Lecture 3: Anxiety Disorders

• Anxiety brain circuitry

  • Amygdala and hippocampus communicate with each other
  • Hippocampus lets amygdala know about past memories to indicate if you should be anxious about xyz or not
  • Bed nucleus of stria terminalis - communciates with amygdala
  • Hypothalamus = important too
  • Locus ceruleus - regulates sympathetic nervous system activity.

  
• Anxiety

  • Universal human emotions - necessary to adapt to environment
  • Fear response: defensive behaviours, arousal, negative emotions
  • Anxiety: reactions due to anticipation of negative event
• Fear (to threat) is normal.

  Two main responses to threat

  1. Immediate (subcortical) response to threat
  2. Cognitive processing of immediate response to threat
• Immediate (subcortical) response to threat

  • Visual and auditory stimuli reach the thalamus and travel to the amygdala
  • The amygdala alerts other brain structures including the hypothalamus (HPA axis) and locus coeruleus
  • surges in cortisol and noradrenaline = sweaty palms, tachycardia, increased blood pressure.
  • The individual is prepared for a “fight or flight response.”

  
• Cognitive processing of immediate response to threat

  • Information is sent from the thalamus to the cortex and basal ganglia for cognitive processing
  • These regions analyse raw data from the sensory organs and decide whether to continue or discontinue the fear response.
  • If it is decided to maintain the fear response, the amygdala remains on the alert (to help make further appropriate behavioural responses).
  • Cognitive input lets you know whether you need to worry about something or not
• Anxiety is a universal human emotion - necessary to adapt to our environment
• Pathological Anxiety

  • First recognised as disorders in 1980’s
  • Originally diagnosed as “stress” or “nerves”
  • 17% of our population, experienced more by women than men
  • Indigenous population: 16.5% (20% in women, 12% males)
  • Charlotte Bronte (Jane Eyre): 1952 suffered anxiety with depression
  • Sigmund Freud: suffered panic disorder (‘spells’)
  • “Neurotic Anxiety”: overwhelmed by id (internal drives, instincts)
• Pathological Anxiety

  • Panic-agoraphobia syndrome
  • Phobias
  • Generalised anxiety disorder (GAD)
  • Obsessive-Compulsive Disorder (OCD)
  • Post-traumatic stress disorder (PTSD)
  • Social anxiety disorder (SAD)
  • Anxiety is a factor in Depression
• Anxiety

  • Overlapping circuitry with Phobias/Panic disorder
  • Cingulate activation
  • Amygdala/hippocampus
  • Occipital (specific trigger)
  • Periaqueductal grey
  • Involved in defence mechanisms
• Generalised Anxiety Disorder

  • Excessive on-going anxiety without reason or focus
  • Overactivity of the sympathetic nervous system
  • Continual tension
  • Focus on possible impending danger/disaster
• Neurotransmtiters involved in GAD

  • Noradrenaline
  • Serotonin
  • Dopamine
• Noradrenaline in Generalised Anxiety Disorder

  • Noradrenaline systems are overactive – central and peripheral

  
• Serotonin in Generalised Anxiety Disorder

  • Increased activity due to lack of Serotonin in:
  • Basal ganglia
  • Inability to adequately process information from the environment
  • Cerebral cortex (prefrontal)
  • Inability to adequately execute appropriate responses to information from environment
  • Limbic cortex/ Amygdala
  • Emotion & control of hypothalamus
  • Serotonin isn't plentiful in the dotted lines. This means hyperactivity of neurons.
  • 5HT1A receptor is worked on by serotonin. If serotonin acts on this receptor, it calms neurons down (IPSPs)
  • With no serotonin in this area, it becomes overactive

  
• Obsessive-Compulsive Disorder (OCD) (dopamine greatly involved)

  • Obsession with ‘something’ and are compelled to act on it
  • Obsessed with dirt, germs - compelled to wash excessively
  • Obsessed with danger in household - will recheck appliances
  • Obsessed with symmetry or order
  • May be caused by uncontrolled communication (loop) between frontal, striatal and thalamic structures?
  • Lesions of frontal (cingulate) cortex neurons (cingulotomy) breaks the loop and helps OCD patients
• Neurotransmitters involved in OCD

  • Noradrenaline
  • Serotonin
  • Dopamine
• Noradrenaline in Obsessive-Compulsive Disorder (OCD)

  • Note less cerebellar and sympathetic outflow than GAD
  • Similar to GAD with noradrenaline but no sympathetic outflow that was very high in GAD
  • For OCD, only when they're worried about something. People with GAD are worried ALL the time.

  
• Serotonin in Obsessive-Compulsive Disorder (OCD)

  • *similar to GAD but what's different to GAD is that OCD involves the hippocampus too*
  • Increased activity due to lack of Serotonin in:
  • Cerebral cortex
  • Less focused information from environment
  • Basal ganglia/Thalamus
  • Inability to adequately interpret & process information from the environment
  • Hippocampus *only addition to GAD*
  • Disturbances in memory processes
  • Limbic cortex/ Amygdala
  • Emotion & control of hypothalamus

  
• Dopamine in Obsessive-Compulsive Disorder (OCD)

  • Increased dopamine function in basal ganglia (Nigrostriatal) produces repetition of habits
  • Different from GAD again
  • Substantia nigra to striatum = nigrostriatal
  • Mesolimbic pathway and nigrostriatal pathway communicate with each other. Starts at mesolimbic, ends with nigrostriatal and repetition of habits

  
• Posttraumatic Stress Disorder (PTSD)

  • Exposed to an extremely traumatic situation
  • Rape
  • War combat
  • Sudden loss of a family member or friend
  • Memories and associated fear are very difficult to suppress
  • Can be triggered at anytime by surroundings
  • Leads to intense anxiety
  • “inability to extinguish conditioned cues”
• Posttraumatic Stress Disorder (PTSD)

  • Effects on neural circuits are less well defined
  • Amygdala:hippocampus increased -> Ratio between amygdala and hippocampus get increased
  • Amygdala dominates information from the hippocampus - leads to exacerbation of negative emotion linked to the memory of event
  • Amygdala becomes stronger. Hippocampus decreases/shrinks
  • So amygdala dominates any info coming from hippocampus --> get memory --> "This is really scary!! React like this!"

  
• Anxiety

  • HPA axis = involved in release of cortisol (arousal hormone)
  • Hippocampus main role
  • Fight against amygdala to suppress the hypothalamus
  • "The memory actually isn't that bad"
  • Amygdala role
  • Drive the hypothalamus
  • This increases release of cortisol and actives autonomic nervous system.
  • Prefrontal cortex
  • Shuts down the amygdala
  • Upper cortical input --> tells amygdala to calm down
  • But in PTSD, this connection is lost
  • People who are resilient to PTSD maintain connection between prefrontal cortex and amygdala
• • Hippocampus and amygdala fight together to affect the hypothalamus
  • Hippocampus = suppress hypothalamus (don't freak out! the memory isn't that bad!)
  • Amygdala = drives hypothalamus (freak out! this is scary!)
  • The hypothalamus regulates autonomic nervous system (peripheral)
  • The pituitary gland tells the adrenal gland to secrete hormones into the blood (cortisol)
  • PFC tells amygdala to shut down / quell. - chill out!

  
• Those with PTSD lose control of the prefrontal cortex. This means the prefrontal cortex can no longer tell the amygdala to calm down!
• Cortisol activates the hippocampus

  • When cortisol is released by the adrenal glands into the body, it comes back up and gives positive feedback to the hippocampus - tells it to shut down (we don't need you anymore!)
  • Stress - hippocampus shrinks because of cortisol
  • The positive feedback to hippocampus leads to negative feedback to the hypothalamus (inhibits hypothalamus)
  • ACTH is not released

  
• PTSD has increased Amygdala:Hippocampus

  • Hippocampus is now smaller = less efficient at inhibiting ACTH release. So the pituitary gland releases lots of ACTH which then tells adrenal gland to increase cortisol
  • Less ability to shut down hypothalamus. So now amygdala is dominating
  • PTSD = abnormal cortisol or abnormal noradrenaline

  
• Anxiety & PTSD (normal vs. maladaptive)

  • Hippocampus & amygdala fight each other
  • Hippocampus-->suppress hypothalamus (reduce anxiety). (Prefrontal cortex also tries to stop amygdala)
  • Amygdala-->drive hypothalamus (increase anxiety)
  • Hypothalamus communicates with pituitary gland which releases ACTH.
  • ACTH triggers adrenal glands and tells it to release cortisol
  • Cortisol release--> positive feedback to hippocampus which inhibits hypothalamus (adaptive - good!)
  • ACTH is not released!
  • PTSD though...hippocampus=less efficient at inhibiting ACTH. Amygdala dominates=more ACTH=more cortisol release
• Common Neural Circuits of Anxiety

  • All noradrenaline neurons are overactive
  • Select serotonin neurons are underactive
  • Leads to overactivity of neurons in the area
  • OCD also has increased dopamine activity in basal ganglia
• Treatments for Anxiety

  • Anxiety disorders have hyperactive neural circuitry
  • How can we reduce (over) activity of neurons?
  • GABA can silence neurons so we want to increase GABA!
• Silencing the Overactive Brain

  • Increase negative charge into the neuron (chloride ions Cl-)
  • Negative charge helps silence overactivity
  • enhance inhibitory neurotransmission (IPSP)
  • enhance GABA receptor activation to enhance Cl-
  • GABA-A receptor = chloride channel - enhance this!
• Treatments for Anxiety

  • Early treatments consisted of using barbiturates
  • Act as GABA Receptor agonists (enhance GABA-A receptor cells to increase Cl- coming in) - not very selective
  • High incidence of side effects (sedation, fatal overdose)
  • Highly addictive
  • Best used as anaesthetics
  • Overtaken by the benzodiazepines (benzos) (1970-80’s)
  • More selective as GABA receptor agonists
• Benzodiazepines

  • Benzodiazepines enhance the effect of GABA on it’s receptor
  • Benzodiazepines have their own binding site on the GABA receptor: Bz1 and Bz2
  • The GABA-A receptor can bind both GABA and Benzodiazepines to enhance receptor function on the dendrite of the neuron
• The GABA-A Receptor (gamma amino butyric acid)

  • If you have GABA binding to the receptor, it'll open and let chloride ions into the cell.
  • If you have benzodiazepine, it'll cause the channel to stay open for a lot longer - let more chloride in.

  
• Normal GABA Neurotransmission

  1. GABA is held in the vesicles of the presynaptic terminal. GABA-A receptors are on postsynaptic dendrite.
  2. With action potential, GABA is released into the synapse
  3. GABA gets attracted to GABA-A receptors which activate
  4. Activation of GABA-A receptors. They open up and let Cl- into next neuron=IPSPs - inhibits this part of neuron

  Benzodiazepines

  1. Benzos enhance GABA effect
  2. Benzo binds to receptor and keeps it open for a lot longer! = more Cl- come in = larger IPSPs in postsynaptic dendrite (noradrenergic) = more chance of inhibiting whole neuron

  
• Benzodiazepines

  • Reduce anxiety and aggression
  • Produce sedation (can be used for insomnia)
  • Treatment is effective immediately (oral absorption good)
  • Adverse side effects: sedation, tolerance, dependence
  • Need a more specific treatment

  Examples of Benzodiazepines

  • The *azepams!*
  • Diazepam; Lorazepam etc. (valium)
• Anxiety Treatments II

  • Treatments for anxiety are shifting from the ‘global’ treatment with benzodiazepines to more specific treatments
  • Specifically decrease noradrenaline?
  • only beneficial for peripheral effects
  • beta-adrenoceptor antagonists (e.g. propranolol - Deralin) are used to stop sympathetic overload
  • Recent meta-analysis shows not effective
  • Specifically increase serotonin?
  • Yes! Use a selective serotonin re-uptake inhibitor
  • or agonists at the serotonin 5HT1A receptor
• List of treatments for anxiety

  • Benzodiazepines (global)
  • beta-adrenoceptor antagonists (specific for noradrenaline but not effective)
  • SSRI (selective for serotonin)
  • Agonists at serotonin 5HT1A receptor (selective for serotonin)
• 5-HT Receptors Metabotropic

  • 5-HT1
  • 5-HT2
  • 5-HT3
  • 5-HT4
  • 5-HT5
  • 5-HT6
  • 5-HT7

  We want to target 5HT1A receptor for serotonin
• Normal serotonin neurotransmission

  1. Serotonin in vesicles of presynaptic terminal
  2. 5HT1A receptors in postsynaptic membrane
  3. NOT channels
  4. Metabotropic receptors = needs metabolic process (signalling mechanism needed behind receptor to open it. Not as simple as ionotropic receptor)
  5. Action potential received=serotonin (5HT) released into synapse
  6. Serotonin binds to 5-HT1A receptor-->activates Gi inhibitory protein
  7. Serotonin inhibits post-synaptic neuron=IPSP
  8. Serotonin gets taken up through serotonin transporter (SERT)
  9. Serotonin then gets broken down (metabolised) or repackaged into vesicles

  
• Serotonin neurotransmission in anxiety

  1. Serotonin levels are reduced in the vesicles of the presynaptic terminal already
  2. Due to this, small levels of serotonin released into synapse
  3. Less serotonin can bind to 5HT1A receptors and less Gi inhibitory proteins to active the receptors
  4. Less serotonin = less postsynaptic inhibitory effect
  5. Less reuptake w/SERT and repackaged into vesicles

  
• SSRI Function

  1. Keep serotonin in the synapse
  2. Serotonin transporter (SERT) is blocked by SSRI
  3. With next action potential, more serotonin will stay in the synapse
  4. Effect of serotonin lasts longer and more receptors are bound by 5-HT activated by Gi inhibitory proteins.
  5. More IPSPs
  6. Effect of serotonin is restored!

  Reduced levels of serotonin in anxiety can be alleviated by SSRI