PowerPoint Presentation

Nuts & Bolts Plan for TodayNext week: Review session (bring clicker!) and exam

Lecture (Grupe & Nitschke; Shackman)

Take-home critical thinking questionsWe probably will not have time to review together

You are free to answer 2 of the questions detailed in this powerpoint -or- to address questions from the last lecture

Q #4 is to peer review a paper that I am writing

How many would be interested in hearing the 5-min flash talk that I will be giving in Boston on Saturday?

PSYC 210:

Dissecting broad-band N/NEinto its key constituents

Part 2 of 2AJ Shackman22 April 2014How many people here are funded directly or indirectly by the NIH?

2

Like the anxiety disorders, dispositional anxiety is a complex, multidimensional phenotype involving changes in . The central challenge is to dissect the neural mechanisms that underlie each of these dimensions and to understand how they contribute to risk for developing psychopathology.

3

Dan & Jack (UW-Madison)John Curtin (UW)Christian Grillon (NIMH)David Walker (Emory)Mike Davis (Emory)

Me (UMD)Dissecting Uncertainty: 5 ComponentsStudents

What were the 3 components or intermediate phenotypes that we discussed last time?5Dissecting Uncertainty: 5 ComponentsElevated estimates of threat likelihood and intensity

Hyper-vigilance

Deficient safety learning (and over-generalization)

Elevated threat avoidance

Elevated reactivity (or deficient regulation of reactions) to uncertain or ambiguous threat

. 5 transdiagnostic intermediate phenotypes that support chronically elevated NE and pervasive anxiety6Dissecting Uncertainty: 5 ComponentsElevated estimates of threat likelihood and intensity

Hyper-vigilance

Deficient safety learning (and over-generalization)

Elevated threat avoidance

Elevated reactivity (or deficient regulation of reactions) to uncertain or ambiguous threat

. 5 transdiagnostic intermediate phenotypes that support chronically elevated NE and pervasive anxiety7Concerned for his safety, Paul locks his bedroom door instead of investigating. Having avoided exploring the situation, Paul is left withunresolved uncertaintyabout the source of the noisesFurthermore, not having learned that the situation was safe, Paul will be more likely to assume the worst the next time he hears a noise in the night.4. Avoidance: Deleterious Consequences4. Avoidance: Deleterious Consequences4. Avoidance: Deleterious ConsequencesAvoidant behavior and thoughts, including worrisome thoughts and safety behaviors, prevent anxious individuals from being exposed to evidence that might contradict negative predictions about the future

Avoidance can therefore heighten threat expectancies under conditions of uncertainty

Because events that are avoided or worried about typically fail to occur, maladaptive avoidance tendencies are reinforced and anxious individuals develop false beliefs that they prevented these negative outcomes

In short, they do not take advantage of opportunities for extinction4. Avoidance: Deleterious ConsequencesAvoidant behavior and thoughts, including worrisome thoughts and safety behaviors, prevent anxious individuals from being exposed to evidence that might contradict negative predictions about the future

Avoidance can therefore heighten threat expectancies under conditions of uncertainty

Because events that are avoided or worried about typically fail to occur, maladaptive avoidance tendencies are reinforced and anxious individuals develop false beliefs that they prevented these negative outcomes

In short, they do not take advantage of opportunities for extinction4. Avoidance: Deleterious ConsequencesAvoidant behavior and thoughts, including worrisome thoughts and safety behaviors, prevent anxious individuals from being exposed to evidence that might contradict negative predictions about the future

Avoidance can therefore heighten threat expectancies under conditions of uncertainty

Because events that are avoided or worried about typically fail to occur, maladaptive avoidance tendencies are reinforced and anxious individuals develop false beliefs that they prevented these negative outcomes

In short, they do not take advantage of opportunities for extinction4. Avoidance: Deleterious ConsequencesAvoidant behavior and thoughts, including worrisome thoughts and safety behaviors, prevent anxious individuals from being exposed to evidence that might contradict negative predictions about the future

Avoidance can therefore heighten threat expectancies under conditions of uncertainty

Because events that are avoided or worried about typically fail to occur, maladaptive avoidance tendencies are reinforced and anxious individuals develop false beliefs that they prevented these negative outcomes

In short, they do not take advantage of opportunities for extinction

Students

What might anxious avoidance look like in daily life? Everyday manifestations of avoidanceBarlow et al. Clin Psychol Sci 2013; Grupe & Nitschke Nature Rev Neurosci 201314

I cross the street to avoid talking to someone I know.

I avoid doing thingslike picking up the phone when it rings or going to partiesbecause of my anxiety.Everyday manifestations of avoidanceBarlow et al. Clin Psychol Sci 2013; Grupe & Nitschke Nature Rev Neurosci 201315

I cross the street to avoid talking to someone I know.

I avoid doing thingslike picking up the phone when it rings or going to partiesbecause of my anxiety.What mechanisms support elevated avoidance?Barlow et al. Clin Psychol Sci 2013; Grupe & Nitschke Nature Rev Neurosci 2013Presently, VERY LITTLE IS known about the neural mechanisms underlying avoidance behavior in humans and other primates. 16Hyper-sensitivity to punishment and errors

I cross the street to avoid talking to someone I know.

I avoid doing thingslike picking up the phone when it rings or going to partiesbecause of my anxiety.Barlow et al. Clin Psychol Sci 2013; Grupe & Nitschke Nature Rev Neurosci 2013NONETHELESS, Its widely believed that this behavioral profile reflects hyper-sensitivity to punishment. If someones hyper-sensitive to criticism, for instance, we would expect that they would behave in a way that minimizes the risk of being criticized. Recent work has extended this idea, showing that dispositionally anxious individuals, and some anxiety patients, are also hypersensitive to their own errors, a form of internal or endogenous negative feedback17Hyper-sensitivity to errorsShackman et al. Nature Rev Neurosci 2011; Cavanagh & Shackman J Physiol Paris in press

For instance, in the flanker task, subjects are instructed to respond to the central arrow go right and ignore the flanking arrows go left, 18Hyper-sensitivity to errorsplotted negative up

Shackman et al. Nature Rev Neurosci 2011; Cavanagh & Shackman J Physiol Paris in pressErrors in this case accidentally going left are associated with an event-related potential, the error-related negativity. The error-related negativity is consistently larger in dispositionally anxious individuals. 19The Error-Related Negativity (ERN) isgenerated in the midcingulate cortex

Shackman et al. Nature Rev Neurosci 2011; Cavanagh & Shackman J Physiol Paris in pressThe error related negativity is generated in the midcingulate cortex. 20The Error-Related Negativity (ERN) is emotional

Shackman et al. Nature Rev Neurosci 2011; Cavanagh & Shackman J Physiol Paris in pressThe ERN can be considered emotional21The Error-Related Negativity (ERN) is emotional

MCCError-Related Negativity(reduced by anxiolytics)Shackman et al. Nature Rev Neurosci 2011; Cavanagh & Shackman J Physiol Paris in pressIt is dampened by anxiolytic drugs, like benzodiazepines. 22The Error-Related Negativity (ERN) is emotional

MCC

Error-Related Negativity(reduced by anxiolytics)Error-Potentiated Startle

Shackman et al. Nature Rev Neurosci 2011; Cavanagh & Shackman J Physiol Paris in pressErrors, like other aversive states, potentiate the startle reflex. 23Cognitive potentials are also generated in the midcingulate cortex

MCCShackman et al. Nature Rev Neurosci 2011; Cavanagh & Shackman J Physiol Paris in pressBUT the MCC is not just sensitive to emotion; IN FACT, a whole family of evoked-potentials is generated in this region, some of which are prototypically cognitive24Cognitive potentials are also generated in the midcingulate cortex

N2MCC

Cognitive Control Models: e.g., Yeung, Botvinick & Cohen, Psych Bull, 2004Shackman et al. Nature Rev Neurosci 2011; Cavanagh & Shackman J Physiol Paris in pressFor instance, the N2 is generated in the midcingulate. The N2 is a sensitive measure of conflict, here the conflict between the central and flanking arrows, and has played a crucial role in the development of prominent computational models of cognitive control. Now where things get really interesting is25These cognitive potentials are alsoenhanced in anxious individuals

Shackman, Shackman et al. under reviewThat these seemingly cognitive signals are also enhanced in anxious individuals26Both emotional (ERN, FRN) and cognitive(N2) potentials are consistently enhanced

Cavanagh & Shackman J Physiol Paris in press

Ticks indicate the correlationbetween anxiety and one of the ERP componentsfor each of the 47 studiesFRN: feedback-related negativityIn fact, a recent meta-analysis indicated that higher levels of dispositional anxiety are consistently associated with the size of the error related negativity, feedback-related negativity, as well as the more prototypically cognitive N2 evoked potential. This convergence between putatively cognitive and emotional evoked potentials is consistent with evidence from brain imaging studies that negative affect pain and cognitive control that is, emotion & cognition -- are tightly integrated in the midcingulate . 27Shackman et al. Nature Reviews Neurosci 2011Large-scale meta-analysis of the imaging literature

shackmanlab.orgFDR q> cues that invariably precede high-intensity shocks

e.g., Cues preceding shock on either 20% or 60% of trials >> 100% certainty

e.g., Unpredictably timed, neutral tones elicit more amygdala activity and anxious behavior in mice and humans than the identical tones when they are predictable

Observations indicate that uncertainty itself without aversive outcomes causes elevated anxiety5. Increased Reactivity to Uncertainty/AmbiguityUnpredictably timed, neutral tones:5. Increased Reactivity to Uncertainty/AmbiguityHerry et al J Neurosci 2007

Details Are Not ImportantUnpredictably timed, neutral tones:5. Increased Reactivity to Uncertainty/AmbiguityHerry et al J Neurosci 2007

Increase AmygActivation

Details Are Not ImportantUnpredictably timed, neutral tones:5. Increased Reactivity to Uncertainty/AmbiguityHerry et al J Neurosci 2007

Increase AmygActivation

IncreaseAnxietyDetails Are Not ImportantUnpredictably timed, neutral tones:5. Increased Reactivity to Uncertainty/AmbiguityHerry et al J Neurosci 2007

Increase AmygActivation

IncreaseAnxietyIncreaseBoth

Details Are Not ImportantUnpredictably timed, neutral tones:5. Increased Reactivity to Uncertainty/AmbiguityHerry et al J Neurosci 2007

Increase AmygActivation

IncreaseAnxietyIncreaseBoth

Details Are Not ImportantObservations indicate that uncertainty itself, in the absence of potential danger, can increase anxiety

Suggests that uncertainty is another active ingredient that causally contributes to the anxious phenotypeClinically effective anti-anxiety agents, such as benzodiazepines and mild alcohol intoxication, selectively reduce anxiety elicited by uncertain threat (but are relatively ineffective for acute fear in response to imminent, certain danger)

This indicates that elevated reactivity to uncertainty is another key active ingredient in the anxious phenotypePharmacological EvidenceGrupe & Nitschke NRN 2013; Bradford et al. Psychol Sci in pressClinically effective anti-anxiety agents, such as benzodiazepines and mild alcohol intoxication, selectively reduce anxiety elicited by uncertain threat (but are relatively ineffective for acute fear in response to imminent, certain danger)

Reinforces the idea that elevated reactivity to uncertainty is another key active ingredient that causally contributes to N/NE and clinical anxietyPharmacological EvidenceGrupe & Nitschke NRN 2013; Bradford et al. Psychol Sci in pressPutting It All Back Together AgainGrupe & Nitschke NRN 2013Putting It All Back Together AgainGrupe & Nitschke NRN 2013

Details Are Not ImportantPutting It All Back Together AgainGrupe & Nitschke NRN 2013

The arrows represent educated guesses

but we know that these processesinteract and recursively influence one another(as with the unpredictable tones and vigilance)Details Are Not Important5 core constituents of the anxious phenotype1. Inflated estimates of threat certainty or intensity/cost

2. Hypervigilance (attentional threat bias)Active ingredient/CausalPresent in BIAmygdala, direct or indirect influence on sensory cortex

3. Deficient safety learning and overgeneralizationAnxious individuals learn certain, imminent threat just finePredicts first onset; present in BIdlPFC, vmPFC, BNST?

4. Cognitive and behavioral avoidanceMCCCircuit centered on the MCC may help to orchestrate some of the other processesKey hub

5. Hyper-reactivity to uncertainty and ambiguityActive ingredient/CausalExtended amygdala (amygdala, BNST)

6. These processes interact in ways that reinforce pervasive, chronic distress and arousal a la Pete and Paul.

Key Take Homes5 core constituents of the anxious phenotype1. Inflated estimates of threat certainty or intensity/cost (mountain out of a molehill)

2. Hypervigilance (bias to allocate excess attention to threat or scanning for threat-relevant information)Active ingredient/CausalPresent in BICircuits centered on the amygdala, poised to directly/indirectly influence sensory cortex

3. Deficient safety learning and overgeneralization of anxiety to other cues and contextsAnxious individuals learn about clear and imminent threats just finePredicts first onset; present in BI

4. AvoidanceCircuit centered on the MCC may help to orchestrate behavioral avoidance 5. Hyper-reactivity to uncertainty and ambiguityActive ingredient/CausalExtended amygdala (amygdala, BNST)

6. These processes likely interact in complex ways that reinforce pervasive, chronic distress and arousal a la Pete and Paul.

Key Take Homes5 core constituents of the anxious phenotype1. Inflated estimates of threat certainty or intensity/cost (mountain out of a molehill)

2. Hypervigilance (bias to allocate excess attention to threat or scanning for threat-relevant information)Active ingredient/CausalPresent in BICircuits centered on the amygdala, poised to directly/indirectly influence sensory cortex

3. Deficient safety learning and overgeneralization of anxiety to other cues and contextsAnxious individuals learn about clear and imminent threats just finePredicts first onset; present in BI

4. AvoidanceCircuit centered on the MCC may help to orchestrate behavioral avoidance 5. Hyper-reactivity to uncertainty and ambiguityActive ingredient/CausalExtended amygdala (amygdala, BNST)

6. These processes likely interact in complex ways that reinforce pervasive, chronic distress and arousal a la Pete and Paul.

Key Take Homes5 core constituents of the anxious phenotype1. Inflated estimates of threat certainty or intensity/cost (mountain out of a molehill)

2. Hypervigilance (bias to allocate excess attention to threat or scanning for threat-relevant information)Active ingredient/CausalPresent in BICircuits centered on the amygdala, poised to directly/indirectly influence sensory cortex

3. Deficient safety learning and overgeneralization of anxiety to other cues and contextsAnxious individuals learn about clear and imminent threats just finePredicts first onset; present in BIReflects extended amygdala (BNST)

4. AvoidanceCircuit centered on the MCC may help to orchestrate behavioral avoidance 5. Hyper-reactivity to uncertainty and ambiguityActive ingredient/CausalExtended amygdala (amygdala, BNST)

6. These processes likely interact in complex ways that reinforce pervasive, chronic distress and arousal a la Pete and Paul.

Key Take Homes5 core constituents of the anxious phenotype1. Inflated estimates of threat certainty or intensity/cost (mountain out of a molehill)

2. Hypervigilance (bias to allocate excess attention to threat or scanning for threat-relevant information)Active ingredient/CausalPresent in BICircuits centered on the amygdala, poised to directly/indirectly influence sensory cortex

3. Deficient safety learning and overgeneralization of anxiety to other cues and contextsAnxious individuals learn about clear and imminent threats just finePredicts first onset; present in BIReflects extended amygdala (BNST)

4. AvoidanceCircuit centered on the MCC may help to orchestrate behavioral avoidance 5. Hyper-reactivity to uncertainty and ambiguityActive ingredient/CausalExtended amygdala (amygdala, BNST)

6. These processes likely interact in complex ways that reinforce pervasive, chronic distress and arousal a la Pete and Paul.

Key Take Homes5 core constituents of the anxious phenotype1. Inflated estimates of threat certainty or intensity/cost (mountain out of a molehill)

2. Hypervigilance (bias to allocate excess attention to threat or scanning for threat-relevant information)Active ingredient/CausalPresent in BICircuits centered on the amygdala, poised to directly/indirectly influence sensory cortex

3. Deficient safety learning and overgeneralization of anxiety to other cues and contextsAnxious individuals learn about clear and imminent threats just finePredicts first onset; present in BIReflects extended amygdala (BNST)

4. AvoidanceCircuit centered on the MCC may help to orchestrate behavioral avoidance 5. Hyper-reactivity to uncertainty and ambiguityActive ingredient/CausalExtended amygdala

6. These processes likely interact in complex ways that reinforce pervasive, chronic distress and arousal a la Pete and Paul.

Key Take Homes5 core constituents of the anxious phenotype1. Inflated estimates of threat certainty or intensity/cost (mountain out of a molehill)

2. Hypervigilance (bias to allocate excess attention to threat or scanning for threat-relevant information)Active ingredient/CausalPresent in BICircuits centered on the amygdala, poised to directly/indirectly influence sensory cortex

3. Deficient safety learning and overgeneralization of anxiety to other cues and contextsAnxious individuals learn about clear and imminent threats just finePredicts first onset; present in BIReflects extended amygdala (BNST)

4. AvoidanceCircuit centered on the MCC may help to orchestrate behavioral avoidance 5. Hyper-reactivity to uncertainty and ambiguityActive ingredient/CausalExtended amygdala

6. These processes likely interact in complex ways that reinforce pervasive, chronic distress and arousal a la Pete and Paul.

Key Take HomesTake Home Critical Thinking QuestionsTake Home Critical Thinking QuestionsPlease select any 2

You are also free to respond to any of the questions from the last lecture that you have not already answered. Take Home Critical Thinking QuestionsTraditionally, psychology and philosophy have divided the mind into 3 faculties: emotion, cognition, and will. Does this trichotomy make sense? E.g., throughout the semester, we have discussed the key features of E and N. Oftentimes, these traits and their associated states (PE and NE) are conceptualized as emotional. Hence, their neural correlates have been considered the emotional brain, consistent with the traditional trichotomy. But are they really just emotional (hot) or do they fundamentally involve processes that we usually consider cognitive (cold)? What are the implications for the emotional vs. cognitive brain? For the trichotomy?Take Home Critical Thinking Questions2. Briefly describe an example from your own life, that of a friend, or a hypothetical example that exemplifies 1 of the 5 intermediate phenotypes described by Grupe & Nitschke.Take Home Critical Thinking Questions3. Briefly describe some specific ways (psychological or neural) in which deficient safety learning might be related to heightened reactivity to uncertain/ambiguous threat. Take Home Critical Thinking Questions4. I am in the midst of writing a review that closely parallels the structure of our class.

Download the paper from Canvas:shackman_stock_lemay_fox_Q2_041515.docx

What do you think? What are your suggestions for strengthening the not-quite-done manuscript? What are the most important future research challenges for me to highlight in the Discussion?Time-PermittingReview QuestionsIndividuals with high levels of N/NE are characterized byInflated estimates of threat likelihoodAbnormally low estimates of threat intensity

Anxious individuals attentional bias to threat can be re-trained using computerized tasks. Which is the best answer?This is clinically effective, albeit weaklyRetraining the bias produces a lasting diminution in anxiety (e.g. in a public speaking task)Furthermore, CBT targeting excess anxiety reduces the attentional bias (reverse effect)Collectively, these mechanistic findings indicate a causal role

Anxious individuals tend toAllocate excess attention to threatAre faster to respond to the dot-probe when it occurs at the same location as a negative wordBoth

Hypervigilance may reflectThe direct influence of the amygdala on sensory cortexRobust projections from the amygdala to the visual cortexAn indirect influence of the amygdala, mediated by acetylcholine neurons sitting in the basal forebrain (nucleus basalis of Meynert); wake up!All of the above

Anxious individuals tend to showHeightened anxiety (startle) in response to clear and imminent threat (CS+)Excess anxiety to uncertain and ambiguous danger (CS- , ITI)

Anxious individuals tend toOvergeneralize anxiety to cues that resemble genuine dangers (e.g., Lisseks parametric rings)Show anxiety that is strictly limited to threat

Individuals with anxiety disordersHave difficulties tuning their anxiety and learning what is safe (safety learning deficit)This promotes to chronic, pervasive anxiety, arousal, and stress; they dont know when its safe to relaxAnd predicts who will develop an anxiety disorder All of the above

Individuals with a childhood history of extreme BI, a facet of N/NE, showHypervigilance on the dot-probe taskElevated startle during periods of objective safetyBoth

The EndExtra Slides

Cavanagh & Shackman J Physiol Paris in pressBut115

Cavanagh & Shackman J Physiol Paris in press

Cavanagh & Shackman J Physiol Paris in press

Cavanagh & Shackman J Physiol Paris in pressTo address this key question, we turned to well-established EEG measures of cognitive control 118

Cavanagh & Shackman J Physiol Paris in press; Cavanagh & Frank TiCS 2014. 119

Cavanagh & Shackman J Physiol Paris in press; Cavanagh & Frank TiCS 2014For instancethe flanker task is associated with response conflict, go left or go right120

N2

Cavanagh & Shackman J Physiol Paris in press; Cavanagh & Frank TiCS 2014

This conflict elicits the N2, a sensitive index of conflict monitoring generated in the midcingulate121

The conflict-sensitive N2 is maximal at frontal-midline sensors, shown here122

Cavanagh & Shackman J Physiol Paris in press; Cavanagh & Frank TiCS 2014

123

ERN

Cavanagh & Shackman J Physiol Paris in press; Cavanagh & Frank TiCS 2014

But whats really remarkable is that these putatively cognitive signals are attenuated by anxiolytic compounds, like the benzodiazepines, and co-vary with individual differences in anxiety. For instance, in a recent meta-analysis

124Shackman et al. Nature Rev Neurosci 2011; Cavanagh & Shackman J Physiol Paris in press

Jim Cavanagh and I showed that the N2, the feedback-related negativity, and the error-related negativity are larger in individuals with heightened levels of anxiety when they were performing standard lab assays of cognitive control. 125Shackman et al. Nature Rev Neurosci 2011; Cavanagh & Shackman J Physiol Paris in press