May 2023 The Nature and Neurobiology of Negative Affect: States, Traits, & Disorders

Presented by: Professor Alex Shackman, University of Maryland

May 21, 2023

 Welcome! In this multidisciplinary 3-hour workshop, we will explore the current state of our scientific understanding of negative emotional states and traits, their roots in the brain, and their relevance to psychiatric disease. A major focus of the workshop will be on fear- and anxiety-related states and traits, and their relevance to internalizing illness.

Emotional states, traits, and disorders reflect bidirectional interactions between the brain and psychosocial experience. Understanding the emotional brain requires a deep understanding of behavior, ethology, and emotion theory. Conversely, neurobiology has provided unique insights into the nature of the emotional mind—insights that cannot be obtained using ratings or other behavioral measures. In short, the psychology and biology of emotion are interdependent, and we cannot make much progress in one without the other. Accordingly, in this workshop we will delve deeply into both areas and explore their relevance to anxiety disorders and depression.

What I Want for You …

• Be Engaged. Be a hunter of information: seek out what is interesting and useful to you.
• Be Skeptical. Critically consider the claims. Decide for yourself whether you think it’s true, and what it means for theory or practice. Just because something is published, doesn’t mean it’s true. Even if the approach is solid, the claims are often over-simplified or over-sold!
• Be Heard. Speak up and share your ideas—even in moments where it feels scary or pointless. Be prepared to ask questions and participate in discussions. There are many opportunities for us to learn from one another. Learning can stem from sharing knowledge or from asking questions. More often than not, many of your colleagues will be wrestling with the same question. Help them by asking.

 Enjoy! Have a positive experience! Let me know early and directly if you are encountering any trouble or barriers. I’m excited to have you aboard and want you to get the most out of this opportunity to learn more about the science of negative affect!

 General Learning Objectives

At the end of this workshop, you will be able to …

• Describe the nature of neuroticism/negative emotionality (N/NE), with a focus on adult personality

• Explain the nature, epidemiology, and public health consequences of the internalizing disorders

• Understand the relevance of N/NE to the development of internalizing illness, with a focus on David Barlow’s transdiagnostic conceptual framework

• Describe the relevance of the amygdala to adaptive and maladaptive negative affect  

Overview of the Learning Modules

Module 0. A Brief Introduction

Module 1. Neuroticism/Negative Emotionality (N/NE) and the Emotional Disorders

Individuals—whether that be human adults, children, or even monkeys—differ in their propensity to experience and express negative emotions. What role does negative affect play in the development of anxiety disorders and depression (often collectively dubbed the ‘emotional disorders’ or ‘internalizing spectrum’)? In this wide-ranging module, we will explore the epidemiology of the emotional disorders, briefly review diagnostic criteria, and drill into prospective-longitudinal evidence. A major portion of the module will be devoted to David Barlow’s integrative model of N/NE and the emotional disorders, which has important implications for understanding the etiology and the nosology of mood and anxiety disorders, and serves to reinforce recent efforts focused on transdiagnostic phenomena, including the National Institute of Mental Health’s Research Domain Criteria (RDoC) initiative and the Hierarchical Taxonomy of Psychopathology (HiTOP) framework. We will touch on work by Roman Kotov, Lee Anna Clark, David Watson, Hans Ormel, Bertus Jeronimus, Randy Auerbach, the Global Burden of Disease consortium, and many others. 

Module 2. The Neurobiology of Negative Affect: Focus on the Amygdala

The neural systems underlying fear and anxiety are complex and distributed across a number of brain regions. In this module, we will explore work to understand the most intensively scrutinized of these regions, the amygdala. The major focus of this module will be on basic science perspectives, including pioneering work in rats by Joe LeDoux, Mike Davis, and the Blanchards; recent perturbation and imaging studies in rodents and monkeys; as well as imaging, lesion, and microstimulation research in humans. A major focus of the module will be on the fascinating case of Patient S.M., a woman with selective damage to the amygdala. In the final section of this module, we will briefly explore the most important implications of this body of research for understanding emotional disorders. We will touch on work by Alex Shackman, Andrew Fox, Ned Kalin, Justin Feinstein, Ralph Adolphs, Dan Tranel, Antoine Bechara, Hannah and Tony Damasio, Cory Inman, Kate McLaughlin, Johnna Swartz, Ahmad Hariri, Martin Paulus, and Murray Stein. 

Optional Readings

Module 1. Neuroticism/Negative Emotionality (N/NE) and the Emotional Disorders

• Hur … & Shackman Prog Brain Res 2019 (Sections 2.1-2.3)
• Barlow et al. Clin Psychol Sci 2013
• Shackman et al. Psychol Bull 2016
• Sauer-Zavala & Barlow 2021 (book-length treatment of N/NE, emotional disorders, and the Unified Protocol for treatment)
• Mood and Anxiety Disorders: Primers and Large-Scale Surveys
  • Craske et al. Nature Disease Primers 2017 (easy-to-digest primer on anxiety disorders)
  • Otte et al. Nature Disease Primers 2016 (easy-to-digest primer on depression)
  • GBD 2019 The Lancet 2020 (WHO global burden of disease; online visualizations at http://ghdx.healthdata.org/gbd-results-tool)
  • Substance Abuse and Mental Health Services Administration 2019 (large-scale survey of mental illness and addiction among US young adults and youth)
  • CDC Suicide Update 2018 (epidemiology of suicide in the US)
  • Baranne & Fallssard Child Adolesc Psychiatry Ment Health 2018 (clear description of the strengths and limitations of different measures of mortality and morbidity)
• Clark et al. Psychol Sci in the Public Interest 2017 (comprehensive review of historical and contemporary perspectives on classifying and diagnosing mental illness, with substantial implications for research, clinical practice, public policy, and patient experience; highlights the truth and consequences of different iterations of DSM and RDoC, including the ‘smoke-filled back room’ decisions that led to DSM-5; this is not for the fainthearted, but should be rewarding for those willing to invest the time)
• Kotov et al. Psychol Med 2022 (HiTOP: hierarchical-dimensional approaches to mental illness)
• Kotov et al. Ann Rev Clin Psychol 2021 (HiTOP: hierarchical-dimensional approaches to mental illness)
• Hopwood et al. Nature Reviews Psychol 2022 (contemporary perspective on what, if anything, distinguishes personality from psychopathology)

Module 02. The Neurobiology of Negative Affect: Focus on the Amygdala

• Hur et al. Prog Brain Res 2019 (Sections 2.4-2.7)
• Feinstein et al. Curr Biol 2011 (Patient SM)
• Fox & Shackman Neurosci Lett 2019 (mini-review of the extended amygdala’s contributions to fear and anxiety, including recent work in humans, monkeys, rodents)
• Shackman & Fox American J Psychiatry 2021 (short overview of 20 years of neuroimaging studies of fear and anxiety)
• Feinstein et al. 2016 (a more detailed description of Patient SM, including her real-world trials and tribulations)

Detailed Learning Objectives

Module 1. Neuroticism/Negative Emotionality (N/NE) and the Emotional Disorders

• Key characteristics of N/NE?
• What’s an ‘emotional’ (sometimes termed ‘internalizing’) disorder?
• How is N/NE related to the emotional disorders? Cross-sectional data? Prospective longitudinal data?
• Are the emotional disorders

• • Common or rare? Has the frequency changed over time among youth and young adults?
  • Debilitating?
  • Associated with other adversities?
  • Associated with longer or shorter life?
  • Economic burden?
  • Public health burden?

• Key cross-cutting features of anxiety disorders? Under or over-treated?
• Key features of major depressive disorder (MDD)? Under or over-treated?
• Does N/NE confer risk for a particular diagnosis or an extended family of closely related disorders?
• Briefly describe Barlow’s claim that N/NE and the emotional disorders reflect a common cause.

• • Briefly describe the different lines of evidence
    • Which 3 lines of evidence show that emotional disorders and N/NE co-vary?
    • Which 2 lines of more mechanistic or causal evidence suggest that they reflect a common root cause?
    • Which 2 lines of research begin to address the biological substrates of the common cause?

• Are DSM diagnoses natural kinds waiting to be discovered or a convenient heuristic?
• What is the internalizing spectrum of disorders? Why do scientists and clinicians conceptualize the anxiety disorders and depression as a spectrum (name one piece of evidence)?
• What explains why individuals develop particular disorders, according to Barlow?
• Do negative experiences need to be directly experienced to nudge individuals toward a particular disorder? Or, is there evidence suggesting that vicarious or observational learning could be at play?
• Is N/NE a cause, a symptom, or ‘the same as’ the emotional disorders?

• • What is the key piece of evidence?

Module 2. The Neurobiology of Negative Affect: Focus on the Amygdala

• Is the amygdala a singular “thing” or a collection of things?
• What kinds of regions does the amygdala project to?

• • How is this related to triggering or orchestrating states of fear and anxiety?

• What is the relevance of the amygdala to fear conditioning or ‘learned’ fear?

• • What are the consequences of amygdala damage?

• What is ‘fear potentiated startle’ (FPS)?

• • How is FPS measured in rodents?
  • In humans?

• What is the relevance of the amygdala to innate, intrinsic, or ‘unlearned’ fears?

• • Is there causal/mechanistic evidence?
  • Is there brain imaging evidence?

• How is the amygdala related to freezing, shyness, and behavioral inhibition (BI) in monkeys?

• • Is there causal/mechanistic evidence?
  • Imaging evidence?

• What is the relevance of individual differences in amygdala activity/reactivity to individual differences in N/NE, including trait anxiety? To adults with a childhood history of extreme BI? Briefly describe the brain imaging evidence.
• Patient SM

• • What is the nature of Patient SM’s neurological damage?
  • What are the consequences for the experience and expression of fear and anxiety in naturalistic settings (e.g., exotic pet store, haunted house)?
  • Does Patient SM show deficits in her ability to learn from scary experiences in the real world? Does she avoid people and situations that were associated with trauma?
  • How does she look when you ask her to complete paper-and-pencil measures of trait anxiety (N/NE)? High, low, normative?

• Amygdala Stimulation/Video Clip

• • What are the consequences of amygdala stimulation in humans?

• What 2 lines of evidence suggest that the amygdala exerts ‘bi-directional’ control over fear and anxiety?
• Does this evidence mean that you can conclude that the amygdala is a ‘fear/anxiety’ center? Or is it possible that the amygdala is sensitive to a wide range of stimuli and participates in a broad spectrum of psychological processes?
• What is the relevance of the amygdala to mood and anxiety disorders (sometimes termed ‘emotional’ or ‘internalizing’ disorders)?

• • Is it more or less reactive in patients?

• Do individual differences in amygdala reactivity in the scanner prospectively predict the onset of anxiety disorders in the future?

• • What is the relevance of exposure to stress or negative life events (e.g. terrorist attack)?
  • Is the association between amygdala reactivity and mental illness conditional on exposure to negative life events (NLE x Amygdala Reactivity à Mood/Anxiety Symptoms & Disorders)?

• Do anxiety reducing drugs (e.g. benzodiazepines) alter amygdala reactivity?
• Is the amygdala only related to fear and anxiety?

• • Does it contribute to trust?
  • To personal distancing?

• If you observe activation in the amygdala, is it safe to conclude that an individual (or group of individuals) is feeling scared, anxious, or fearful? Is amygdala activation sensitive AND specific to fear and anxiety? Or, is it sensitive AND non-specific?
• Optional (Appendix Slides): Is the amygdala necessary for all kinds of fear, anxiety, and panic? Is there any evidence that Patient SM can experience panic? What are the implications for our understanding of the amygdala?

About the Instructor

Professor Alex Shackman is an Associate Professor in the Department of Psychology (Clinical & CNS Area Groups), core faculty member of the interdepartmental Neuroscience and Cognitive Science (NACS) Program and the Maryland Neuroimaging Center (MNC), and Director of the Affective and Translational Neuroscience Laboratory at the University of Maryland. His work has been continuously supported by the NIH since 2016 and has led to nearly 100 papers and chapters. He served as the Co-Editor of The Nature of Emotion, is an Associate Editor at the Journal of Psychopathology and Clinical Science (formerly Journal of Abnormal Psychology), and co-edited three special issues focused on the neurobiology of emotional states, traits, and disorders. He is a Fellow of the Association for Psychological Science; an active member of the Affective Neuroimaging Collaboratory, ENIGMA, and Hierarchical Taxonomy of Psychopathology (HiTOP)  consortia; and a standing member of the NIH Adult Psychopathology and Disorders of Aging (APDA) study section. Most of his work is focused on understanding the nature and brain bases of fear- and anxiety-related states, traits, and disorders. When extreme, anxiety contributes to a variety of debilitating, treatment-resistant mental illnesses, including internalizing disorders, addiction, and psychosis. To understand the origins and course of this liability, is group uses a range of tools—including multimodal neuroimaging (MRI, PET), psychophysiology, neuroendocrine measures, ecological momentary assessment (EMA), geolocation tracking, semi-structured clinical and life-stress interviews, and genetic analyses—in adult and pediatric patients, university students, community members, and monkeys. More recently established secondary lines of research are focused on graduate student health and wellbeing, and psychiatric nosology. Professor Shackman lives in Ellicott City, Maryland with his wife, mother-in-law, two children, a dog, and two cats.