Neuroanatomy of Emotion, Fear, and Anxiety

1. Neuroanatomy of Emotion, Fear, and Anxiety

2. Outline • Neuroanatomy of emotion • Critical conceptual, experimental design, and interpretation issues in neuroimaging research • Fear and anxiety • Anxiety disorders • Anxiety-related processes in healthy volunteers and patients • Brain functional activation – fMRI • Brain functional connectivity – fMRI • Brain structural connectivity – diffusion tensor imaging (DTI) • Brain morphometry – anatomical MRI • Next steps for neuroscience research on anxiety

3. What is Emotion?

4. Key Brain Areas for Emotion Dagleish (2004) Nat. Rev. Neurosci.

5. Key Brain Areas for Emotion

6. Neuroanatomy of EmotionKey Brain Areas and Their Affect-related Functions Dorsolateral PFC: Approach-related positive affect (left) Orbitofrontal cortex: Affective evaluation; decoding punishment and reward value Withdrawal-related negative affect; threat- related vigilance (right) Insula: Representation of the body’s internal state; interoception Anterior cingulate cortex (ACC): Top-down modulation; conflict detection Amygdala: Vigilance for motivationally salient events; threat detection; emotional memory Hippocampus: Declarative memory; spatial navigation; contextual fear Insula and ACC: Integration of sensory, affective, cognitive, and autonomic processing

7. Neuroanatomy of EmotionKey Brain Areas and Their Affect-related Functions Nucleus Accumbens: Reward processing; positive emotion; salience detection

8. DLPFC Insula Visual Cortex Thalamus ACC OFC Amygdala Hippocampus

9. Neuroimaging of Anxiety and DepressionCritical Conceptual, Design, and Interpretation Issues • Emotion perception ≠ emotion experience ≠ emotion production • Conditions and stimuli must be appropriately matched (e.g., physical characteristics) • Asymmetries can be concluded only on basis of appropriate statistical tests

10. Hariri et al. (2002) Science

11. Hariri et al. (2002) Science

12. Hariri et al. (2002) Science

13. Thomas et al. (2001) Arch. Gen, Psychiatry

14. Neuroimaging of Anxiety and DepressionCritical Conceptual, Design, and Interpretation Issues • Emotion perception ≠ emotion experience ≠ emotion production • Conditions and stimuli must be appropriately matched (e.g., physical characteristics) • Asymmetries can be concluded only on basis of appropriate statistical tests • Go beyond merely documenting which brain areas show group differences in functional activation • Associations with brain structural differences, brain connectivity, and behavior • Develop a paradigm relevant to anxiety/depression symptoms • Ground the paradigm in basic neuroscience research with healthy populations • Replication

15. What is Fear? What is Anxiety?

16. What is Anxiety? An emotional state characterized by anticipatory affective, cognitive, and behavioral changes in response to uncertainty about potential future threat Uncertainty and Anticipation Model of Anxiety (UAMA) Grupe & Nitschke (2013) Nature Rev. Neurosci

17. Uncertainty and Anticipation Model of AnxietyFive Key Psychological Processes • A central feature of all anxiety disorders is aberrant and excessive anticipatory responding under conditions of threat uncertainty • This model identifies five processes involved in adaptive responses to threat uncertainty that function maladaptively in anxiety • Inflated estimates of threat cost and probability • Increased threat attention and hypervigilance • Deficient safety learning • Behavioral and cognitive avoidance • Heightened reactivity to threat uncertainty Grupe & Nitschke (2013) Nature Rev. Neurosci.

18. Uncertainty and Anticipation Model of AnxietyBrain Circuitry of Five Key Psychological Processes Grupe & Nitschke (2013) Nature Rev. Neurosci.

19. Neuroanatomy of Anxiety DisordersKey Brain Areas Dorsolateral prefontal cortex (dlPFC) Insula Anterior cingulate cortex (ACC) Amygdala Hippocampus Orbitofrontal cortex (OFC) Ventromedial prefrontal cortex (vmPFC)

20. Imaging Research on Anxiety DisordersSummary • Neural responses to anxiety-provoking stimuli (symptom provocation paradigms) • Social (SAD) • Phobogenic (specific phobia) • Traumatic (PTSD) • Obsessional (OCD) • Panic-inducing (panic disorder) • Worry (GAD) • Neural responses to generic emotion stimuli • Emotional faces • IAPS slides

21. Imaging Research on Anxiety DisordersSummary Etkin & Wager (2007) Am. J. Psychiatry

22. Imaging Research on Anxiety DisordersSummary • Neural responses to anxiety-provoking stimuli (symptom provocation paradigms) • Social (SAD) • Phobogenic (specific phobia) • Traumatic (PTSD) • Obsessional (OCD) • Panic-inducing (panic disorder) • Worry (GAD) • Neural responses to generic emotion stimuli • Emotional faces • IAPS slides • Does this get at heart of anxiety and what is debilitating about it?

23. Imaging Research on Anxiety DisordersPathophysiology of Anxiety • Understanding anxiety and why it can be debilitating • Maladaptive associations between fear responses and specific stimuli/situations that are not inherently dangerous • Develop new associations between those stimuli/situations and safety – then strengthen them through practice (e.g., exposure-based psychotherapy) • Anticipation about bad things that might happen in the future • Target such anticipatory processes to directly diminish anxiety (e.g., cognitive strategies that also require practice)

24. Emotional Anticipation ParadigmEvent-related fMRI 2.5-s delay 4.5-s delay 2.5-s delay 4.5-s delay 0:00 0:19 0:38 0:57 . . . . . Nitschke et al. (2006) NeuroImage

34. Neural Circuitry of Anticipating Aversion Anticipation of and Response to Aversive compared to Neutral Pictures Amygdala Anterior Cingulate Right Dorsolateral PFC Hippocampus Insula Orbitofrontal Cortex n = 21 Nitschke et al. (2006) NeuroImage

35. Neural Circuitry of Anticipating Aversion Anticipatory Functions of Brain Areas Implicated • Anticipation of aversion recruits the same brain areas as exposure to aversion • Amygdala (threat detection, emotional memory) – Mackiewicz et al. (2006) Proc. Natl. Acad. Sci. • Hippocampus (declarative memory, contextual fear) – ibid. • Insula (representation of the body’s internal state, interoception) • ACC (top-down modulation) – Sarinopoulos et al. (2010) Cerebral Cortex • Right Dorsolateral PFC (threat-related vigilance, withdrawal-related negative affect) – Nitschke et al. (2006) NeuroImage • OFC (affective evaluation, positive and negative affect) – ibid. • Are there anomalies in this circuitry in anxiety disorders? • Anticipation about negative outcomes is central to the debilitating consequences seen in anxiety disorders

36. Group Differences in Amygdala GAD Patients Show Elevated Anticipatory Activity R n = 26 Nitschke et al. (2009) Am. J. Psychiatry

37. ACC Activity and Treatment Response Pretreatment Anticipatory ACC Activity Predicts Response to Effexor r = -0.82 r = -0.84 n = 14 Nitschke et al. (2009) Am. J. Psychiatry

38. Diffusion Tensor Imaging (DTI) Key Structural Pathways for GAD • Are there white matter connections corresponding to the anticipatory abnormalities observed in GAD? • The vmPFC and ACC have been implicated in top-down modulation of the amygdala and other regulatory functions • The uncinate fasciculus is a major white matter tract that connects vmPFC/ACC areas to the amygdala

39. Uncinate Fasciculus DTI-based Tractography

40. Group Differences in Uncinate FasciculusGAD Patients Show Reduced Structural Connectivity n = 88 Tromp et al. (2012) Arch. Gen. Psychiatry

41. Uncinate Fasciculus Structural ConnectivityAssociations with Anticipatory Amygdala-ACC Functional Connectivity n = 88 Tromp et al. (2012) Arch. Gen. Psychiatry

42. Group Differences in Functional Connectivity GAD Patients Show Reduced ACC-Amygdala Negative Coupling n = 88 Tromp et al. (2012) Arch. Gen. Psychiatry

43. Group Differences in Orbitofrontal CortexGAD Patients Show Reduced Volume L y=56 n = 88 Hernandez et al. (in prep.)

47. Group Differences in InsulaGroup X Stimulus Interaction for Anticipation Period y = 21 R Kerr et al. (in prep.)

48. Group Differences in Anterior CingulateGroup X Stimulus Interaction for Anticipation Period p.001 Kerr et al. (in prep.)

49. Anticipation and Anxiety DisordersConclusions and Clinical Implications • Anticipatory dysfunction is a central feature of anxiety disorders that demands our attention in the lab and the clinic • Role in pathophysiology • Promise as prognostic tool • Potential as therapeutic target • Treatments targeting anticipatory processes in identified brain regions may reduce anxiety, negative affect, and suffering • Psychotherapy, medication, biofeedback, transcranial magnetic stimulation (TMS), deep brain stimulation, cortical stimulation • Regulatory mechanisms are likely compromised in anxiety disorders • Role in pathophysiology • Potential as therapeutic target • Teaching effective regulation skills for overcoming anticipatory dysfunction, worry, and other symptoms

50. Neuroanatomy of Anxiety DisordersFuture Directions • Future directions in the field • Identification of variables and patient groupings showing promise for alternative nosology of anxiety-related pathology • Computational classifier approach using decision tree methodology, cluster analysis, and support vector machines • Identification of variables showing promise for guiding treatment decisions • MRI scans as component of intake screening