Neuroimaging and intersubjectivity in psychiatry

Knut SchnellDep. Of General Psychiatry Translational Psychiatric Therapy Research

Mission: Illustrate the principles of experimental Psychopathology of intersubjective functions

Concepts of Intersubjective functions

Experimental psychopathology of ToM- and Empathy functions: ToM, Empathy

Experimental model of psychotherapy-effects on intersubjective functions in (chronic) Depression: Perceived functionality

Social brain Hypotheses (Brothers 1990, Dunbar 1998)

– Expansion of brain driven by social demands– Positive correlation of neocortex expansion and size of social groups in

primates

(Dunbar 2003, reprinted from Barrett et al. 2002)

(Adolphs 2003)

Mission

Proposed intersubjective functionsin humans

Imitation, Representation of Intentions Mirror Neurons

Sharing Feelings Empathy

Representing mental content Theory of Mind

Recognizing interpersonal effects Perceived Functionality

Joint attention …

Mirrorneurons in primates

Iacoboni & Dapretto NRN 2006adapted from Rizzolatti et al. 2001

ImitationRepresentation of Intentions

Mirror-Neurons in Humans

Iacoboni & Dapretto NRN 2006 adapted from Iacoboni et al. 1999

Intention, not movement or objects codedIacoboni & Dapretto NRN 2006 adapted from Iacoboni et al. 2005

Fig. 1. Experimental design. Subjects made sinusoidal movements with their right arm at the same time as observing movements that were either congruent or incongruent with their own movements. In each condition, the subject (S) was instructed to make sinusoidal movements of their right arm from the shoulder, which were either vertical or horizontal at a rate of 0.5 Hz. While making these arm movements, the subject observed movements made by another effector situated facing the subject, either the right arm of the experimenter (E) or a robotic arm (R), that were either congruent or incongruent with the executed movements. In addition, there were two baseline conditions in which the subject moved their arm either horizontally or vertically without watching anything.

Kilner, J. M., Paulignan, Y., & Blakemore, S. -J. Current Biology, (2003)

Interference with observed motion depends on self-reference (human/non-human)

Motor contagion

Theory of Mind

• Ability to understand, that other subjects have mental states (desires, beliefs, emotions), to recognize such mental states and to act on this basis

• Develops between 3. and 4. years of age

Imaging of ToM-functions in humans

Cartoons (Gallagher at al., 2000)

Stories (Fletcher et al., 1995)

Comic strips (Brunet et al., 2000)

mPFC

anterior medialPFC

TPJtemporoparietal junction

STSSulcus temporalis superior

Neuroanatomy of the ToM-network

OFCLateral Orbitofrontal Cortex

Empathie: Definition

For Basic Emotions like fear and happiness and complex emotions like guilt Restrains humans from aggressve behaviour, can motivate altruistic

behaviour

The Ability to share the feelings of another human being without direct Stimulation by affective stimuli

Hein & Singer define empathy “as an affective state, caused bysharing of the emotions or sensory states of another person” (Hein and Singer, 2008).

Empathy in mice?

In contrast to affective contagion, empathy is bound to the individual awareness that a specific emotion was primarily initiated in the other person (Hein and Singer, 2008).

Empathy in Humans

Shared activation for pain experienceof the partner

Singer et al. 2004

Empathy= Shared Pain?

In contrast to Hein & Singers restrictive definition of empathy, mentalizing is defined by Frith & Frith as “the process by which we make inferences about mental states” (Frith and Frith, 2006) and does not only include the inference about another persons’ motivational states and beliefs but also the immediate recognition and the cognitive inference about other persons’ emotional states.

Empathie after social Interaction

Empathy for pain subsequent to social interaction in women and men

Activation of Nc. Acc.by pain of unfair players

in women and men

Singer et al. 2006

Relation between Self-Reported Empathy and Motor Identification with Imagined AgentsMarzoli et al., 2011

Simulation-Systems: Shared experience by isofunctional activation of limbic and sensorimotor regions (AI, ACC, or SII) during observation of a feeling, acting and perceiving human subject

Theory-Systems: Mental State Attribution/Mentalising by functional network of social inference: medialem PFC , inferior parietal and superior temporalem Cortex and esp. TPJ

Empathic Accuracy: Correlation between rated timecourse of affective states from filmed target participants and perceivers (viewers)

Accuracy is correlated with brain activity during video pressentation

Brunet-Gouet & Decety, 2006

Theory of Mind regions overlap with emotion processing regions

Is there an overlap between ToM and Empathy? Does the term term “cognitive empathy” (Preston and de Waal, 2002) represent a meaningful neurofunctional conceptWhat are the functions of STS, TPJ, OFC and mPFC?

mPFCanterior medialPFC

TPJtemporoparietal junction

STSSulcus temporalis superiorOFCLateral Orbitofrontal Cortex

Paradigm

A Paradigm:Distinction of perspective and affective contentNo immediately contagious affective contentRandomized stories/instructions

8.5 sec 8.5 sec 8.5 sec

Demands

difference?

- = +difference?

- = +

„Instruktion“ 32 stories

Design

6.5 sec

Nur für Bild 2 und 3 relevant!

- = +

- = +

Design (questions / stories randomised)

1st PP 3rd PP

( cognitive )

visuospatial

Affective

Nur für Bild 2 und 3 relevant!

- = +

- = +

Nur für Bild 2 und 3 relevant!

- = +

- = +

Nur für Bild 2 und 3 relevant!

- = +

- = +

Main effect of affective content:Activation of anteriorer parts of ToM network

Results

Main effect of 3rd Person PerspectiveActivation of posterior ToM Network, TPJ, FEF, Precuneus

Results

Results

Simple effectsV isuospatial; A ffective1. Person; 3. Person

InteraktionV isuospatial; A ffektiv1. Person; 3. Person

Results

Finally:„cognitive empathy“ can be renderered as a defined neurophysiological functional state, which is not „cold“ but rather linked to the activation of the amygdala.

Experimental psychopathology of ToM- and Empathy-functions

Impaired Inference on the mental states of others: in autism spectrum disorders (Baron-Cohen, 2001)in affective disorders (Inoue et al., 2006; Kerr et al., 2003)in schizophrenia (Brunet-Gouet and Decety, 2006; Walter et al., 2009) defined as an explicit target for psychotherapy (Bateman and Fonagy, 2008).

• Paranoid delusions associated mit Attributional Bias: Erklärung von aversiven Ereignissen durch den Einfluss anderer. Martin & Penn 2002

• Störung der mentalen Perspektivübernahme bei schizophrenen Patienten. Sprong et al. 2007, Bora et al. 2009

- = + - = +

Fühlt sich die Hauptperson besser, genauso oder schlechter als im Bild zuvor?

>

Sind mehr, gleichviele oder weniger lebende Wesen abgebildet als im Bild zuvor?

soziale Kognition

Störungen der selektiven sozialen Selbst-/Fremdreferenz

n=109 Gesunde

>>

Walter*, Schnell*, Erk* et al, 2010, Mol. Psychiatry

Genetically determinated functioanl impairment of selective Selbst-/Other-perspective taking as a mediator of schizophrenia risk?

Effect of a genetic Polymorphismu (rs1344706) associated with increased risk for schizophrenia during selective perspective taking

Main Effect

soziale Kognition

Experimental model of psychotherapyeffects on intersubjective functions in (chronic) Depression: Perceived functionality

An fMRI-Modell of learned helplessness in depression (Seligman 1978), preoperative causal thinking (McCullough 2000), derived from own experiences in CBASP practice…

Existential question :Does my behavior affect the affective state of others?

CD-patient: „I can‘t believe that it affects your mood if I tell you I was succesful in resolving the fight with my daughter !“

Basic ideas

S

Significant other /Traum

atic interpersonal experience

CBASP

Modify cognitiveschema

Interpersonal Discrimination/Perception of Functionality

SO

PatientTherapistSignificant other

S

R

C

We will improve the perception of interpersonal functionality!

Hmm, „perception of functionality“ … what am I supposed to do?

The fundamental question:

McCulloughBrain

Bandura 1978

„If I (O) do this (R), the other person (S) will do that (C) “

(with a probality of E‘ %)

StimulusOrganism

Reaction

Consequence

Behavioral Model

Hypotheses I (Basic Study) Continuous update of predictive models of social partners, enables affective self-regulation through prediction of their affective reactions

Hypotheses II (Clinical Trial CBASP vs Escitalopram) Update of predictive models of others is impaired in chronic depression

Hypotheses

I : Basic Study

Simulation of an occasional conversation

n=21 Healthy Subjects, fMRI, 3Tesla Siemens Trio, TR 2,07s

I Basic Study

Event related fMRI design

Positiver?

Happy hour! Taxes raised!

predictedReaction?

Happy hour! Taxes raised!

E´=E?

Is my model congruent with the reaction?

12 incongruent12 congruent

12 incongruent12 congruent

12 congruent12 congruent

response response

Equal number of happy and aversive reactions for every partner,i.e. no classical conditioning !!! but operand contingencies differ !!!

How does the brain detect differences in operand contigencies ?

I Basic Study

How reliable is this person? (Whom can I trust?)

I Basic Study

pre training post training post fMRI

Training fMRI

n=21 Healthy Subjects

I Basic Study

How reliable is this person? (Whom can I trust?)

-40

-30

-20

-10

0

10

20

30

40

50

60

70

1 2 3

100% 50%

-

>0.001 >0.025

Perceived functionality

**

Identification of contingent partner

Diff

eren

ce in

trus

t rati

ngs

[mm

]

PreTraining

PostTraining

PostfMRI

Difference [mm]?

*

12

3

I Basic Study

unpredictable > predictable Partner

n=21 Healthy Subjects

Effect of contingencies of partners

p>0.001 uncorrected

100%50%

(neutral expression)Theory of Mind –network dmPFC, TPJ, ant. Insula/IFG

Schnell et al. in press

I Basic Study

Regulatory effect of interpersonal response prediction on affective reactions?

I Basic Study

Amygdala

unpredicted > predicted angry response

Predictions about affective responses modulate activation of limbic regions

Prediction effect: Angry response of unpredictable partners

Display p<0.001 uncorrected

50%

I Basic Study

Right Amygdala p<0.05 FWE coorected for ROI /AAL

Summary I:

i.) Update of interpersonal model- contingency associations in social interaction is represented in specific neural network and behaviour

ii.) Predictions about affective responses modulate activation of the amygdala

I Basic Study

Clinical Trial: CBASP vs EscitalopramPreliminary findings

II CBASP vs Escitalopram

Dual centre study

Bonn: Henrik Walter (Berlin), Dieter Schoepf (Bonn), Knut Schnell (Heidelberg)

Freiburg: Elisabeth Schramm, Ingo Zobel (Freiburg)

Hypotheses II (Clinical Trial CBASP vs Escitalopram) Update of predictive models of others is impaired in chronic depression

II CBASP vs Escitalopram

Comparison ofn=14 (11/2010: 18 ) CD Patients (Mean Age 40,2 years; SD 11,49; 11f) Acute treatment completed: 8 CBASP, 6 ADn=12 controls (Mean Age 38,4 years, SD 11,9, 7f)

II CBASP vs Escitalopram

Week 8 Week 28Baseline

acute continuation

CBASP

CM+Escitalopram

fMRI fMRI

100% 50%

-

Impaired perceived functionality in CD

Identification of contingent partner

Difference [mm]?1

23 Δ 2-1

Difference in trust ratings Pre-Post Training [mm]

?

II CBASP vs Escitalopram

-40

-30

-20

-10

0

10

20

30

40

50

60

70

1

HCCD patients

*

Before treatment: Impaired discrimination of contingent social partners in CD

100% 50%

-

Improvement of perceived functionality

Difference [mm]?

?

-40-30-20-10

010203040506070

1 2

CBASP

AD

HCt0 t1 (12 sessions, 8 weeks)

Difference in trust ratings Pre-Post Training [mm]

*

Identification of contingent partner

II CBASP vs Escitalopram

Amygdala

Predictions about affective responses modulate activation of amygdala

p<0.001 uncorrected

unpredicted > predicted angry response

Affective prediction effect: Angry response of unpredictable partner

II CBASP vs Escitalopram

BASIC STUDY

P<0.005 uncorrected

N=8 CBASP, n=6 AD

Interaction of time x treatment in regulatory prediction effect in right Amygdala: Increase of regulatory effect in CBASP group

II CBASP vs Escitalopram

unpredicted > predicted angry response

Affective prediction effectAngry response of unpredictable partner

MNI [18 0 -15]

Summary

Distinct intersubjective functions can be rendered by neuroimaging

Impaired intersubjective functions contribute to the emergence of disorders like schizophrenia

Intersubjective functions are promising targets to dismantle the mechanisms of psychotherapy

Thank you !

In contrast to affective contagion, empathy is bound to the individualawareness that a specific emotion was primarily initiated in the otherperson (Hein and Singer, 2008).

In contrast to the restrictive definition of empathy, mentalizing isdefined by Frith & Frith as “the process by which we make inferencesabout mental states” (Frith and Frith, 2006b) and does not only includethe inference about another persons’ motivational states and beliefsbut also the immediate recognition and the cognitive inference aboutother persons’ emotional states.

Modulation des Mentalisierungs-Netzerkes durch die Amygdalae mittels emotionaler Signale und kognitiven Fokus eine fMRT-Studie

Durch den affektiven

Zustand eines anderen

Verusrsacht

selbst einen Affekt haben

Affektive Isomorphie

kausale Beziehung der Affekte

Explizit Repräsentiert

Motiviert sein zu prosozialem

Verhalten

Prototypisches Beispiel

MimikrieLächeln weil jemand anderes lächelt

Emotionale AnsteckungSich amüsieren, weil jemand lacht

Persönliches Leidensich unentspannt fühlen, weil jemand leidet

Affektive (hot) EmpathieSich traurig fühlen, weil jemand traurig ist

Kognitive (cold) Empathie= Affektive Theory of Mind / Kognitive Empathie

Schließen, das jemand anderes glücklich ist

MitleidMitleid haben weil jemand deprimiert ist

SympathieEmpathische Betroffenheit

Mitleid haben und helfen wollen, weil jemand deprimiert ist

Table 1: Overview over different concepts related to empathy

92

Paradigma

7.5 sec 7.5 sec 7.5 sec

Antwort?

- = +

10

GeschichtenAntwort?

- = +

„Fühlt sich die Hauptperson schlechter, gleich oder besser als auf dem vorherigen Bild?“

93

Hypothesen

Kategorielle Effekte

• Emotionale Signale > keine emotionale Signale:

• TPJ erhöhte Aktivität; Erhöhte Aktivität im rechten posterioren STS→ Story, Kausalität und Intention verständlicherGallagher HL et al. (2003)

• Erhöhte Aktivität in Temporallappen-Polen→ Angemessenes Verhalten deutlicher erkennbarGallagher HL et al. (2003)

• Erhöhte Amygdala-Aktivität→ Emotionaler Zustand u.A. an Gesichtsausdruck erkennbarMorris JS et al. (1998)

• Weniger Aktivität im PFC → Aufgabe leichter

94

Hypothesen

Konnektivität

• Emotionale Signale > keine emotionale Signale:

• Verstärkte Konnektivität Amygdalae mit ToM-Arealen

Effekte auf das vegetative Nervensystem

• Veränderte Hautleitfähigkeit (SCR)→ Efferenzen der Amygdalae zum vegetativen Nervensystem

95

Methoden

Probanden• N=22 psychisch gesunde, rechtshändige Probanden (13 m) • 23,73 Jahre (SD=3,06).

Daten Aquirierung• 3-Tesla Siemens Trio• 334 whole brain scans (funktioneller Lokalisator: 235 whole brain

scans)• TR =2070, TE =30, slice thickness =3.5 mm, matrix =64 x 64

Datenanalyse• SPM5 mit Matlab 7.1 und Matlab 7.6• 2nd level: One Sample T- Tests• SEM; PPI

96

Ergebnisse• TomFeel > SelfNum zeigt typische ToM-Regionen

→ Funktioneller Lokalisator des ToM-Netzwerkes

p < 0,001 (uncorr.)

p < 0,05 (FWE)

97

ErgebnisseFace > NoFace

• Erhöhte Aktivität: FFA, Haxby JV et al. (2002)Temporallappen-Pol (rechts) außerdem pSTS (rechts)

p < 0,05 (FDR)

98

ErgebnisseNoFace > Face

• erhöhte Aktivität in frontalen Bereichen → Größere kognitive Leistung nötig

• Anteriores Cingulum (Empathie)Singer T et al. (2004)

p < 0,001 (uncorr.)

99

Ergebnisse

Face > NoFace; parametrisch moduliert

• Zusätzliche Aktivierung in rechter Amygdala

p < 0,001 (uncorr.)

100

Ergebnisse

NoFace > Face; parametrisch moduliert• Aktivierung in okzipitalen Bereichen

p < 0,05 (FDR)

101

Ergebnisse

Effektive Konnektivität (SEM)• Erstellen eines Pfadmodells mittels CoCoMac und berechnen des „best fitting” Modells

102

ErgebnisseEffektive Konnektivität (SEM)• Erstellen eines Pfadmodells mittels CoCoMac und berechnen des „best fitting” Modells

103

ErgebnisseEffektive Konnektivität (SEM)• Erstellen eines Pfadmodells mittels CoCoMac und berechnen des „best fitting” Modells• T-Test über die Gruppe, ob sich Verbindungen von 0 unterscheiden

PPI

105

Ergebnisse

PPI• Rechte Amygdala zeigt veränderte Konnektivität

mit rechtem orbitofrontalem Cortex und linkem BA 10 in Abhängigkeit der Condition

p < 0,001 (uncorr.); k = 8 Voxel

PPI

• Rechte Amygdala zeigt veränderte Konnektivität mit rechtem orbitofrontalem Cortex und linkem BA 10 in Abhängigkeit der Condition

106

Ergebnisse

p < 0,001 (uncorr.); k = 8 Voxel

107

ErgebnissePPI

• Rechte Amygdala zeigt veränderte Konnektivität mit rechtem orbitofrontalem Cortex und linkem BA 10 in Abhängigkeit der Condition

p < 0,001 (uncorr.); k = 8 Voxel

108

ErgebnissePPI

• Rechte Amygdala zeigt veränderte Konnektivität mit rechtem orbitofrontalem Cortex und linkem BA 10 in Abhängigkeit der Condition

p < 0,001 (uncorr.); k = 8 Voxel

109

ErgebnissePPI

• Linke Amygdala zeigt veränderte Konnektivität mit linkem BA 10 und linkem ACC in Abhängigkeit der Condition

p < 0,001 (uncorr.); k = 5 Voxel

110

ErgebnisseVergleich der Reaktionszeiten bei Face und NoFace• Signifikant längere Reaktionszeit bei NoFace als bei Face

(p = 3,9866 * 10-4)

Einfluss der Condition auf SCR• Kein signifikanter Unterschied in der Höhe der SCR in Bezug auf die Condition (p = 0,1294)

111

Vielen Dank für die Aufmerksamkeit

Fragen?

Anmerkungen?

CBASP

Being caused by an other’s affective

state1

Being in anaffective

state oneself

Affective isomorphy

Explicit repre-

sentation of causal

affective relations2

Being motivated

for prosocial behavior

Prototypical example

MimicrySmiling because someone else is smiling

Emotional Contagion

Feeling amused, because others are laughing

Personal distressFeeling uneasy, because someone suffers

Affective (hot) Empathy

Feeling sad, because someone else is sad

Cognitive (cold) Empathy= Affective Theory of Mind

Inferring that someone feels happy

CompassionFeeling pity, because someone is depressed

SympathyEmpathic concern

Feeling pity and wanting to help, because someone is depressed and wanting to help

Table 1: Overview over different concepts related to empathy

Soziale Kognition: Versuch einer Schematisierung