Lecture 7b

Thursday, September 20, 2018 20:21

Neuroanatomy + Clinical disorder

Ventricles
Four main fluid-filled cavities within the brain that contain cerebral-spinal-fluid
(CSF)
- Provides cushioning for the brain
- Reservoir of hormones and nutrients for the CNS
- Provides exchange medium between the brain and blood

- Four main ventricles: lateral ventricles main capity in the brain; third ventricle
is more in the central around the mid-brain; fourth ventricle located in the
hind brain; central canal run out the spinal cord
Blood-brain barrier (BBB)
Semi-permeable membrane that surrounds blood vessels and the brain
- Separates blood from CSF
- Prevents most chemicals from entering the brain
- Essential to protection against viruses and bacteria
Active transport-protein mediated transport that will pump certain chemical across
the BBB
BBB is essential for health--however it can make it difficult to treat brain-based
disease because it is not easy to administer drugs. E.g. Parkinson's Disease, it
cannot only inject Dopamine because it cannot cross the blood -brain barrier. Find
compounds that help Dopamine formation, symposia

Mood disorders: Major depressive 心境障碍

Diagnosis-DSM-V most common mood disorder
Life time prevalence=3.5%(~70% of diagnoses are women)
Symptoms--must be present for more than 2 weeks
compounds that help Dopamine formation, symposia

Mood disorders: Major depressive 心境障碍

Diagnosis-DSM-V most common mood disorder
Life time prevalence=3.5%(~70% of diagnoses are women)
Symptoms--must be present for more than 2 weeks
Depressed mood, diminished interests, lack of energy and motivation, inability to
concentrate, indecisiveness, insomnia or hypersomnia, weight loss/gain, feelings of
worthlessness and hopelessness, sometimes suicidal thoughts.
Severe cases---psychotic symptoms such as delusions (strong believe in something
not quite accurate, personal responsible for the hurricane) and hallucinations
(might experience hearing voice they are what was)

Mood disorders: Bipolar Disorder (BD)

- Less common than MDD---aka manic depressive disorder
- Unlike MDD (unipolar-single mood state), BD patients oscillate(振荡）
between depression and mania 狂热 (2 mood states)
- Shift in one mood state
Mania=a state of hyperactivity, euphoria, excitement, inflated sense of self,
minimal sleep, delusions of grandeur(I am so important, important to
anything such as in society or community that have this unrealistic feelings),
anger/irritability
- Manic state will last much shorter but depressed state will last for years or
longer. Link to environmental factor, trigger these states.
▪ Patient may undergo varying episode durations in each state (depressed or
manic)
▪ May last for years, months, days
▪ Equally reported in men and women
▪ Lifetime prevalence = ~1%
▪ High-risk suicide in depressed state

Mood disorders: Biological factors

Genetics
- Adoption studies: presence of mood disorder in biological parents greatly
increased the risk of mood disorder in the child given up for adoption--
however, mood disorder in the adoptive parents does not have an effect.
- Twin studies: concordance rate--identical twins (60%) fraternal twins --
different genes(30%). Environmental influences exposure to actual
development of the disorder.
Suggests a genetic predisposition (vulnerability) to developing mood disorder
- Genetics play a role, but it is not the only influence
- Other environmental triggers may include: stressful/ traumatic life
experiences, hormonal changes in women after birth (postpartum
depression), changes in season to winter!(seasonal affective depression)

Mood disorders: in the brain

 - Genetics play a role, but it is not the only influence
- Other environmental triggers may include: stressful/ traumatic life
experiences, hormonal changes in women after birth (postpartum
depression), changes in season to winter!(seasonal affective depression)

Mood disorders: in the brain

Functional Magnetic Resonance Imaging (fMRI)
- Technique used to measure brain activity
- By measuring cerebral blood flow (CBF), researchers gain an indication of
brain activity in specific regions
- This is because neural activity relies on oxygen and energy (sugars-glucose)
to function-these are carried in the blood. Thus more blood flow=more
neuronal activity
- Need the blood to flow the area of the brain that it been used to provide
nutrients. Follow the blood flow, identify which area of the brain is more
active.
- Take one healthy person's image and one major depressive person's image,
the very red region that showing lot more activity in MDD patient than the
normal person. Manage depressive, disorder.
- Increased activation in the: Amygdala-emotional and stress responses.
PFC(medial orbital)-modulate/inhibit emotional expression
- Decreased activation in the: Dorsal anterior cingulate cortex--attention and
sensory processing. Frontal area, relate to attention and sensory processing,
integrating that information. People with MDD have an emotional
dysregulation, not very expressive of that dysregulation--feel extremely
sadness that they don't show it. Hyperactive with the amygdala, feeling one
emotion more and more, pre-frontal cortex is function, that inhibiting their
motion that they are not actually showing the fact of their emotion.

Monoamine (MA) Theory of Depression

People with depression do not produce enough NT, low MA activity that class of
NT, dopamine (working memory, alertness, motivation will reduce if not enough)
and serotonin in relation to deprive symptoms how they do attributed to move
regulation

Monoamine (MA) Theory of Depression: Drug Evidence

Drugs that reduce monoamine levels can cause depression
- Reserpine-a blood pressure medication that is linked with depression in ~20%
of users--synaptic vesicles 'leak' the NT MA's which are destroyed by MAO in
the axon terminal
Drugs that increase monoamine levels can cause mood elevation and mania-like
states
- Amphetamines and cocaine-temporarily 'boost' MA's in the synapse (e.g.
cocaine is an indirect dopamine agonist that works by blocking transporter
re-uptake)
- Produces euphoric, hyperactive states-often followed by depression when
the drug wears off
states
- Amphetamines and cocaine-temporarily 'boost' MA's in the synapse (e.g.
cocaine is an indirect dopamine agonist that works by blocking transporter
re-uptake)
- Produces euphoric, hyperactive states-often followed by depression when
the drug wears off
Most anti-depressant drugs aim to initially increase monoamine levels
- MAO inhibitors--block transporter MAO
- Selective Serotonin Re-uptake inhibitors--e.g. Prozac blocks the re-uptake of
serotonin from the synapse

Monoamine (MA) Theory of Depression: limitations

Delayed Therapeutic Effects
- Mostly applied to unipolar MDD
- Anti-depressants result in immediate changes in MA levels in the brain
- Therapeutic effect is delayed--i.e. changes in behaviour are often not seen
for 4-6 weeks from starts of treatment.
- What is causing this delay?--some evidence suggests that anti-depressants
increase the production of new neurons! This takes a couple of weeks, and
may be responsible for alleviating the depressive symptoms--rather than
direct MA effects.
Contradictory Therapeutic Effects
Some newer-anti-depressants that are effective actually BLOCK monoamine
activity, rather than increasing it!
E.g. Serzone and Avanza are 5-HT antagonists block 5-HT receptors-this is an
obvious paradox
Conscious of the fact

Schizophrenia 精神分裂症 (SCZ)

▪ Rare mental health condition that affects, ~1% of the population worldwide
▪ Onset typically late teens/early 20's ---coincides with the maturation of the
PFC
▪ Slightly more common in men vs women(depend on the research focusing on
which region)
Characterized by:
Positive symptoms: Behavioural manifestations
▪ Disorganized thought
- Jumbled/loosely connected ideas that have no logical sense
▪ Delusions
- Bizarre ideas/beliefs (e.g. conspiracy theories)
▪ Hallucinations
- Visual or auditory (e.g. hearing voices)
Negative symptoms: Behavioural deficits
▪ Anhedonia-inability to experience pleasure
▪ Flat/blunted emotional response
▪ Apathy/lack motivation
Negative symptoms: Behavioural deficits
▪ Anhedonia-inability to experience pleasure
▪ Flat/blunted emotional response
▪ Apathy/lack motivation

Schizophrenia: Biological factors

Genetics
Adoption studies:
▪ Single biological parent that has SCZ --15% chance
▪ Both biological parents have SCZ--50 % chance
Twin studies: concordance rate--identical (50%), fraternal (15%)
Environmental stressors
▪ Must trigger the disease in predisposed 先有倾向的 people
▪ There are cases where people develop SCZ with no family history of the
disorder
E.g., prenatal/neonatal environment--antibody incompatibility between baby and
mother, viral infection or starvation during pregnancy
▪ Drug use and psychological stress can trigger psychotic episodes in
predisposed people
Schizophrenia: in the brain
Structural abnormalities
▪ Enlarged ventricles--fewer neurons
▪ Shrunken hippocampus-fewer neurons & disorganized neuronal connections
▪ PFC (pre-frontal cortex) shows reduced gray matter (white matter is the axon
that have myelin which gave the white effects, gray matter is cell body and
dendrites, if we do not have enough dendrites, receiving less influences; if
don't have axon terminals are unable to project to those area) --fewer
neurons, reduce the functioning ultimately
▪ Gray matter region make out of cortex and white matter region inside
PFC
▪ During psychotic episode/positive symptoms--PFC is hyperactive
▪ Periods between episodes--deficient/reduced activity in the PFC.

Dopamine Hypothesis
Mesolimbic dopamine system 中脑边缘多巴胺系统
▪ Initiated by DA-releasing neurons in the VTA (midbrain)
▪ Projects to nucleus accumbens (NA) and other pre-frontal areas
▪ Functions: Pleasure and reward seeking behaviours, addiction, emotions, and
perception-onset of positive symptoms
D2 receptors
▪ Increased DA release
▪ Increased D2 receptor expression
▪ More receptors are waiting for the dopamine to bind and create those post-
synaptic potential, overall we get the hyperactive system
 ▪ Increased DA release
▪ Increased D2 receptor expression
▪ More receptors are waiting for the dopamine to bind and create those post-
synaptic potential, overall we get the hyperactive system

Dopamine Hypothesis: evidence

Drugs that increase DA activity
▪ Amphetamines (DA agonist) that target D2-receptors and produce temporary
symptoms that resemble psychosis (almost indistinguishable from psychotic
SCZ episodes)
Antipsychotic drugs (neuroleptics) used for treatment aim to reduce DA activity
▪ Mostly dopamine antagonists that block D2 receptors
▪ Reduces the amount of DA that can have an effect of the post-synaptic
neuron
▪ Highly effective at reducing positive symptoms of SCZ.

Dopamine Hypothesis: limitations/problems

Relatively limited explanations provided to explain the onset of negative and
cognitive symptoms
More recent research has proposed that the D1 receptors may be involved in
reducing dopamine transmission in the PFC via the Mesocortical dopamine system
(pathway function: cognitive, working memory, attention, emotional bhx, and
learning
▪ Research has shown hypofunction of D1 receptors.
Evidence
▪ Limited
▪ People give drugs to stimulate D1 receptors, regain their normal behaviour.
Drugs that block D1 receptors in healthy people show weak negative and
cognitive dysfunction including problems with working memory and
attention. Just relate to the positive symptoms.
Does increased/decreased dopamine activity cause of SCZ? Or is this just a
symptom of the disorder?
Other brain abnormalities in SCZ may be causing DA dysfunction
Not enough GABA could lead to increased DA release and coinciding DA effects,
initiated hyperactive dopamine system, if enough GABA in dopamine system
inhibiting those neurons, the dopamine system wouldn't be regulated
GABA-inhibitroy NT.

SCZ: competing hypotheses

Summary:
initiated hyperactive dopamine system, if enough GABA in dopamine system
inhibiting those neurons, the dopamine system wouldn't be regulated
GABA-inhibitroy NT.

SCZ: competing hypotheses

Summary:

Epilepsy
Brain disorder characterized by seizures
- Seizures can be considered to be abnormal intensely synchronized electrical
discharges in the brain
- Seizures are seen to originate from a 'cluster' of abnormally excitable neurons
(AKA epileptic focus)
Genetic studies of epilepsy show impaired GABA synthesis
People with such genetic mutations show seizure in infancy
Drugs that increase GABA are used as anticonvulsants-treatment for epilepsy

Types of seizures
- Spread rapidly from the epileptic focus to widespread brain regions
- Typically result in loss of consciousness
- Petit mal: patient loses consciousness for very brief period
- Grand mal: patient loses consciousness, collapses, and undergoes convulsions
for a brief period.
Partial seizures
- Seizures are restricted to specific areas of the brain-closest to the epileptic
focus
- May result in involuntary movements, unusual sensations
- Temporal epilepsy: primary symptom is hallucinations and sudden
personality/emotional changes--typically no loss of consciousness, but often
shows signs of confusion
Epilepsy: GABA dysfunction
Receptors
- GABA a receptors---ligand-gated receptor/channel--controls entry of Cl- ions
into the cell
- GABA b receptors---increases K+ and Cl-, block Ca2+, inhibits pre-synaptic
release of other transmitters
- They won't open the gate by themselves but will trigger and send signal to
other channels to conduct different ions
Epilepsy: Synapse--GABA or GABA a dysfunction
If there is less GABA released into the synapse or GABA a receptor dysfunction:
 - GABA b receptors---increases K+ and Cl-, block Ca2+, inhibits pre-synaptic
release of other transmitters
- They won't open the gate by themselves but will trigger and send signal to
other channels to conduct different ions
Epilepsy: Synapse--GABA or GABA a dysfunction
If there is less GABA released into the synapse or GABA a receptor dysfunction:
- Reduce IPSPs
- EPSPs would have a greater effect on the membrane potential
- Faster depolarization to reach the threshold and fire an AP
- The neuron has become more excitable
- Less IPSP, less Cl- will be enter the neuron, accumulate the temporal and
spatial
GABA b dysfunction
- Reduce the amount of K+ that leaves the cell

Parkinson's Disease
- Mental activity: depression and anxiety; dementia, memory loss, slow
thinking; difficulty swallowing and chewing
Major symptoms include:
- Tremor (trembling hands, arms, legs, jaw, face)
- Rigidity (stiffness of the limbs, trunk or facial expression
- Slowness (loss of spontaneous movement)
- Postural insatiability (impaired balance and coordination)

Parkinson's Disease: in the brain

- Dopamine system, not enough ganglia release
Treatment: due to BBB, DA cannot cross and enter the brain via the blood stream
- L-dopa work to reduce the symptoms and slow-down the disease progression
- Negative side effect: restlessness, hallucinations, sleep disturbances