emotional testssocial and emotional tests

•• Without such tests, we will not be able to identify these Without such tests, we will not be able to identify these patients early in the disease coursepatients early in the disease course

•• As diseaseAs disease--modifying treatments become available, early modifying treatments become available, early diagnosis will be essential to timely interventiondiagnosis will be essential to timely intervention



Predominantly right temporal Predominantly right temporal lobe FTLD patients:lobe FTLD patients:

•• Not initially recognized Not initially recognized based on language or other based on language or other cognitive symptomscognitive symptoms

•• Most likely subtype of FTLD Most likely subtype of FTLD to be mistaken for to be mistaken for psychiatric or personality psychiatric or personality pathology; most resistant pathology; most resistant to assessment and careto assessment and care

•• Temporal lobe FTLD Temporal lobe FTLD patients more likely to have patients more likely to have ubiquitin positive ubiquitin positive neuropathologyneuropathology

VBM of empathyVBM of empathy

Early diagnosis Early diagnosis early treatmentearly treatment

Acknowledgements & thanksAcknowledgements & thanks

•• Bruce Miller, M.D.Bruce Miller, M.D.•• Joel Kramer, Joel Kramer, Psy.DPsy.D..•• Maria Luisa GornoMaria Luisa Gorno--Tempini, M.D., Ph.D.Tempini, M.D., Ph.D.•• Bill Seeley, M.D., Ph.D.Bill Seeley, M.D., Ph.D.•• Howard Rosen, M.D.Howard Rosen, M.D.•• Stephen Allison, B.S. Stephen Allison, B.S. •• Christine Stanley, B.A.Christine Stanley, B.A.•• Shenly Glenn, B.A.Shenly Glenn, B.A.•• . . .and many more at the UCSF Memory and Aging Center. . .and many more at the UCSF Memory and Aging Center•• Also, Mike Weiner at the SF VA Magnetic Resonance Spectroscopy UAlso, Mike Weiner at the SF VA Magnetic Resonance Spectroscopy Unitnit

This research was supported in part by:This research was supported in part by:–– National Institute on Aging 5 K23 AG021606National Institute on Aging 5 K23 AG021606--0303–– National Institute on Aging PPG P01 AG1972403National Institute on Aging PPG P01 AG1972403–– Larry L. Larry L. HillblomHillblom Foundation #2002/2JFoundation #2002/2J–– UCSF General Clinical Research Center M01UCSF General Clinical Research Center M01--RR00079RR00079

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