PRESENTATION BY JUAN-CARLOS ANDALUZ

PAPER

LANG ET AL 2013

PATHOLOGICAL ANXIETY AND FUNCTION/DYSFUNCTION IN THE BRAIN’S FEAR/DEFENSE CIRCUITRY

FROM FEAR TO ANXIOUS MISERYFACTOR ANALYSES

• Factor analyses suggest that the different anxiety diagnoses may not be unitary phenotypes as assumed by current assessment practice !

• Epidemiological studies of anxiety and mood disorder comorbidity have emphasized a core internalizing dimension comprised of two classes of disorders: fear and “anxious misery” !

• Phobic disorders are classified as fear disorders whereas generalized anxiety disorder, dysthymia, and depression are characterized by pervasive distress and better captured by an anxious-misery factor.

!• PTSD more closely associated with anxious-misery factor

(the conventional PTSD diagnosis encompasses patients with a clear fear diathesis as well as patients with the more complex diathesis of chronic anxious misery).

STARTLE POTENTIATION & THE ANXIETY DISORDERS

• Large differences in fear startle potentiation observed over the spectrum of anxiety disorders

!• Startle reflex potentiated in specific phobia patients while panic disorder with agoraphobia

(PAD) and generalized anxiety disorder (GAD) groups failing to show evidence of exaggerated startle when imagining personally relevant fear cues

!• There is a linear trend across the anxiety spectrum that is opposite in direction to the

startle potentiation gradient, with the highest BDI scores associated with the least fear potentiation

WITHIN-DIAGNOSIS VARIABILITY

• Single trauma group showed dramatic startle potentiation during personal fear imagery !• Multiple trauma group showed much reduced fear potentiation and higher ratings of negative affectivity as

well as increased incidence of co-morbid depression and other anxiety diagnosis, longer chronicity and higher interview ratings of disorder severity

BLUNTED STARTLE REFLEX & NEGATIVE AFFECTIVITY

• Patients without agoraphobia show significant fear potentiation during fear-relevant imagery !• Panic disorder patients with agoraphobia show blunted blunted reflex activity that increases with agoraphobia

severity !• Once again suppressed probe startle reflexes were accompanied by an increase in broad self-reported negative

affectivity

• Circumscribed social phobia patients show strong startle potentiation during imagery o their performance fear !• Non-depressed generalized social phobia patients show markedly potentiated startle reflexes for all social

threat scenes !• A decreased potentiation is evident in generalized social anxiety patients with comorbid major depression !• The most extreme symptoms of enhanced negative affectivity can be seen in generalized social phobia patients

with comorbid depression

THE DIAGNOSTIC SPECTRUMMORE BLUNTED STARTLE POTENTIATION FOR DISORDERS OF ANXIOUS MISERY

• Depending on trauma frequency (and associated negative affectivity) PTSD patients are located at each extreme the startle/anxiety spectrum

!• This evidence suggests that startle potentiation is meditated by fear/defense circuit activation and that

these factors are associated with a severe dysregulation of the neural networks involved

THE FEAR/DEFENSE CIRCUITNEURAL IMAGING STUDIES OF ANXIETY DISORDER AND DEPRESSION

• The fear/defense circuit activated in normal fear conditioning is implicated in the pathophysiology of the anxiety disorders !• neural imaging experiments across 3 anxiety disorders (social phobia, specific phobia & PTSD) showed greater than matched

comparison subjects in the amygdala and insula, structures linked to negative emotional responses !• Regions involved in this circuit (as differentiated between depressed & non-depressed participants) include areas of the

medial & inferior PFC, anterior cingulate, insula, superior temporal gyrus and basal ganglia

• Imagining either pleasant or unpleasant events significantly increases amygdala activation (almost similar activation between pleasant and unpleasant contents)

!• Pleasant stimuli may include: scenes of joy (winning a lottery), erotic content (sexual encounters) !• Neutral scenes may include daily activity such as doing laundry !• Unpleasant stimuli may include survival threat (auto accident), animal attacks, contamination (someone vomits on your

hand)

• Imagining either pleasant scenes prompts unique increases in functional activity of both the nucleus accumbens and the medial PFC

!• The opposite (a dramatic reduction in regional blood flow) is observed during unpleasant

imagery

• Strong linear relationship found between pleasantness and functional activity for both mPFC and NAc

!!!• Significant increase in bold activity when

imagining the most pleasant contents !!!• Significant decrease when imagining the

most unpleasant contents !!!• The decrease in bold activity could

indicate inhibition of the appetitive system in aversive arousal

• Low-BDI group shows some amygdala enhancement when imagining unpleasant scenes, compared to neutral scenes

!• High-BDI group fails to show heightened amygdala activity when imagining aversive

events !• These findings suggest a possible circuit dysregulation involving the amygdala during

fear challenges in individuals high in depression/anxious misery

CONCLUSIONS

• Anxiety disorders are distributed along a dimension of pathology extending from patients that show focal, exaggerated fear reactions (specific phobia, social performance anxiety) to patients with more generalized anxiety and mood symptoms, aka disorders of anxious misery (panic disorder with agoraphobia, generalized anxiety disorder)

!• The startle response varies across the anxiety spectrum !• Blunting of fear-potentiated startle is associated with anxiety disorder chronicity (severely

blunted in patients with disorders classified as anxious misery) !• The anxiety disorder severity continuum is characterized by progressive negative

affectivity !• Startle potentiation is mediated by activation of the brain’s fear/defense circuit !• Pathophysiology could be explained by hypothesis that motivational circuits are

compromised and increasingly dysregulated in patients in which the anxious misery symptom complex has greater prominence