Task 4. Biological substrate of panic and anxiety
Learning goals
What brain areas are involved in anxiety and fear?
not that detailed. Look how each anxiety relates to the fear network
Fear network:
- Amygdala: Detecting emotional salience, this is important for survival
- Insula: Intercept self-awareness, feeling. this is where you create a feeling of anxiety.
This is relevant for yourself, for your own ideas etc. You also have emotional feelings that
come from ACC.
- ACC: Creates approach and avoidance. This also involves this conflict between approach
and avoidance
Example: amygdala notices something bad, the amygdala also provokes the bodily reaction.
In the insula the emotional aspects are signed to it, gives you feelings of fear. The ACC
triggers you to run away.
Nees, F. and Flor, H. (2014) Neuroanatomy and Neuroimaging, in The Wiley Handbook of
Anxiety Disorders
Introduction
Patients suffering from anxiety disorders have been reported to show a wide range of
behaviors associated with altered neural functions in specific brain regions. As main
characteristics, an attentional bias toward threat-related stimuli and a negative
interpretation of emotionally ambiguous stimuli. Dysfunctional processes related to the
cognitive control of emotional processes involve brain regions such as the amygdala, the
prefrontal cortex (PFC), specifically dorsolateral, dorsomedial, and ventromedial parts, and
the anterior cingulate cortex (ACC), the orbitofrontal cortex (OFC), the insular cortex, the
periaqueductal gray (PAG), the thalamus, the hypothalamus, and the striatum. Whereas
ventromedial PFC parts are more involved in negative and positive emotional states,
dorsolateral parts are more active during goal-oriented processing of emotional states. The
amygdala has been identified as important for the perception and expression of emotion,
specifically for fear-related negative affect and in fear conditioning, and is assumed to code
the value or salience of a stimulus. Together with further brain regions such as the insula,
which is involved in subjective feelings and emotion processing in general, and the ACC,
which has been related to approach and avoidance behaviour during fear learning, this
circuit has been referred to as the fear network.
Fear conditioning processes represent an important mechanism. Previously neutral stimuli
have been shown to provoke emotional distress, vigilance, hyperarousal, or avoidance
behaviour. The amygdala plays an important role in the acquisition and expression of
conditioned fear, while its extinction is thought to also depend on the PFC. Additionally, the
hippocampus plays a central role in contextual modulation of fear acquisition and extinction
of memory-related processes such as reinstatement and renewal.
,Functional and structural neuroimaging studies
General anxiety disorder (GAD)
- Functional imaging studies A higher response of the amygdala and insula to fearful or
aversive pictures in GAD and during briefly presented threat is identified. However, a
hyporesponsivity in patients compared to healthy controls was also partly reported.
These inconsistencies could be related to preexisting differences in brain resting state
and connectivity.
The medial PFC, specifically the dorsal and rostral ACC, was hyperresponsive to fearful
faces in adolescent GAD patients. GAD patients also failed to activate ventral ACC parts
and the dorsomedial PFC in an emotional conflict task. In addition, during maintenance
and reappraisal of negative images, GAD patients showed reduced dorsolateral and
dorsomedial PFC response. These findings suggest a dysfunction in the more automatic
modulation of emotions in GAD and might also explain the difficulty in controlling worry
as a core GAD symptom.
- Structural imaging studies White and gray matter abnormalities could be observed
that may partly explain the impaired cognitive control of anxiety in GAD as well as
excessive and persistent worrying. Larger volumes and higher fractional anisotropy in the
amygdala, which was additionally significantly correlated with higher levels of anxiety
and worrying, and lower fractional anisotropy in the cingulate cortex were also found in
GAD. Symptom severity was positively correlated with dorsomedial PFC and ACC volume
in GAD.
So, dysfunctions in brain regions associated with emotional processing and social behavior
are important (e.g. amygdala, insula, ventromedial PFC). Findings on PFC hyper- and
hyporesponsivity can be due to individual differences: high uncertainty-intolerant GAD
patients had higher rostral and subgenual ACC response, low uncertainty GAD patients had
deactivation in the rostral and subgenual ACC. The striatum could be involved too.
Social phobia/ social anxiety disorder (SAD)
- Functional imaging studies During fear conditioning, higher amygdala and
hippocampal responses to the conditioned stimulus in SAD were found. In addition,
neutral faces used as conditioned stimuli elicited amygdala activation and in one study
also orbitofrontal activation that is usually only seen in response to emotional faces. A
generally higher amygdalar response to angry vs. neutral faces and to happy/schematic/
angry/neutral facial expressions was found in SAD also outside a learning context and
was positively associated with symptom severity, state-trait anxiety, and reports of fear.
However, one study reported lower amygdala response to social anxiety-provoking task.
High vs. low socially anxious individuals showed reduced fusiform gyrus responses to
faces of strangers, suggesting that those individuals actively avoid socially challenging
situations by averting their gaze away from them and this might contribute to social
deficits and social withdrawal. As a consequence, SAD patients may recruit neural
systems for ‘alarm’ responses to a larger extent in interpersonal situations, while healthy
individuals would activate neural cognitive control mechanisms that allow an appropriate
interpretation of the context. For the PFC, a higher rostral ACC response was reported to
pictures of disliking peer, facial fear expressions and disgust. One study reported a lower
response in the ventromedial PFC. There were also inconsistencies in the dorsal ACC
where higher response to harsh facial expressions, disgust, and negative comments, but
, lower response to the anticipation of public speaking and schematic angry faces were
found.
Although there is consistent evidence that the amygdala and the PFC are main regions of
interest, the insular cortex seems to play a role as well: enhanced responses during
anticipation of public speaking and during presentation of emotional facial expressions,
but also lower response during public speaking and implicit sequence-learning task.
- Structural imaging studies Larger gray matter volume was found in the
parahippocampal, middle occipital, bilateral supramarginal, and angular cortices and left
cerebellum and lower gray matter volume in the left lateral OFC and bilateral temporal
poles and in the right posterior inferior temporal gyrus and the right
parahippocampal/hippocampal gyrus, which was negatively associated with social fear.
Increased left inferior temporal volumes and significant negative association of right
rostral ACC thickness and social anxiety were also found.
So, the amygdala, the (medial) PFC, and the insula can be considered important regions
involved in SAD. However, the findings are inconsistent and require more detailed analyses
in the future, also with respect to specific individual disorder-related characteristics.
Specific phobias
- Functional imaging studies A hyperresponsivity in the amygdala, insula, hippocampus,
dorsomedial PFC, ACC, thalamus, and the supplementary motor areas were found during
anticipation and processing of phobia-related stimuli. Different subregions of the ACC
were found as relevant for specific phobia. While some studies observed a higher rostral
ACC response, others reported decreased dorsal ACC response to phobia-related stimuli
after CBT. Moreover, lower medial OFC response was shown to increase from pre- to
posttreatment in a treatment.
- Structural imaging studies there are suggestions that the rostral ACC and the insular
cortex are thicker in patients with animal phobias, but details are missing
So, in patients with specific phobia a hyperresponsivity of the amygdala, insula, and dorsal
ACC in response to disorder-relevant stimuli was observed, while findings with respect to the
rostral ACC are quite heterogeneous. Alterations in the amygdala may be more general and
the prefrontal, insula, and OFC responses may account for state anxiety or the expectation
of adverse intero- and exteroceptive cues
Posttraumatic stress disorder (PTSD)
- Functional imaging studies The amygdala, hippocampus and medial prefrontal regions
play a central role. Amygdala hyperresponsivity was found for symptom provocation or
fear learning in PTSD. A reduced amygdala response corresponds to higher resilience in
PTSD. In addition, there is a positive correlation between amygdala response and PTSD
symptom severity, a lower amygdala response after CGT, and a negative association
between the amygdala response pretreatment and a positive treatment response.
The PFC in contrast was shown to be hyporesponsive in PTSD, although some studies did
not find differences in the dorsal ACC. However, there was a negative association
between the medial PFC and symptom severity. A higher medial PFC response
posttreatment was positively associated with symptom improvement, although not
consistently observed.
, Although the hippocampus was also reported to be hyperactivated, a number of studies
demonstrated lower hippocampal response in PTSD. This is in line with treatment studies
that showed higher hippocampal response in PTSD patients after successful treatment.
Moreover, during fear acquisition and extinction, trauma-related imagery, retrieval of
neutral or emotional stimuli and higher response in insula was observed. Findings of a
positive association between insula activation and symptom severity, support the
assumption of insular hyperresponsivity as an important factor of PTSD.
- Structural imaging studies a volume reduction was found in the hippocampus, ACC,
the frontal gyri, insula and left temporal gyrus in PTSD. Additionally, reduced fractional
anisotropy in the medial and posterior corpus callosum was related to PTSD. Lower
hippocampal volume and the association of hippocampal volumetric differences with
PTSD severity and of abnormalities in frontal-limbic structures might result in difficulties
in identifying safe contexts, and in re-experiencing the trauma.
There is need to further investigate amygdala volume in PTSD in more detail, and
underline the potential role of early and adult trauma.
Lower gray matter volumes in the medial PFC and dorsal and ventral ACC were found in
PTSD and were associated with PTSD symptoms. This negative association might be
related to a failure to inhibit the amygdala as a central component of the “fear network.”
Reduced gray matter volume in the left dorsal ACC was found in PTSD patients. In trauma
survivors the gray matter volume in the bilateral cuneus, right frontal lobe, right middle
occipital lobe, left anterior and middle cingulate cortex was negatively correlated with
PTSD symptoms, while patients’ symptom scores correlated negatively with gray matter
volume in the right ACC and bilateral superior medial frontal lobe.
So, an important role of the amygdala, the medial PFC, the ACC, the insula, and the
hippocampus in the pathophysiology of PTSD was confirmed in several studies. It is assumed
that a hyperresponsivity of the amygdala along with a hyporesponsivity of the medial PFC or
ACC are associated with deficits in the automatic control of emotion, a higher fear response,
and traumatic memory persistence and that deficits in hippocampal activation result in
impaired contextual information processing.
Panic disorder
- Functional imaging studies A hyperresponsivity in the amygdala, thalamus, and
hippocampus along with a hyporesponsivity of frontal cortical regions in response to
symptom provocation tasks are important. This might result in higher fear and thus
account for panic attacks, based on the failure of a top-down inhibition of the amygdala
by the PFC. Patients with panic disorder tend to develop a general fear of negative
events. Higher rostral ACC response during anticipation of anxiety and imagery of high
vs. low anxiety-related situations, and additionally in the dorsal ACC during presentation
of happy faces, were also found.
Additional findings include a higher response in the striatum, and a lower response in the
insula and the brain stem during anticipation of anxiety in panic patients.
- Structural imaging studies There are only few studies on structural imaging, which
revealed that panic patients display diminished volumes in the left and right temporal
lobe, left and right amygdala, and left hippocampus. Higher gray matter volume in the
rostral pons and the left insula and reduced volume in the PFC, the left parahippocampal
gyrus, and the putamen were also found. The putaminal volume reduction was
negatively associated with symptom severity and the duration of the disorder.
