Shackman Psyc210 Module16 SplittingConstituents Part1

PowerPoint Presentation

Nuts and Bolts Plan for TodayLecture (Grupe & Nitschke; Macleod)If we run low on time, we will finish during the next lecture

Take-home critical thinking questions

PSYC 210:

Dissecting broad-band N/NEinto its key constituents

Part 1 of 2AJ Shackman20 April 2015How many people here are funded directly or indirectly by the NIH?

2Todays Conceptual RoadmapIn prior lectures, weve talked about N/NE and its facet, BI.

Exploded View of Porsche 917 EngineTodays Conceptual RoadmapBut what exactly does it mean to be neurotic, to show high levels of NE or BI?

What are the key ingredients of this anxious phenotype?

How are these components physically organized in the brain?

Can we break it down, psychologically and neurally?

What do you guys think?

Exploded View of Porsche 917 EngineTodays Conceptual RoadmapBut what exactly does it mean to be neurotic, to show high levels of NE or BI?

What are the key ingredients of this anxious phenotype?

How are these components physically organized in the brain?

Can we break it down, psychologically and neurally?

What is the value of dissecting?

Exploded View of Porsche 917 EngineBrief reminder of what we already know about intermediate phenotypes, using C/SC as an illustrationStudents: How Might We Go About Determining the Substrates of a Trait (e.g., C/SC)?

Try to forge a link betweenT&P: Variation in C/SC and

Candidate Cause: Some other process or measure (psychological or biological cause)

StudentsHow might we go about this?Quantify individual differences in C/SC

One-Shot Self-Report Multi-Informant Behavioral CompositeIn either case, you end up with a single number

Students: Why is this potentially problematic??Quantify individual differences in C/SC

One-Shot Self-Report Multi-Informant Behavioral CompositeIn either case, you end up with a single number

Students: Why is this potentially problematic??But one number is not a sensible approach

Mayor Ford (Toronto)Mayor Barry (DC)More than one process at work (psychological process, neural circuit, genetic variants)C/SC is Complex

C/SC is Complex

Complexity impedes the search forsimple substrates

Need to simplify! Focus on one key element at a time.Defined by constellation of symptoms, not causes (pathophysiology), including alterations in thought, language, behavior, and mood

Complexity is compounded by the Dim Sum Buffet problemdifferent ways to get there (polythetic diagnostic categories)

Outward manifestations are often non-specific (aka transdiagnostic)

C/SC is Complex

Complexity impedes the search forsimple substrates

Need to simplify! Focus on one key element at a time.Defined by constellation of symptoms, not causes (pathophysiology), including alterations in thought, language, behavior, and mood


Outward manifestations are often non-specific (aka transdiagnostic)

C/SC is ComplexComplexity and heterogeneity impedes the search for simple substrates

Need to dissect or decompose! Focus on one key element at a time.Defined by constellation of symptoms, not causes (pathophysiology), including alterations in thought, language, behavior, and mood


Simpler Intermediate PhenotypesDelay of GratificationComplexity impedes the search forsimple substrates

Need to simplify!

Lets apply this strategy to N/NEHang on! - Why Bother?

Students: What do we know about the impact of N/NE on important, real-world outcomes such as mental health

Kessler et al 2012; Bystritsky 2006; Whiteford et al 2013Globally: depression, substance abuse, and anxiety disorders, including panic disorder, obsessive-compulsive, and post traumatic stress cause TREMENDOUS SUFFERING and the loss of more than 100 M life years to illness, disability, and death. COLLECTIVELY, these DATA UNDERSCORE the importance of clarifying the mechanisms that confer risk

20Dispositional anxiety is a key risk factor

increased risk Anxiety, mood, and substancedisordersBarlow et al. 2013; Clauss & Blackford 2012; Kotov et al. 2010; Watson & Naragon-Gainey 2014Dispositional anxiety is a key risk factor - Individuals who characteristically respond to potential threat with extreme anxiety & behavioral inhibition are much more likely to develop these disorders compared to those who dont.

21Students

But exactly do we mean by N/NE?

What kinds of processes seem to be involved?Barlow et al. 2013; Clauss & Blackford 2012; Kotov et al. 2010; Watson & Naragon-Gainey 2014Neuroticism, as measured by factor-analytic [self-report] scales, is a conceptual hodgepodge ofcognitions, behavior, emotions, and symptoms

Seymour Epstein 1994 Epstein Psychol Inquiry 1994

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.

24

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

Me (UMD)

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

Me (UMD)Uncertainty is the Core Feature of AnxietyAnxiety can be thought of as a future-oriented emotional state

Characterized by anticipatory cognitive, behavioral, physio, and emotional changes in response to uncertain threat

Normal and adaptive when appropriately titrated to the likelihood and severity of threat

Maladaptive when conducted excessively, e.g., when threat is distal, improbable, inconsequential

Mountain out of a molehill

Lost opportunity for allocating resources to other activities that are rewarding & promote positive affect, e.g.,foraging, fornicating, playing, parenting, etc.

Uncertainty is the Core Feature of AnxietyAnxiety can be thought of as a future-oriented emotional state














Normal and adaptive when appropriately titrated to the likelihood and severity of threat (false alarms can be good)

Maladaptive when conducted excessively, e.g., when threat is remote, improbable, inconsequential















Uncertainty is the Core Feature of AnxietyGrupes central claim is that the common denominator across dispositional anxiety (T&P) and the anxiety disorders is aberrant and excessive anticipatory responding under conditions of uncertain or ambiguous threat

And this reflects alterations in a core set of brain regions

Focus on the MCC

What if??

Uncertainty is the Core Feature of AnxietyGrupes central claim is that the common denominator across dispositional anxiety (T&P) and the anxiety disorders is aberrant and excessive anticipatory responding under conditions of uncertain or ambiguous threat

And that this reflects alterations in 5 key neuropsychological processes

Including the MCC

What if??

Dissecting Uncertainty: 5 ComponentsElevated estimates of threat likelihood and intensity

Elevated vigilance

Deficient safety learning

Elevated threat avoidance (behavioral / cognitive)

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

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

Elevated vigilance





Elevated vigilance





Elevated vigilance


Elevated threat avoidance



Elevated vigilance





Elevated vigilance




. 5 transdiagnostic intermediate phenotypes that support chronically elevated NE and pervasive anxietytransdiagnostic = more than one anxiety disorder (diagnosis)Dissecting Uncertainty: 5 ComponentsElevated estimates of threat likelihood and intensity

Elevated vigilance




. 5 transdiagnostic intermediate phenotypes that support chronically elevated distresstransdiagnostic = more than one anxiety disorder (diagnosis)Under scrutiny, these processes tend to blur together.

For example, heightened vigilance and arousal (startle) during periods of learned safety

So, 5 may be more heuristic than carving nature at her joints

And in fact Dan acknowledges this 42Lets meet Pete and PaulAdaptive Anxiety: The Case of PetePete, home alone one night, hears rustling in the bushes and loud banging sounds outside his house. Pete feels uncertain about whether these noises are benign (curious raccoons) or threatening (burglars). An adaptive response to this uncertainty begins with a rational assessment of the probability of threat [EST]: few burglaries occur in this neighborhood, and similar noises have never turned out to be dangerous before. Pete turns down the television to give more attention to what may be outside, but this heightened vigilance [VIGIL] is balanced by attention to cues that indicate safety [SAFE LEARN]. Because Petes security system is silent and the windows and doors are locked, he has reliable signs that nobody has entered his house. Nevertheless, Pete explores the situation to reduce nagging questions [AVOID]. Heading downstairs, he sees trash strewn about the garbage cans and surmises the likely culprit was a raccoon. Despite some unresolved uncertainty, Pete can calm his racing heart [REACT/REG] and fall asleep knowing that all signs point towards safety.Adaptive Anxiety: The Case of PetePete, home alone one night, hears rustling in the bushes and loud banging sounds outside his house. Pete feels uncertain about whether these noises are benign (curious raccoons) or threatening (burglars). An adaptive response to this uncertainty begins with a rational assessment of the probability of threat [EST]: few burglaries occur in this neighborhood, and similar noises have never turned out to be dangerous before. Pete turns down the television to give more attention to what may be outside, but this heightened vigilance [VIGIL] is balanced by attention to cues that indicate safety [SAFE LEARN]. Because Petes security system is silent and the windows and doors are locked, he has reliable signs that nobody has entered his house. Nevertheless, Pete explores the situation to reduce nagging questions [AVOID]. Heading downstairs, he sees trash strewn about the garbage cans and surmises the likely culprit was a raccoon. Despite some unresolved uncertainty, Pete can calm his racing heart [REACT/REG] and fall asleep knowing that all signs point towards safety.Adaptive Anxiety: The Case of PetePete, home alone one night, hears rustling in the bushes and loud banging sounds outside his house. Pete feels uncertain about whether these noises are benign (curious raccoons) or threatening (burglars). An adaptive response to this uncertainty begins with a rational assessment of the probability of threat [EST]: few burglaries occur in this neighborhood, and similar noises have never turned out to be dangerous before. Pete turns down the television to give more attention to what may be outside, but this heightened vigilance [VIGIL] is balanced by attention to cues that indicate safety [SAFE LEARN]. Because Petes security system is silent and the windows and doors are locked, he has reliable signs that nobody has entered his house. Nevertheless, Pete explores the situation to reduce nagging questions [AVOID]. Heading downstairs, he sees trash strewn about the garbage cans and surmises the likely culprit was a raccoon. Despite some unresolved uncertainty, Pete can calm his racing heart [REACT/REG] and fall asleep knowing that all signs point towards safety.Adaptive Anxiety: The Case of PetePete, home alone one night, hears rustling in the bushes and loud banging sounds outside his house. Pete feels uncertain about whether these noises are benign (curious raccoons) or threatening (burglars). An adaptive response to this uncertainty begins with a rational assessment of the probability of threat [EST]: few burglaries occur in this neighborhood, and similar noises have never turned out to be dangerous before. Pete turns down the television to give more attention to what may be outside, but this heightened vigilance [VIGIL] is balanced by attention to cues that indicate safety [SAFE LEARN]. Because Petes security system is silent and the windows and doors are locked, he has reliable signs that nobody has entered his house. Nevertheless, Pete explores the situation to reduce nagging questions [AVOID]. Heading downstairs, he sees trash strewn about the garbage cans and surmises the likely culprit was a raccoon. Despite some unresolved uncertainty, Pete can calm his racing heart [REACT/REG] and fall asleep knowing that all signs point towards safety.Maladaptive Anxiety: The Case of PaulNext door lives Paul, a chronic worrier with GAD, who hears the same noises and experiences similar feelings of uncertainty. Instead of objectively weighing the likelihood of alternative outcomes, Paul immediately imagines burglars entering his home [EST]. Uncontrollable worries and cascading what if thoughts course through his head, and he generates increasingly elaborate scenarios of what evils may befall him. He becomes increasingly attuned to every movement in the branches or creak in the floorboards of his old house [VIGIL]. Owing to Pauls exclusive attention towards potential threat, he does not notice that his security system is silent [SAFE LEARN]. Concerned for his safety, Paul locks his bedroom door instead of investigating [AVOID]. Having avoided exploring the situation, Paul is left with greater unresolved uncertainty than Pete about the source of the noises. He tries to sleep but his racing heart and sweaty palms keep him from relaxing [REACT/REG]. 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. Maladaptive Anxiety: The Case of PaulNext door lives Paul, a chronic worrier with GAD, who hears the same noises and experiences similar feelings of uncertainty. Instead of objectively weighing the likelihood of alternative outcomes, Paul immediately imagines burglars entering his home [EST]. Uncontrollable worries and cascading what if thoughts course through his head, and he generates increasingly elaborate scenarios of what evils may befall him. He becomes increasingly attuned to every movement in the branches or creak in the floorboards of his old house [VIGIL]. Owing to Pauls exclusive attention towards potential threat, he does not notice that his security system is silent [SAFE LEARN]. Concerned for his safety, Paul locks his bedroom door instead of investigating [AVOID]. Having avoided exploring the situation, Paul is left with greater unresolved uncertainty than Pete about the source of the noises. He tries to sleep but his racing heart and sweaty palms keep him from relaxing [REACT/REG]. 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. Maladaptive Anxiety: The Case of PaulNext door lives Paul, a chronic worrier with GAD, who hears the same noises and experiences similar feelings of uncertainty. Instead of objectively weighing the likelihood of alternative outcomes, Paul immediately imagines burglars entering his home [EST]. Uncontrollable worries and cascading what if thoughts course through his head, and he generates increasingly elaborate scenarios of what evils may befall him. He becomes increasingly attuned to every movement in the branches or creak in the floorboards of his old house [VIGIL]. Owing to Pauls exclusive attention towards potential threat, he does not notice that his security system is silent [SAFE LEARN]. Concerned for his safety, Paul locks his bedroom door instead of investigating [AVOID]. Having avoided exploring the situation, Paul is left with greater unresolved uncertainty than Pete about the source of the noises. He tries to sleep but his racing heart and sweaty palms keep him from relaxing [REACT/REG]. 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. Not just grown upsSee what it is, you might feel betterSee what it is, you might feel betterOnce you know what's thereYou might find you don't need to be scared

I couldn't help but feel royally scaredWhen I saw a strange lump on the floorBut when I saw what was thereMy favorite stuffed bearI wasn't afraid anymore

You know, I was grrr-ifficly scaredWhen I saw a creepy shadow on the wallBut it was just a light shiningOn silly Mr. LizardThat made him look so very very tallOnce we saw what was thereWe knew he had nothing to fear

See what it is, you might feel betterSee what it is, you might feel betterOnce you know what's thereYou might find you don't need to be scared

I heard a sound that gave me such a frightI couldn't see what it was, it was out of sightLet's see what it isIt's a frogSee what it is, you might feel betterSee what it is, you might not be afraid

We saw a large shape that gave us a scareIt looked like a really really big bearLet's see what it isIt's a rockSee what it is, you might feel betterSee what it is, you might not be afraidSee what it is, you might feel betterOnce you see what's there you might not feel so afraid

Start @ 19:15 https://www.youtube.com/watch?v=nisqIXwxHms

Drill into the 5 constituents1. Inflated Estimates of Threat Likelihood/IntensityInstead of objectively weighing the likelihood of alternative outcomes, Paul immediately imagines burglars entering his home1. Inflated Estimates of Threat Likelihood/IntensityEvidence for inflated estimates of threat?Judgment BiasesAnxious individuals overweight the probability of negative events

1. Inflated Estimates of Threat Likelihood/IntensityEvidence for inflated estimates of threat?Judgment BiasesAnxious individuals overweight the probability of negative events

2. HypervigilancePaul becomes increasingly attuned to every movement in the branches or creak in the floorboards of his old house

2. HypervigilancePaul becomes increasingly attuned to every movement in the branches or creak in the floorboards of his old houseDot-Probe Vigilance TasktimeHypervigilance: Meta-Analytic Evidencesee also Van Boekstaele et al Psychol Bull in pressHypervigilance: Meta-Analytic Evidence

see also Van Boekstaele et al Psychol Bull in pressHypervigilance: Meta-Analytic Evidence

see also Van Boekstaele et al Psychol Bull in pressCan Hypervigilance be Re-Trained?Ann Rev Clin Psychol 2012see also Van Boekstaele et al Psychol Bull in pressCan Hypervigilance be Re-Trained?Ann Rev Clin Psychol 2012see also Van Boekstaele et al Psychol Bull in press

Students

Whats at stake? Whats the clinical or scientific value of studying retraining?Manipulate vigilance to test whether it causally contributes to anxiety

Test the therapeutic efficacy of attention retrainingConventional CBTIntrospective insight into thoughts that trigger anxiety and mentally challenging those thoughts

RetrainingDirectly modify cognitive biases thru extended task practiceNot dependent on introspectionMore akin to learning a new motor skillRetraining Vigilance: GoalsAnn Rev Clin Psychol 2012Van Boekstaele et al Psychol Bull in press [see also Tobon JCP 2011]; MacLeod & Clarke CPS 2015Manipulate vigilance to test whether it causally contributes to anxiety

Test the therapeutic efficacy of attention retrainingConventional CBTIntrospective insight into thoughts that trigger anxiety and mentally challenging those thoughts


Test the therapeutic efficacy of attention retrainingConventional Cognitive-Behavioral Therapy (CBT)Introspective insight into thoughts that trigger anxiety and mentally challenging those thoughts


Test the therapeutic efficacy of attention retrainingConventional Cognitive-Behavioral Therapy (CBT)Introspective insight into thoughts that trigger anxiety and mentally challenging those thoughts

RetrainingDirectly modify cognitive biases thru extended task practiceNot dependent on introspectionMore akin to learning a new motor skill (or exposure Tx)Focused and can be gameifiedRetraining Vigilance: GoalsAnn Rev Clin Psychol 2012Van Boekstaele et al Psychol Bull in press [see also Tobon JCP 2011]; MacLeod & Clarke CPS 2015Dennis Clin Psychol Sci 2014

Dennis Clin Psychol Sci 2014

In this game two animated characters will appear on the screen. Shortly after, they will burrow into a hole. One of them will cause a path of grass to rustle behind it. With your finger, trace the path of the rustling grass, beginning from the burrow. Try to complete this task as quickly and as accurately as possible.

Dennis Clin Psychol Sci 2014

In this game two animated characters will appear on the screen. Shortly after, they will burrow into a hole. One of them will cause a path of grass to rustle behind it. With your finger, trace the path of the rustling grass, beginning from the burrow. Try to complete this task as quickly and as accurately as possible.

In the ABM condition, a trail of grass appeared in the location of the non-threat sprite on every trial, whereas in the placebo training condition, trails were equally likely to appear in the location of the angry/threat or neutral/non-threat sprites

Vigilance causally contributes to elevated anxiety

In nonclinical samples exposed to one-shot lab sessions, retraining has been found to reduce

stress elicited by subsequent exposure to simple cognitive stressors (anagram/puzzle challenges)

anxiety ratings and behaviors (assessed by raters) when delivering a public speech

intrusive, apprehensive thoughts during a worry induction

Retraining Vigilance: Lessons LearnedAnn Rev Clin Psychol 2012Van Boekstaele et al Psychol Bull in press [see also Tobon JCP 2011]; MacLeod & Clarke CPS 2015Vigilance causally contributes to elevated anxiety


















anxiety ratings and behaviors (assessed by raters) when delivering a public speech (e.g. Dennis mobile app study)





anxiety ratings and behaviors (assessed by raters) when delivering a public speech (e.g. Dennis mobile app study)







Retraining Vigilance: Lessons LearnedAnn Rev Clin Psychol 2012Van Boekstaele et al Psychol Bull in press [see also Tobon JCP 2011]; MacLeod & Clarke CPS 2015Retraining Vigilance: Lessons LearnedBiol Psychiatry 2010Retraining appears to be effective at reducing clinical anxiety

Van Boekstaele et al Psychol Bull in press [see also Tobon JCP 2011]; MacLeod & Clarke CPS 2015

Retraining Vigilance: Lessons LearnedBiol Psychiatry 2010Retraining appears to be effective at reducing clinical anxiety


Trained 57 individuals with social phobia

Those trained to attend to nonthreatening cues demonstrated greater reductions in self-reported, behavioral, and physiological (CSR) measures of anxiety in response to a public speaking challenge than those in the attend to threat and control conditionsRetraining Vigilance: Lessons LearnedBiol Psychiatry 2010Retraining appears to be effective at reducing clinical anxiety



Those trained to attend to nonthreatening cues demonstrated greater reductions in self-reported, behavioral, and physiological (CSR) measures of anxiety in response to a public speaking challenge than those in the attend to threat and control conditionsRetraining Vigilance: Lessons LearnedBiol Psychiatry 2010Retraining appears to be effective at reducing clinical anxiety



Those trained to attend to nonthreatening cues demonstrated greater reductions in self-reported, behavioral, and physiological (CSR) measures of anxiety in response to a public speaking challenge than those in the attend to threat and control conditions

Similar effects reported for cortisol and examination stress

Retraining appears to be effective at reducing clinical anxiety

Retraining Vigilance: Lessons Learned

Biol Psychiatry 2010Van Boekstaele et al Psychol Bull in press [see also Tobon JCP 2011]; MacLeod & Clarke CPS 2015Retraining appears to be effective at reducing clinical anxiety


Biol Psychiatry 2010Van Boekstaele et al Psychol Bull in press [see also Tobon JCP 2011]; MacLeod & Clarke CPS 2015Retraining appears to be effective at reducing clinical anxiety


Biol Psychiatry 2010Furthermore Van Boekstaele et al review evidence that conventional CBT reduces the attentional bias to threat, consistent with the idea that hypervigilance is one of the active ingredients in clinically significant anxiety (see also Reinecke et al Biol Psychiatry 2013) Van Boekstaele et al Psychol Bull in press [see also Tobon JCP 2011]; MacLeod & Clarke CPS 2015Where do hyper-vigilance and related kinds of risk assessment behaviors come from?May reflect the direct influence of the amygdala on sensory cortex

90Vuillemier et al. Nat Neurosci 2004

FFA: Fusiform Face AreaAND Amyg lesions eliminate the enhanced activity typically elicited by fear faces in the visual cortex. Furthermore, as one would expect, this circuit appears to be sensitive to stress. In particular, 91Vuillemier et al. Nat Neurosci 2004

FFA: Fusiform Face AreaAND Amyg lesions eliminate the enhanced activity typically elicited by fear faces in the visual cortex. Furthermore, as one would expect, this circuit appears to be sensitive to stress. In particular, 92Hyper-vigilance could also reflect an indirect influence of the amygdala oncortical sensory systemsIndirect Influence via the Basal Forebrain

Details Are Not Important

Details Are Not Important

Wake Up!Details Are Not Important

Basal Forebrain (N.B. of M.)

Basal Forebrain (N.B. of M.)

Basal Forebrain (NB of M): Cortical ArousalRabbits: Whalen et al J Neurosci; Kapp et al Beh Neurosci

Basal Forebrain (NB of M): Cortical ArousalRabbits: Whalen et al J Neurosci; Kapp et al Beh Neurosci Learned Threat (CS+)Increases Neuronal Spiking in the NB of M

Learned ThreatIncreases Cortical Arousal(EEG Desynchronization;Less is More)NB of M SpikingPredictsCortical Arousal

CeA StimulationCan Drive This Effect(CeA NB of M ArousalDetails Are Not ImportantBasal Forebrain (NB of M): Cortical ArousalRabbits: Whalen et al J Neurosci; Kapp et al Beh Neurosci Learned Threat (CS+)Increases Neuronal Spiking in the NB of M

Learned Threat (CS+)Increases Cortical Arousal(EEG Desynchronization;Less is More)NB of M SpikingPredictsCortical Arousal





CeA StimulationCan Drive This Effect(CeA NB of M Arousal)Indirect Influence via the Basal Forebrain

3. Deficient Safety Learning3. Deficient Safety LearningOwing to Pauls exclusive attention towards potential threat, he does not notice that his security system is silent[and so remains in a state of apprehensive distress] Pete [attends to] to cues that indicate safety. Because his security system is silent and the windows and doors are locked, he has reliable signs that nobody has entered his house.Safety signals indicate the absence of threat; relieve individuals from a state of anticipatory anxiety

Under conditions of uncertainty, weak or non-existent contingencies between cues and aversive outcomes make it difficult to discriminate safety from threat (CS- vs. CS+)

Heightened reactivity (startle) to objectively safe conditions (CS-, ITI) has been observed across anxiety disorders

3. Deficient Safety Learning

Lissek et al Biol Psychiatry in pressSafety signals indicate the absence of threat; relieve individuals from a state of anticipatory anxiety

Heightened reactivity (startle) to objectively safe conditions (CS-, ITI) has been consistently observed across anxiety disorders





Lissek et al Biol Psychiatry in press

Safety signals indicate the absence of threat; relieve individuals from a state of anticipatory anxiety





Not just startle



Heightened reactivity (startle) to objectively safe conditions (CS-, ITI) has been consistently observed 3. Deficient Safety Learning


Heightened reactivity (startle) to objectively safe conditions (CS-, ITI) has been consistently observed 44 studies (>2,000 Ss), including a broad spectrum of self-report andphysiological measures of conditioned fear/anxiety



Heightened reactivity (startle) to objectively safe conditions (CS-, ITI) has been consistently observed 44 studies (>2,000 Ss), including a broad spectrum of self-report andphysiological measures of conditioned fear/anxiety

Patients with anxiety disordersdo not differ in their response to conditioned threat cues (CS+), but doshow elevated responses to safety cues(CS-)


3. Deficient Safety LearningThis is a Really Big DealFor a long time, it was thought that neurotic, anxious individuals are characterized by heightened fear learning and excessive responsiveness to the CS+ (the black bars in the figure)and that we could understand anxiety by elucidating the substrates of fear learning

But it has grown increasingly clear that this is generally not the case

Rather, neurotic/anxious individuals show difficulties discriminating threat from safety, manifesting as heightened reactions to ostensibly safe cues and contexts (white and grey bars in the figure)

3. Deficient Safety LearningThis is a Really Big DealFor a long time, it was thought that neurotic, anxious individuals are characterized by heightened fear learning and excessive responsiveness to the CS+ and that we could understand anxiety by elucidating the substrates of fear learning








Rather, neurotic/anxious individuals show difficulties discriminating threat from safety, manifesting as heightened reactions to ostensibly safe cues and contexts (CS-, ITI)

3. Deficient Safety LearningThis is a Really Big DealThis is specific to studies involving the use of noxious electric shock (or darkness)

Anxious individuals show exaggerated FPS when you turn out the lightsanother kind of diffuse threatand this is reduced by benzodiazepines

Increased ITI/Baseline startle is not observed in other kinds of non-emotional startle studies

Suggests that it does not simply reflect hyper-reactivity to the novelty of the lab, personnel, or procedures, but instead reflects a response to diffuse or remote threat: being in a shock study / having electrodes in-place / darkness

cf. Grillon et al PlosOne 20133. Deficient Safety LearningThis is a Really Big DealThis is specific to studies involving the use of noxious electric shock (or darkness)












cf. Grillon et al PlosOne 2013

Lissek (NIMH, Minnesota)Hypothesized that heightened reactions to safety cues might reflect a kind of over-generalization

Because the CS+ and CS, in a given study, are similar (e.g., both colored lights, both faces), patients appear to emotionally mistake the CS- for the CS+


Noted that the CS+ and CS in a given study tend to be physically similar (e.g., both colored lights, both faces)

Anxious individuals appear to over-generalize from the CS+ to the CS-, in terms of their emotional response (but not in terms of contingency reports)


Noted that the CS+ and CS in a given study tend to be physically similar (e.g., both colored lights, both faces)

Hypothesized that anxious individuals over-generalize from the CS+ to the physically similar CS-, in terms of their emotional response (but not in terms of contingency reports)

Students: How might you test this overgeneralization hypothesisin the lab?Overgeneralize?Lissek Dep and Anx 2012

Overgeneralize?Lissek Dep and Anx 2012

Overgeneralize?Lissek Dep and Anx 2012Elevated startle (FPS) relative to CS-

Overgeneralize?Lissek Dep and Anx 2012

Elevated startle (FPS) relative to CS-Lissek Dep and Anx 2012

Elevated startle (FPS) relative to CS-Overgeneralized Fear LearningJ Abnormal Psychol 2012Prospectively Predicts Disorder Onset

J Abnormal Psychol 2012

Prospectively Predicts Disorder OnsetReeb-Sutherland JAACAP 2009Present in Teens with High Childhood BIReeb-Sutherland JAACAP 2009Present in Teens with High Childhood BI

What brain circuits support sustained anxiety in response to diffuse, uncertain, or remote threat?

suggests that this sustained anxiety reflects the central extended amygdala, including the lateral divisions of the central and bed nuclei. 138

TO UNDERSTAND the relevance of this system in primates, in this next study we focused on young monkeys with STABLE & extreme levels of behavioral inhibition

139To understand the relevance of this circuit in primates, we focused on a group of young monkeys with stable and extreme behavioral inhibition (BI)Extreme behavioral inhibition (BI) confers risk

In humans, extreme BI is a key risk factor for the development of anxiety, depression, and co-morbid substance abuse. In particular, . To identify extreme BI in young monkeys.141Stable and extreme behavioral inhibition (BI)

Total N = 109

Details Are Not ImportantWe screened 109 individuals on 2 occasions one week apart and identified those with stable high and those with stable low levels of behavioral inhibition. As you can see, the stable high group froze 20 times more than the low group in response to the human intruder. Next, to assess sustained anxiety in the absence of threat142Nothing (Empty Control)

18-FDGInjection18-FDGInjection

No IntruderIntruder ThreatControlActiveNo Intruder(FDG uptake)No Intruder(FDG uptake)

Shackman*, Fox* et al in prepAssessing sustained anxiety following threat

Details Are Not Importantthe extreme groups were assessed on 2 more occasions. In the control condition, subjects were placed alone in the test cage for 30 min. Next, they received an 18-FDG injection and were again placed in the test cage alone. At the end of the 30 min, the subject was anesthetized and positioned in the PET scanner, allowing us to quantify brain metabolism during the preceding 30 min behavioral assessment. 143Nothing (Empty Control)




Details Are Not ImportantThe active condition was identical to the control condition with one critical difference specifically, 144Nothing (Empty Control)




Details Are Not ImportantExposure to the human intruder during the initial 30 min. 145Nothing (Empty Control)




Details Are Not ImportantComparison of the two physically identical conditions allowed us to test whether the animals with extreme behavioral inhibition show differential freezing or brain activity following threat . Behaviorally, this revealed, 146

Shackman*, Fox* et al in prep

That the high BI group showed significantly elevated freezing following threat. The high-BI group also showed 147

Shackman*, Fox* et al in prep

Paxinos et al 2009

elevated metabolism in the bed nucleus following threat. Significant group differences were not observed in the central nucleus or other regions of the amygdala. These findings indicate that148

Shackman et al. PNAS 2013; Birn*, Shackman* et al. under review; Shackman, Fox et al., in prep

1495 core constituents of the anxious phenotype (3 down, 2 to go!)1. 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 phenotype (3 down, 2 to go!)1. Inflated estimates of threat certainty or intensity/cost






Key Take Homes5 core constituents of the anxious phenotype (3 down, 2 to go!)1. Inflated estimates of threat certainty or intensity/cost (mountain out of a molehill)







2. Hyper-vigilance (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






2. Hyper-vigilance (bias to allocate excess attention to threat or scanning for threat-relevant information)Active ingredient/CausalCircuits 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 BIKey Take Homes5 core constituents of the anxious phenotype (3 down, 2 to go!)1. Inflated estimates of threat certainty or intensity/cost (mountain out of a molehill)


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)Key Take HomesTake Home Critical Thinking QuestionsDan Grupe highlighted the importance of 5 intermediate phenotypes. Did he miss anything important?

Take Home Critical Thinking Questions2. Watch Paul Whalens brief TEDx talk (https://www.youtube.com/watch?v=DeAMRUnrgbA) [

Documents

Shackman Psyc210 Module16 SplittingConstituents Part1