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Neural circuits of emotions 2:Neural circuits of emotions 2:Extended amygdala, insula, anterior Extended amygdala, insula, anterior

cingulate gyrus, and otherscingulate gyrus, and others

Anders Gade, Copenhagen University

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Limbic areasLimbic areas

.. .. The limbic system is a The limbic system is a concept in perpetual searchconcept in perpetual searchfor a definitionfor a definition Heimer et al., 2008, p.22

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Extended amygdalaExtended amygdala

AnteriorAnteriorcingulatecingulategyrusgyrus

Orbital and ventromedialOrbital and ventromedialprefrontal cortex - -prefrontal cortex - -mPFC-amygdala mPFC-amygdala connectivityconnectivity

Gade

The The extended extended amygdalaamygdala

- A role in anxiety, - A role in anxiety, addiction, and addiction, and

stress disorders stress disorders

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Coronal section at the level of the anterior commissureCoronal section at the level of the anterior commissure

Substantia Substantia innominatainnominata

BBSSTTLL

amygamyg

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Yellow: Yellow: The extended amygdalaThe extended amygdala

Coronal sectionsCoronal sectionsat four levels, at four levels, from accumbens from accumbens (A) to caudal (A) to caudal amygdala (D)amygdala (D)

Red: Cholinergic cell groups

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The basal forebrain contains an extension of the basal ganglia,The basal forebrain contains an extension of the basal ganglia,overlapping the cholinergic cell groups and the extended amygdalaoverlapping the cholinergic cell groups and the extended amygdala

The extended amygdalaThe extended amygdala(Cental nucleus, stria terminalis,(Cental nucleus, stria terminalis,

bed nucleus, and other cell groups)bed nucleus, and other cell groups)

Alain Dagher

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Extended amygdalaExtended amygdala

Extended amygdala: Autoradiography of amino Extended amygdala: Autoradiography of amino acid transport after injection in the central nucleus acid transport after injection in the central nucleus (Ce) of the amygdala(Ce) of the amygdala

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Yellow: Yellow: The extendedThe extendedamygdalaamygdala

Coronal sectionsCoronal sectionsat four levels, at four levels, from accumbens from accumbens (A) to caudal (A) to caudal amygdala (D)amygdala (D)

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Gade, A. (2012)Gade, A. (2012)Angstens neuropsykologi,Angstens neuropsykologi,I Leth & Hoff Esbjørn I Leth & Hoff Esbjørn (red.), (red.), Angst hos børnAngst hos børn. . Dansk Psykologisk Dansk Psykologisk Forlag (pp.45-108)Forlag (pp.45-108)

Academic Press, 2008Academic Press, 2008

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Extended amygdala: role in anxiety - best referenceExtended amygdala: role in anxiety - best reference

Shown with fMRI in anticipatory anxiety in 3 studies:Shown with fMRI in anticipatory anxiety in 3 studies:Straube et al., (2007). Straube et al., (2007). NeuroImage, 37NeuroImage, 37, 1427-36, 1427-36Somerville et al. (2010). Somerville et al. (2010). Biol.Psychiatry, 68Biol.Psychiatry, 68, 416-424, 416-424Alvarez et al., (2011). Alvarez et al., (2011). NeuroImage, 55NeuroImage, 55, 389-400, 389-400#2625d,e,f#2625d,e,f

New suggestion: Role of extended amygdala in the acute New suggestion: Role of extended amygdala in the acute fear-enhancing effects of SSRIs: fear-enhancing effects of SSRIs: Ravinder et al., 2013Ravinder et al., 2013

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Biol.Psychiatry, 68Biol.Psychiatry, 68, 416-424, 416-424

Biol.Psychiatry, 68Biol.Psychiatry, 68, 416-424, 416-424

low highanxiety ss.

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Biol.Psychiatry, 68Biol.Psychiatry, 68, 416-424, 416-424

Conjunction analysis: linearly increasing responseConjunction analysis: linearly increasing responseto greater threat + greater in more anxious subjectsto greater threat + greater in more anxious subjects

insulainsula

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InsulaInsula

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SomatosensationSomatosensation

Proprioceptive,Proprioceptive,tactile/haptic,tactile/haptic,& pain & pain (localizable) (localizable)

informationinformation

(in four ’homuncu(in four ’homunculi’)

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Insula - interoceptionInsula - interoceptionCraig (2002). How do you feel?Interoception: the sense of thephysiological condition of the body. Nat.Rev.Neurosci., 3, 655-666

Craig (2009). How do you feel – now? The anterior insula and human awareness. Nat.Rev.Neurosci., 10, 59-70

# 2730a&b

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InsulaInsula

Critchley et al. (2004). Critchley et al. (2004). Nature Neuroscience, 7,Nature Neuroscience, 7, 189-195 189-195#2733a#2733a

RepresentationRepresentationof autonomic of autonomic and other and other bodily statesbodily statesand sensationsand sensations(here heartbeat;(here heartbeat;normal subjects)normal subjects)

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GadeCritchley et al. (2004). Critchley et al. (2004). Nature Neuroscience, 7,Nature Neuroscience, 7, 189-195 189-195#2733a#2733a

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InsulaInsula

emotional aspectsemotional aspectsof painof pain

… … including perception of others’ pain including perception of others’ pain (Singer et al., 2004)(Singer et al., 2004)

ConjunctionConjunctionanalysisanalysisself / otherself / other

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Annu.Rev.Neurosci., 35, 1-23 (2012) #a413-

1e

Modulated by both personality characteristicsModulated by both personality characteristicsand situational contextand situational context

… … exemplified by painexemplified by pain

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Annu.Rev.Neurosci., 35, 1-23 (2012) #a413-1e

Alexithymia – in both Alexithymia – in both normal subjects and normal subjects and autismautism

IngroupIngroupvs.vs.outgroupoutgroup

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Annu.Rev.Neurosci., 35, 1-23 (2012) #a413-1e

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Explicit :Explicit :pain or not ?pain or not ?

Implicit:Implicit:Right or left ?Right or left ?

#2736a

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A) Meta-analysis of fMRI studies of pain empathyB) 2 x 3 patients with lesions in insula or ACC

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Baur et al. (2013), Biol. Psychiatry, 73, 85-92#1549d

32 normal subjects - 32 normal subjects - ”wide dispersion on STAI””wide dispersion on STAI”

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Baur et al. (2013), Biol. Psychiatry, 73, 85-92#1549d

Theoretical model for amygdala-insula interaction in anxietyBlue: bottom-up ”salience” pathway; Read: feedback/interoceptive pathway

Sensoriskinformation

kropstilstandISensory

information

IIStimulus meaning

IIIIncreased attention

aCurrent

body state

badjustment ..autonomic feedback

cAutonomic

reaction

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Anterior cingulate cortexAnterior cingulate cortex

dorsal

ventral /

rostral

caudal

subgenual

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Anterior cingulate cortexAnterior cingulate cortexNeurology: apathyNeurology: apathy(Ch. 14: Disorders of motivation and (Ch. 14: Disorders of motivation and goal-directed behavior)goal-directed behavior)

Cognitive neuroscience and: Cognitive neuroscience and: neuroimaging: effort & neuroimaging: effort & control control (Raichle et al., 1994) (Raichle et al., 1994) #b125aa#b125aa

Depression: subgenual/ventral ACCDepression: subgenual/ventral ACC - small but hyperactive - small but hyperactive (Drevets, 1998)(Drevets, 1998)

Bush, 2000Bush, 2000: a cognitive and : a cognitive and an emotional divisionan emotional divisionDepression & anxiety: hypoactive dACCDepression & anxiety: hypoactive dACC

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dACC - one, two, or many functions ?dACC - one, two, or many functions ?

a)a)Detection & signaling need for adjustments in controlDetection & signaling need for adjustments in controlb)b)Subjective experience of negative affect (pain, fear)Subjective experience of negative affect (pain, fear)c)c)Energizing behaviorEnergizing behavior

””How does it feel when ACC is activated How does it feel when ACC is activated during a cognitive task”during a cognitive task”

Rainville, 2002Rainville, 2002

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Spunt et al., (2012). The phenomenology of errorSpunt et al., (2012). The phenomenology of errorprocessing: The dorsal ACC response to stop-signal processing: The dorsal ACC response to stop-signal errors tracks reports of negative affect. errors tracks reports of negative affect. J.Cogn.Neurosci., 24J.Cogn.Neurosci., 24, 1753-65 , 1753-65 #4685e#4685e

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VBM brain volume in anxiety VBM brain volume in anxiety and depressionand depression

Van Tol et al. (2010), Van Tol et al. (2010), Arch.Gen.Psychiatry, 67Arch.Gen.Psychiatry, 67, 1002-11, 1002-11#1032i#1032i

MDD (N:68)MDD (N:68)

MDD + anxiety MDD + anxiety (N:88)(N:88)

Anxiety without Anxiety without MDD (N:68)MDD (N:68)

NC (N:65)NC (N:65)

Reducedvolume in entirepatientgroup vs.normal Ss

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VBM brain volume in anxiety VBM brain volume in anxiety and depressionand depression

Van Tol et al. (2010), Van Tol et al. (2010), Arch.Gen.Psychiatry, 67Arch.Gen.Psychiatry, 67, 1002-11, 1002-11#1032i#1032i

Depression Depression with onset with onset before age 18 before age 18

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Nature of cingulate control ….Nature of cingulate control ….

Ridderinkhof et al. (2004). The role of the medialfrontal cortex in cognitive control. Science, 306, 443-447 #4680a

Carter, Cohen et al.: conflict-control modelfx Kerns et al., (2004) Science, 303, 1023-1026)

redblue

green

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Nature of cingulate control ….Nature of cingulate control ….

Carter, Cohen et al.: conflict-control modelfx Kerns et al., (2004) Science, 303, 1023-1026)

redblue

green

CC: : CongruentCongruent

II: : IncongruentIncongruent

iIiI: : Incongruent following incongruentIncongruent following incongruent

cIcI: : Incongruent following congruentIncongruent following congruent

ACC conflictACC conflictactivationactivation

dlPFC activation indlPFC activation inhigh adjustment trialshigh adjustment trials

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Nature of cingulate control ….Nature of cingulate control ….

Good discussion:Good discussion:Mangun et al. (2009). Ch. 16Mangun et al. (2009). Ch. 16in Gazzaniga (Ed.) The in Gazzaniga (Ed.) The cognitive cognitive neurosciences,4th ed.neurosciences,4th ed.

Carter, Cohen et al.: conflict-control modelfx Kerns et al., (2004) Science, 303, 1023-1026) #4684c

CC: : CongruentCongruent

II: : IncongruentIncongruent

iIiI: : Incongruent following incongruentIncongruent following incongruent

cIcI: : Incongruent following congruentIncongruent following congruent

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Emotional face-word StroopEmotional face-word Stroop

Etkin et al., 2010Etkin et al., 2010

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Emotional face-word StroopEmotional face-word Stroop

Etkin et al., 2010Etkin et al., 2010

Rostral ACC:Rostral ACC:Also other Also other forms of forms of emotion emotion regulationregulation

Am.J.Psychiatry, 167, Am.J.Psychiatry, 167, 545-554545-554

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Fear conditioning and extinctionFear conditioning and extinction

Milad, M. & Quirk, G. J. (2012). Fear extinction as a model for translational neuroscience: Ten yearsof progress. Annu. Rev. Psychol., 63, 129-151

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Tost & Meyer-Lindenberg, 2010 Tost & Meyer-Lindenberg, 2010 AG# T381aAG# T381a

Interactions between amygdala and Interactions between amygdala and ACC /prefrontal cortexACC /prefrontal cortex

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Pezawas et al., 2005Pezawas et al., 2005

5HTTLPR5HTTLPR

Statistical map –Statistical map –less grey matterless grey mattervolume in volume in S-allele carriersS-allele carriers

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NeuroImageNeuroImage2010201049: 963-97049: 963-970

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Cremers et al., (2010), Cremers et al., (2010), NeuroImage, 49NeuroImage, 49: 963-970: 963-970AG# T027aAG# T027a

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Eluvathingal et al. (2006). Eluvathingal et al. (2006). Pediatrics, 117Pediatrics, 117: 2093-2100: 2093-2100

Medial temporal / medialMedial temporal / medial prefrontal connections: prefrontal connections: Uncinate fasciculusUncinate fasciculus

Diffusion tensorDiffusion tensorneuroimagingneuroimaging(tractography)(tractography)

Normal childNormal child

Adopted fromAdopted fromromanian romanian orphanageorphanage

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Phan et al. (2009) Phan et al. (2009) Biol.Psychiatry, Biol.Psychiatry, 6666, 691-694, 691-694

Uncinate fasciculus in anxietyUncinate fasciculus in anxiety

30 30 patientspatientswith with social social anxiety anxiety + 30 + 30 NC:NC:

Decreased ”fractionelDecreased ”fractionelanisotropy”in uncinate f.anisotropy”in uncinate f.near the orbitofrontal cortexnear the orbitofrontal cortex

Same findings in GADSame findings in GAD

Tromp et al. (2012)Tromp et al. (2012)Arch.Gen.Psychiatry,Arch.Gen.Psychiatry,6969, 925-934, 925-934# 1547e# 1547e

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Tromp et al. (2012) Tromp et al. (2012) Arch.Gen.Psychiatry,69Arch.Gen.Psychiatry,69, , 925-934925-934# 1547e# 1547e

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GadeTromp et al. (2012) Tromp et al. (2012) Arch.Gen.Psychiatry,69Arch.Gen.Psychiatry,69, 925-934, 925-934# 1547e# 1547e

Correlation with rACC-amygdala connectivity Correlation with rACC-amygdala connectivity in implicit emotion regulation task in implicit emotion regulation task (aversion anticipation)(aversion anticipation)

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Extended amygdalaExtended amygdala

AnteriorAnteriorcingulatecingulategyrusgyrus

Orbital and ventromedialOrbital and ventromedialprefrontal cortex - -prefrontal cortex - -mPFC-amygdala mPFC-amygdala connectivityconnectivity

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