Module 2: Anxiety Disorder Notes

Brain Regions Involved in Anxiety Disorders

Fear is an immediate response to a potentially harmful event or object. Anxiety on the other
hand, is prolonged and heightened vigilance for any looming danger in the environment. Once
fear and anxiety’s functional responses become chronic, and heightened to a degree that
generalization of signals to these are not indeed objectively dangerous, this marks the
beginning of Clinical Anxiety Disorders. This pathology generally arises from regions that
control negative emotions, especially fear. Additionally, an absence of positive affect, with
increased negative symptoms depicts the role of limbic system, the fear circuitry and PFC
regions contribution for the disorders.

Anxiety Disorders are based on the emotional reactivity of and regulation of the underlying
neural circuits. The term ‘Emotional Reactivity refers to type and magnitude of a response to
emotion-eliciting events. This involves large number of cortical and sub-cortical regions.’
‘Emotional Regulation refers to an attempt to influence or modulate the intensity, duration and
type of emotion experience, regulatory processes that are deliberate and conscious as well as
those that are reflective and out of conscious awareness. There are several regions of the brain
that are activated during anxiety:

1) Amygdala
• Activate for negative emotional stimuli and unpredictability cues associated with
feelings and behaviour seen for anxiety.
• Lesions to the region lead to inability to perceive danger associated with the previously
interrupted stimuli.
• Activation for fear stimuli, biological, irrelevant information of fear. Suppressed
activity here, leads to lowered expression of fear and anxiety across multiple events.
• Is important for threatening queues in environment, new information that also suggest
a role in hypervigilance seen an anxiety disorders.
• Electrical stimulation of this region has shown fear, anxiety, apprehension. Injection of
benzodiazepines, leads to anxiolytic effects.
• It is also involved in fear conditioning, especially when changes for conditioned
responses occur due to the devaluation of stimuli.
• Two regions of amygdala, fear and anxiety are:
• 1) Basolateral Amygdala (BLA)- receive sensory information from thalamus,
association cortices, which is then projected back to thalamic and cortical regions. This
is seen activated for non-consciously presented, fearful negative emotional
expressions.
• 2)Lateral ventral Amygdala- only for negative stimuli. BLA and the projections to
these regions interact with MPSC regions and sensory cortices.
• 3) Centromedial Amygdala (CMA)- dolsal to BLA with subcortical projections to
brainstem, hypothalamus, & PAG. These involve in physiological responses of fear.
Increased attention via arousal is also observed.

2) Insula
• Between frontal cortex and limbic system, it is involved for responses to negatively
Valent emotional stimuli and information.
• Connected with hypothalamus, PAG, amygdala receives amygdalar projections and
sends to ACC.
• BLA & anterior insular connection, there is variance in anxiety levels. Also responsible
for interceptive awareness and ANS monitoring.
• Insular is linked to the perception of internal bodily responses as dangerous where
encoding of the aversive interceptive cues is faulty.

3) PAG & Hypothalamus

• Important regions in the core limbic circuit and regulate the ENS. PAG involves for
active defensive reactions, feelings of dread for impending threat. Stimulating PAG in
humans leads to cardiovascular reactivity similar to a panic attack.
• PAG activity increases with threat proximity directly. Hypothalamus, ventromedial
region, Multiple projections to PAG and amygdala are responsible for coordinating the
defensive behaviour. The stimulations of the region lead to the panic symptoms and
behaviours.

4) Hippocampus
• Anterior Hippocampus connected to Amit Dalla for emotional task. Ventral
hippocampus relates to anxiety behaviour with projections to hypothalamus and
amygdala. Hippocampus connections to a ACC, PCC, pre-cuneus, anterior
hippocampus are connected to amygdala, striatum dACC, dmPFC and pre-Central
Gyrus.
• Perturbations in dorsal hippocampus leads to acquisition of fear, memory and
extinction of conditioned fear.
• Anxiety disorders are linked to posterior hippocampus for abnormalities of your
memory and extinction.
• Anterior hippocampus leads to general fear or anxiety related behaviour.

5) PFC
1) LPFC
DLPFC & VLPFC are associated with emotional regulation, deliberate effort, full and
conscious regulation of emotions. Unconscious aspects are related to MPFC moreover,
for fear and anxiety regulation.
2) Dorsal, Ventral and Medial Frontal cortex.
• ACC, MPFC for emotional responses.
• Dorsal Acc and dmPFC for appraisal and expression of negative emotions.
• Ventral ACC and VMPFC for emotion regulation.
• Fear conditioning, acquisition- dACC and dmPFC
• Also relates to SNS activity and interceptive awareness, pain, anger, disgust,
rejection. These regions are highly activated within amygdala.
• vACC and vMPFC- fear, extinction and recall of memories, also have negative
correlation with SNS & PAG activation. For explicit emotion, VACC acts as a
mediator between LPFC and Amygdala.
Neurocircuitry of Anxiety in Specific Disorders

1) Social anxiety disorder (SAD)

• Heightened amygdala activity for negative, ambiguous, emotional expressions,
specially, greater activity for anger and contempt in left and right amygdala, for public
speaking, task, phobia- related words, etc.
• Insular dysfunction where greater activation for public speaking, task, negative
emotions and working memory, task or seen. Decreased connectivity between anterior
insular and DACC, insufficient down regulation by cognitive control regions.
• Frontal Lobe dysfunction: Increased VSCC activity for emotional faces, decreased in
VSCC post CBT.
• Higher activation in left IFG, left parahippocampal gyrus in response to negative faces.
• First stressful, cognitive tasks, additional activation along with LPFC of the right
VLPFC and anterior insular was observed.
• Delayed DLPFC reactivity, failure for DACC and DLPFC and VLPFC activity for
autobiographical memories. Reduced positive and negative connectivity between
amygdala and PFC regions.
• Increase limbic activation, hyperactivity in amygdala and insular and VACC and
VLPFC, reduced activity of DLPFC.

2) Specific Phobia
• Hyper activation in amygdala, rapid time to peak activation. Exaggerated, emotional
reactivity, greater insular activity and reduced VMPFC, VSCC activity has also been
observed.
• Fear, circuitry activation, insular, NDSCC with autonomic involvement of arousal,
PFC, OFC activity. Greater activation of amygdala insular, and DACC has also been
observed.

3) Generalized Anxiety Disorder (GAD)

• Generalised anxiety disorder has exaggerated, amygdala, activity, signal severity and
in flexibility. Disruption in amygdala, functional connections, to BLA, cortical regions,
occipital, temporal, and PFC, alteration in limbic regions and insular activation,
disrupted frontal lobe activation.
• dACC and DMPFC greater activation during symptom provocation and reduced
activation during emotional faces. Hyper activity in VLPFC, greater connectivity
between DLPFC and amygdala.

4) Panic Disorder
• Hyper activity of amygdala in response to sensory information. Insufficient top-down
regulation by PFC and increased heart rate, insular activation. Right Amygdala, right
hippocampus and right putamen during panic attack is activated.
• Activation in amygdala is seen due to chronic hyper responsibility. Insular leads to
provoking panic symptoms along with hippocampal hyper activity and PAG activation
for physiological responses. Damage to DACC leads to panic attacks and panic
activates VACC, middle and superior frontal gyrus.
• Increased frontal lobe activity, greater dorsal and VACC activity, decreased DLPFC
activity for positive stimuli decreased VLPFC activity for negative stimuli. Hyper
 activity of insular as hallmark, not always higher activity is seen for amygdala. MPFC
hyper activation and hypo to hyper activation of frontal lobe regions depending on the
cases.

5) PTSD
• Increased amygdala activity as major Hallmark where ventral amygdala sees
hyperactivity and dorsal amygdala sees hypo activity. Insular hyper activity is observed
along with pre-frontal region having hypo and hyper activity. Reduced DACC and
increased VACC during faces stars for emotional stimuli has also been observed.
• DACC, activated for trauma, fear, conditioning and extension, major risk factor for
PTSD. Hypo activation in VACC for face of emotional stimuli due to insufficient
regulation of systems. Decreased activity in VMPFC and nucleus accumbens during
reward processing.
• Memory difficulties in PTST, hippocampal activation. Where posterior hippocampus
is for episodic memory and anterior hippocampus for anxiety related behaviours.
• Posterior hippocampus is connected to VACC and PCC for fear memory abnormalities.
Decreased connectivity between anterior hippocampus and DACC is seen in PTSD,
and GAD.
• Limbic hyper activity, increased response to DACC, DMPFC and hyper activity in
VACC and VMPFC is seen.

Neurotransmitter: Role of GABA receptors in Anxiety

• Among the neurotransmitters that are involved GABA acts as the major inhibitory
neurotransmitter and plays a critical set point role in fear and anxiety circuits. Acute
reduction levels of GABA cause anxiety. For instance, healthy volunteers experienced
panic anxiety symptoms, when GABA A receptors were manipulated in the experiment
by using benzodiazepine agonists.
• A defective GABA system acts as predisposition for continued experiences of anxiety
or fear. GABA A receptor deficit with strongest amounts is seen in cortical areas- OFC,
insula, DLPFC among panic anxiety patients where the severity of symptoms correlates
to the deficit of GABA A receptor.
• GABA A receptor function partial reduction affected hippocampus, cerebral cortex and
some areas of amygdala where display of behaviors indicated anxiety and GAD
symptoms.
• GABA neurons play a key role in acquisition, storage, and extinction of fer in Amygdala
and cerebral cortex. In the Lateral Amygdala, the LTP process is under the GABAergic
feedforward control systems. GABA B receptors block this LTP process, where
Antagonists of GABA B receptors induced LTP and was facilitated at both cortical and
thalamic afferent synapses.
• The central nucleus of Amygdala (CEA) is considered as a major output for fear-related
behavior. The output neurons in this region are under the strong control of inhibitory
neurotransmitter GABA that is located in the lateral subdivision. By using aversive
stimuli disinhibiting the CEA region leads to execution of fear and anxiety responses.
The inhibition of the region operates largely via alpha2, GABA A receptors. Thus,
GABA neurons play a crucial role for inhibition of fear.
• CEA region contains subdivisions that express high levels of neuropeptides that
modulate anxiety and stress-related behavior. Oxytocin exerts strong anxiolytic activity
which can be suppresses by GABAergic neurons within CEA region.
• Activation of GABAergic neurons in Amygdala also underlies the process of
extinction. During extinction, the cortical neurons lack aversive unconditioned stimulus
that are thought to suppress amygdala output. This activity is possible by cortical
activation of GABAergic neurons f the intercalated cell cluster that surround the
amygdala and innervate BLA and Central nuclei. They play a crucial role by blocking
the fear-induced LTP and can alter behaviors.