Anxiety disorders: Neurobiology, neurochemistry and treatment NS Flashcards
Nuclei of the amygdala
Basolateral region - Lateral, basal, accessory basal
Cortico-medial region - Central, medial and cortical
Where is the amygdala located
- Medial temporal lobe
Where does the lateral nucleus of the amygdala receive input from
- Sensory cortex
- Sensory thalamus
Output of lateral nucleus
- Basolateral nucleus
Outputs of basolateral nucleus
- Central nucleus
- Ventral striatum + dorsomedial nucleus of thalamus
- Basal nucleus
Inputs to basolateral nucleus
- Lateral nucleus
- Hippocampal formation
Outputs of basal nucleus
- Central nucleus
- Periaqueductal gray matter
Inputs to central nucleus
- Basolateral nucleus
- Basal nucleus
Outputs of central nucleus
- Hypothalamus
- Midbrain
- Pons
- Medulla
Input to medial nucleus
- main and accessory olfactory bulb
Output of medial nucleus
- Medial basal forebrain and hypothalamus
Amygdala pathway via lateral hypothalamus
Amygdala –> Lateral hypothalamus –> sympathetic activation –> tachycardia, galvanic skin response paleness, pupil dilation, blood pressure elevation
Amygdala pathway via VTA and LC
Amygdala –> VTA, LC, dorsal lateral tegmental nucleus –> activation of dopamine, norepinephrine and acetylcholine –> Behavioural and EEG arousal increased vigilance
Amygdala pathway via paraventricular nucleus
Amygdala –> ACTH release –> corticosteroid release(stress response)
What does the amygdala excite during a stress response
- Sensory info channeled to amygdala
- Amygdala excites LC + hypothalamus
Acute stress response - HPA axis
Hypothalamus releases CRH Pituitary releases ACTH Adrenal cortex releases cortisol (stress hormone) (CRH: corticotropin releasing hormone ACTH: adrenocorticotropic hormone)
Acute stress response - LC
Locus Coeruleus (LC)
releases norepinephrine
which triggers
“fight or flight” responses
Characteristics of stress response
Characteristics of the stress response:
- Avoidance behaviour
- Increased vigilance and arousal
- Activation of the sympathetic division of the ANS
- Release of cortisol from the adrenal glands
How does cortisol cause negative feedback on stress response
- Cortisol excites hippocampus
- Hippocampus has inhibitory effect on HPA
Effect of chronic stress on hippocampus
Chronic activation of glucocorticoid receptors in hippocampus
- increased Ca2+ entry into neurons
- too much Ca2+ - excitotoxic - cells die
Hippocampus can’t feedback to limit cortisol production
Link between anxiety disorders and hippocampus and amygdala
- diminished activity of hippocampus
- loss of feedback to the amygdala
- inappropriate fear responding
(evidence - hippocampal volume in PTSD patients reduced)
Serotonergic vs Norepinephrine systems
Serotonergic systems and Norepinephrine systems project diffusely through the brain and are thought to have opposing functions.
NE release stimulates arousal and alertness
5-HT inhibits Norepinephrine (NE) release
Opposing functions in various brain areas
hippocampus
amygdala
hypothalamus
Balance of NE and 5-HT in panic attacks
Shifted balance between the pathways to NE may be
manifested in Panic Attacks - fear responses to
inappropriate stimuli
SSRIs, by increasing 5-HT release, will push balance back
Features of OCD
Frequently recurring, uncontrollable, anxiety-producing thoughts (obsessions) and impulses (compulsions). Responding to them, e.g. repeated, compulsive hand washing, dissipates associated anxiety.
OCD patients recognize their thoughts and behaviours are senseless
Incidence of OCD
1-2%
Categories of compulsions
counting, checking, cleaning, avoidance (exaggeration of natural human tendencies)
e.g. trichotillomania, onychophagia
OCD - genetics
- Greater concordance with monozygotic than dizygotic twins
* Common underlying genotype for Tourette’s and OCD
Environmental cause of OCD
- Streptococcal infection
- experience also plays a role(eg stressful life events)
What other condition is OCD associated with
• Associated with Tourette’s syndrome – hereditary chronic motor tic disorder (muscular and vocal tics) that has its locus in the basal ganglia
Link between indirect and direct pathways and OCD
• Imbalance between indirect and direct pathways through basal ganglia
Role of direct and indirect pathways in OCD
Direct pathway controlling previously learned behavioural sequences so they become automatic and can be rapidly executed
Indirect pathway involved in suppressing these automatic behaviours allowing the person to switch to other more adaptive behaviours (behavioural flexibility).
Overactivity of direct pathway may lead to these compulsive behaviours without being able to switch them off
Best drugs to treat OCD
SSRIs best drugs for treating OCD, e.g. fluoxetine
but also clomipramine (TCA)
OCD and caudate hyperactivity
The caudate sends GABAergic inhibitory projections to the GP, which sends inhibitory projections to the thalamus, which then projects to the OFC.
It’s possible that OCD involves a disinhibition which leads to activity reverberating in this circuit.
Comparison of biological changes caused by CBT and SSRIs
- Lead to a similar biological change
OCD and OFC dysfunction
Underactivation of OFC in a reversal learning task in patients with OCD and their unaffected relatives, Chamberlain et al, Science, 2008.
New endophenotype for OCD.
(vulnerability marker)
Use of benzodiazepines in OCD
- Good immediate effects, but patients can develop tolerance and there is potential for abuse, and anxiety
SSRIs - OCD
SSRIs are effective, but have a delayed onset. Initially can be anxiogenic
Combination of benzodiazepines and SSRIs - OCD
Combining benzodiazepines and SSRIs initially and then tapering off the BDZs as the SSRIs take effect is an alternative treatment strategy
Regions of the amygdala
- Basolateral
- Cortico-medial
