Neuroanatomy of Emotion Fear and Anxiety Outline Neuroanatomy

Neuroanatomy of Emotion, Fear, and Anxiety

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

What is Emotion?

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

Key Brain Areas for Emotion

Neuroanatomy of Emotion Key Brain Areas and Their Affect-related Functions Dorsolateral PFC: Approach-related Orbitofrontal cortex: Affective evaluation; decoding punishment and reward value positive affect (left) Withdrawal-related negative affect; threatrelated 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: Insula and ACC: Declarative memory; spatial Integration of sensory, affective, navigation; contextual fear cognitive, and autonomic processing

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

DLPFC Insula Thalamus ACC OFC Amygdala Hippocampus Visual Cortex

Neuroimaging of Anxiety and Depression Critical 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

Hariri et al. (2002) Science

Hariri et al. (2002) Science

Hariri et al. (2002) Science

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

Neuroimaging of Anxiety and Depression Critical 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 Ø 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

What is Fear? What is Anxiety?

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

Uncertainty and Anticipation Model of Anxiety Five 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 1. Inflated estimates of threat cost and probability 2. Increased threat attention and hypervigilance 3. Deficient safety learning 4. Behavioral and cognitive avoidance 5. Heightened reactivity to threat uncertainty Grupe & Nitschke (2013) Nature Rev. Neurosci.

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

Neuroanatomy of Anxiety Disorders Key Brain Areas Dorsolateral prefontal cortex (dl. PFC) Orbitofrontal cortex (OFC) Ventromedial prefrontal cortex (vm. PFC) Insula Anterior cingulate cortex (ACC) Amygdala Hippocampus

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

Imaging Research on Anxiety Disorders Summary Etkin & Wager (2007) Am. J. Psychiatry

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

Imaging Research on Anxiety Disorders Pathophysiology of Anxiety § Understanding anxiety and why it can be debilitating 1. Maladaptive associations between fear responses and specific stimuli/situations that are not inherently dangerous ² Develop new associations between those stimuli/situations and safety – then strengthen them through practice (e. g. , exposurebased psychotherapy) 2. Anticipation about bad things that might happen in the future ² Target such anticipatory processes to directly diminish anxiety (e. g. , cognitive strategies that also require practice)

Emotional Anticipation Paradigm Event-related f. MRI 2. 5 -s delay 0: 00 4. 5 -s delay 0: 19 4. 5 -s delay 0: 38 2. 5 -s delay 0: 57 . . . Nitschke et al. (2006) Neuro. Image

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) Neuro. Image

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

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

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

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

Uncinate Fasciculus DTI-based Tractography

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

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

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

Group Differences in Orbitofrontal Cortex GAD Patients Show Reduced Volume L y=5 6 n = 88 Hernandez et al. (in prep. )

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

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

Anticipation and Anxiety Disorders Conclusions and Clinical Implications § Anticipatory dysfunction is a central feature of anxiety disorders that demands our attention in the lab and the clinic Ø Role in pathophysiology Ø Promise as prognostic tool Ø Potential as therapeutic target ² 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 Ø Role in pathophysiology Ø Potential as therapeutic target ² Teaching effective regulation skills for overcoming anticipatory dysfunction, worry, and other symptoms

Neuroanatomy of Anxiety Disorders Future Directions § Future directions in the field 1. Identification of variables and patient groupings showing promise for alternative nosology of anxiety-related pathology ² Computational classifier approach using decision tree methodology, cluster analysis, and support vector machines 2. Identification of variables showing promise for guiding treatment decisions ² MRI scans as component of intake screening

Neuroanatomy of Anxiety Disorders Conclusions § Anxiety cannot be reduced to abnormalities in a single brain § region or system Understanding the neuroanatomy of anxiety disorders and their treatment will come through research simultaneously examining multiple domains Ø Genes, brain anatomy and physiology (morphology, volume, activation, structural and functional connectivity, chemistry), peripheral psychophysiology, behavior, interpersonal relations, environmental factors, cultural and socioeconomic influences § Appreciate complexity of the brain and of anxiety disorders Ø Are we on the right track in our current conceptualization and labeling of anxiety pathology? § Careful not to be wowed by pretty pictures, even in Science, Nature, JAMA, and American Journal Ø Be good consumers of neuroimaging research