1 Gade Emotions and limbic structures 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

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

Gade Saper & Chelimsky, 1984 #3115b Nissl- and histochemical staining for acetylcholinesterase Cholinergic cell groups of the basal forebrain

Gade Saper & Chelimsky, 1984 #3115b

9 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)

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

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

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

13 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

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

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

16 Gade Insula

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

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

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

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

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

22 Gade Eisenberger (2012), Nat.Rev.Neurosci., 13, #a413-4f

23 Gade Shared representations: physical and social pain: Eisenberger (2012), Nat.Rev.Neurosci., 13, #a413-4f

24 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

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

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

27 Gade Science, 315, #7094a

28 Gade Anterior cingulate cortex dorsal ventral / rostral caudal subgenual

29 Gade Anterior cingulate cortex Neurology: apathy (Ch. 14: Disturbances in motivation and goal-directed behavior) Cognitive neuroscience and: neuroimaging: effort & control (Raichle et al., 1994) #b125aa ACC/mPFC: Motivation & hierarchy ((Koechlin … 2009) #a171b 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,

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

41 Gade NeuroImage :

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

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

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 orbito- frontal cortex

46 Gade Hippocampus - optional

47 Gade Papez’ circuit Hippocampus

48 Gade MacLean - Gray - Sapolsky

49 Gade Design: 17 PTSD and 23 non-PTSD twins (monozygotic) Vietnam veterans unexposed twins PTSD non-PTSD PTSD non-PTSD Hippocampus difference a) replication b) neurotoxicity c) genetic predisposition (”vulnerability factor”) predisposition (”vulnerability factor”) AG #1575a 2002

50 Gade Gilbertson et al., 2002, Nat.Neurosci., 5, Correlations between hippocampal volume and PTSD severity Twins with PTSD Unexposed twins (PTSD severity is that of the twin) Conclusion: Predisposing factor !

51 Gade Gilbertson et al., 2002, Nat.Neurosci., 5,

52 Gade Cerebral activation (PET) in fear conditoining and extinction in PTSD Bremner et al., 2005 #1587f Increased amygdala activation in conditioning (control session: upaired CS and US; separate day); PTSD minus controls Decreased cingulate (or vmPFC) activation in extinction

53 Gade Felmingham et al., (2007), Psychol.Sci., 18: #1597a CBT (8 sessions with imaged exposure and cognitive restructuring). fMRI (faces: fear minus neutral) before and after – correlation with improvement Gyrus cingularis ant. Amygdala

54 Gade Exposure therapy Edna Foa Time Magazine 2010 The 100 most influential people in the world

55 Gade