1 Gade Neural circuits of emotions 2: Extended amygdala, insula, anterior cingulate gyrus, and others Anders Gade, Copenhagen University

2 Gade Limbic areas.. The limbic system is a concept in perpetual search for a definition Heimer et al., 2008, p.22

3 Gade Extended amygdala Anterior cingulate gyrus Orbital and ventromedial prefrontal cortex - - mPFC-amygdala connectivity

Gade The extended amygdala - A role in anxiety, addiction, and stress disorders

5 Gade Coronal section at the level of the anterior commissure Substantia innominata BSTLBSTLBSTLBSTL amyg amyg

6 Gade Yellow: The extended amygdala Coronal sections at four levels, from accumbens (A) to caudal amygdala (D) Red: Cholinergic cell groups

7 Gade The basal forebrain contains an extension of the basal ganglia, overlapping the cholinergic cell groups and the extended amygdala The extended amygdala (Cental nucleus, stria terminalis, bed nucleus, and other cell groups) Alain Dagher

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

9 Gade Yellow: The extended amygdala Coronal sections at four levels, from accumbens (A) to caudal amygdala (D)

10 Gade Gade, A. (2012) Angstens neuropsykologi, I Leth & Hoff Esbjørn (red.), Angst hos børn. Dansk Psykologisk Forlag (pp ) Academic Press, 2008

11 Gade Extended amygdala: role in anxiety - best reference Shown with fMRI in anticipatory anxiety in 3 studies: Straube et al., (2007). NeuroImage, 37, Somerville et al. (2010). Biol.Psychiatry, 68, Alvarez et al., (2011). NeuroImage, 55, #2625d,e,f New suggestion: Role of extended amygdala in the acute fear-enhancing effects of SSRIs: Ravinder et al., 2013

12 Gade Biol.Psychiatry, 68, low high anxiety ss.

13 Gade Biol.Psychiatry, 68, Conjunction analysis: linearly increasing response to greater threat + greater in more anxious subjects insula

14 Gade Insula

15 Gade Keysers et al., (2010) Nat.Rev.Neurosci., 11, # a590.. Somatosensation Proprioceptive,tactile/haptic, & pain (localizable) information (in four ’homuncu (in four ’homunculi’)

16 Gade Insula - interoception Craig (2002). How do you feel? Interoception: the sense of the physiological condition of the body. Nat.Rev.Neurosci., 3, Craig (2009). How do you feel – now? The anterior insula and human awareness. Nat.Rev. Neurosci., 10, # 2730a&b

17 Gade Insula Critchley et al. (2004). Nature Neuroscience, 7, #2733a Representation of autonomic and other bodily states and sensations (here heartbeat; normal subjects)

18 Gade Critchley et al. (2004). Nature Neuroscience, 7, #2733a

19 Gade Insula emotional aspects of pain … including perception of others’ pain (Singer et al., 2004) Conjunction analysis self / other

20 Gade Annu.Rev.Neurosci., 35, 1-23 (2012) #a413-1e Modulated by both personality characteristics and situational context … exemplified by pain

21 Gade Annu.Rev.Neurosci., 35, 1-23 (2012) #a413-1e Alexithymia – in both normal subjects and autism Ingroup vs. outgroup

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

Gade Explicit : pain or not ? Implicit: Right or left ? #2736a

24 Gade A) Meta-analysis of fMRI studies of pain empathy B) 2 x 3 patients with lesions in insula or ACC

25 Gade Baur et al. (2013), Biol. Psychiatry, 73, #1549d 32 normal subjects - ”wide dispersion on STAI”

26 Gade

27 Gade Baur et al. (2013), Biol. Psychiatry, 73, #1549d Theoretical model for amygdala-insula interaction in anxiety Blue: bottom-up ”salience” pathway; Read: feedback/interoceptive pathway Sensorisk information kropstilstand I Sensory information II Stimulus meaning III Increased attention a Current body state b adjustment.. autonomic feedback c Autonomic reaction

28 Gade Anterior cingulate cortex dorsal ventral / rostral caudal subgenual

29 Gade Anterior cingulate cortex Neurology: apathy (Ch. 14: Disorders of motivation and goal-directed behavior) Cognitive neuroscience and: neuroimaging: effort & control (Raichle et al., 1994) #b125aa Depression: subgenual/ventral ACC - small but hyperactive (Drevets, 1998) Bush, 2000: a cognitive and an emotional division Depression & anxiety: hypoactive dACC

30 Gade dACC - one, two, or many functions ? a)Detection & signaling need for adjustments in control b)Subjective experience of negative affect (pain, fear) c)Energizing behavior ”How does it feel when ACC is activated during a cognitive task” Rainville, 2002

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

Gade VBM brain volume in anxiety and depression Van Tol et al. (2010), Arch.Gen.Psychiatry, 67, #1032i MDD (N:68) MDD + anxiety (N:88) Anxiety without MDD (N:68) NC (N:65) Reduced volume in entire patient group vs. normal Ss

Gade VBM brain volume in anxiety and depression Van Tol et al. (2010), Arch.Gen.Psychiatry, 67, #1032i Depression with onset before age 18

34 Gade Nature of cingulate control …. Ridderinkhof et al. (2004). The role of the medial frontal cortex in cognitive control. Science, 306, #4680a Carter, Cohen et al.: conflict-control model fx Kerns et al., (2004) Science, 303, ) red blue green

35 Gade Nature of cingulate control …. Carter, Cohen et al.: conflict-control model fx Kerns et al., (2004) Science, 303, ) red blue green C: Congruent I: Incongruent iI: Incongruent following incongruent cI: Incongruent following congruent ACC conflict activation dlPFC activation in high adjustment trials

36 Gade Nature of cingulate control …. Good discussion: Mangun et al. (2009). Ch. 16 in Gazzaniga (Ed.) The cognitive neurosciences,4th ed. Carter, Cohen et al.: conflict-control model fx Kerns et al., (2004) Science, 303, ) #4684c C: Congruent I: Incongruent iI: Incongruent following incongruent cI: Incongruent following congruent

37 Gade Emotional face-word Stroop Etkin et al., 2010

38 Gade Emotional face-word Stroop Etkin et al., 2010 Rostral ACC: Also other forms of emotion regulation Am.J.Psychiatry, 167,

39 Gade Fear conditioning and extinction Milad, M. & Quirk, G. J. (2012). Fear extinction as a model for translational neuroscience: Ten years of progress. Annu. Rev. Psychol., 63,

40 Gade Tost & Meyer-Lindenberg, 2010 AG# T381a Interactions between amygdala and ACC /prefrontal cortex

Gade Pezawas et al., HTTLPR Statistical map – less grey matter volume in S-allele carriers

42 Gade NeuroImage :

43 Gade Cremers et al., (2010), NeuroImage, 49: AG# T027a

44 Gade Eluvathingal et al. (2006). Pediatrics, 117: Medial temporal / medial prefrontal connections: Uncinate fasciculus Diffusion tensor neuroimaging (tractography) Normal child Adopted from romanian orphanage

45 Gade Phan et al. (2009) Biol.Psychiatry, 66, Uncinate fasciculus in anxiety 30 patients with social anxiety + 30 NC: Decreased ”fractionel anisotropy”in uncinate f. near the orbitofrontal cortex Same findings in GAD Tromp et al. (2012) Arch.Gen.Psychiatry, 69, # 1547e

46 Gade Tromp et al. (2012) Arch.Gen.Psychiatry,69, # 1547e

47 Gade Tromp et al. (2012) Arch.Gen.Psychiatry,69, # 1547e Correlation with rACC-amygdala connectivity in implicit emotion regulation task (aversion anticipation)

48 Gade Extended amygdala Anterior cingulate gyrus Orbital and ventromedial prefrontal cortex - - mPFC-amygdala connectivity

49 Gade