neurological disorders

circadian rhythms

• Our body have a 24-hour rhythm. Anything with a 24- hour rhythm is called a circadian rhythm

• Many processes our body does—digestion, sleep, exercise– is best one a specific time of day

• Almost all 24-rhythms in our body are regulated by a single brain area—the suprachiasmatic nucleus (SCN

suprachiasmatic nucleus (SCN)

receives light information from body, eyes, tell body when to start clock

• Is set in morning by light

• Light at night can cause disruption to circadian rhythm

daylight saving effect on circadian rhythm

misalignment betwene DST and cirvcadian rhythm causes spike in diseases, accidents (eg car crash)

• Eg in period in US of DST, increased risk of car crash, (almost 10% increase of incidence)

the brain is complex

• ~86 billion neurons in the brain

• ~40,000 synapses (neuron-neuron connections) on each neuron

• Variable & changing

• Strengthening & weakening connections

burden of disease : DALYs

• Beyond just prevalence and incidence: the Disability-Adjusted Life Years (DALYs)

• # DALYs = Years of life lost (YLL) + years lived with a disability (YLD)

  DALYs: quantifyimg how a disease affects and individual

• Increases number of diseases/disabilites that affect brain

• Quantifying how many years of low quiality of life ar epeple experincing

the cost of brain disease

The ‘cost’ of a disease can include:

• Treatment costs

• Research costs

• Loss of people from workforce

The cost of neurological diseases in USA + Europe, alone, is 1.7 trillion USD

• The entire GDP of Australia (the 13th largest GDP in the world) is ~1.7 trillion USD

types of cells in the brain

Neurons

• the primary cells that hold memories, transmit information, and create our consciousness

Astrocytes

• Cells that regulate the environment around neurons and synapses (connections)

Oligodendrocytes

• Cells that insulate axons (long wire-y bits of neurons) to facilitate electrical transmission

Microglia

• Specialised immune cells of the brain

spatial organisation of the brain

Our brain is left-right flipped

• Or, one hemisphere of the brain controls the contralateral side

• E.g. left side of the brain is responsible for the right side of the body

Our brain is also somewhat top-down flipped

• E.g. The top represents lower visual space, out legs and feet

Some functions are ipsilateral (brain areas are on same side of the body as peripheral organ they control)

• E.g. pain and heat perception

mapping function to brain area

• Sensory and Motor homunculi is how we represent the amount of space in the brain dedicated to that sense or moving that body part

• Each aspect of our consciousness (memory, planning, executive function, perception) has a corresponding brain region

• However, it is much more complex than a single structure=a single function

have areas more involved in a function, but it is a network of brain areas that actually work togetehr to perform a function (esp for more complex/abstract funtions)

stroke

• Any disruption of blood supply to the central nervous system (CNS)—brain and spinal cord

• Hypoxia (lack of oxygen) in the brain leads to cell death in minutes

• Malnutrition (lack of nutrients, such as glucose) can lead to cell death, but in minutes to hours

types of stroke

Ischaemic stroke (85%) - restriction of a blood vessel supplying the brain or spinal cord with blood

• Often due to Thrombosis

• Patient on top

Haemorrhagic stroke (15%)

• Bleeding in the brain due to a leaky or ruptured vessel

• Patient on bottom

Neurons start dying after 1 minute of loss of blood flow

   haemorrhagic: typicaaly more damaging, as harder to fix and blood in brain can create toxic environment for cells

stroke acute symptoms

 generally rapid onset,Breif symptoms, brain can repair and rewire, often not permanent damage (but some strokes do elad to pernanent damage)

symptoms incl:

• Paralysis or numbness or inability to move parts of The face, arm, or leg - particularly on one side of The body

• Confusion- including trouble with speaking

• Headache with vomiting

• Trouble seeing in one or both eyes

• Metallic taste in mouth

• Difficulty in swallowing

• Trouble in walking (impaired coordination)

• Dystonia

• Alexia

• Agnosia

WHY IS HOLDING YOUR BREATH NOT CAUSING A STROKE-LIKE HYPOXIA?

Training your body to dive:

- Higher blood myoglobin

- More productive spleen (more red blood cells)

- Lowered metabolic rate (less oxygen used)

Pre-dive oxygen loading and metabolic suppression

Our anoxic threshold in a trained diver doesn’t often hit for 5-10 minutes

stroke recovery takes brain re-wiring

Motor recovery after stroke (fMRI) Longitudinal fMRI studies showing the recovery after stroke during a right finger tapping task. As is shown, the contralateral cortex is progressively representing the right hand (Rıos et al., 2005).

risk factors of stroke

• age - incidence doubles in each decade after age 55

• sex - higher incidence in male

• ethnicity

• Genetics (32 genes strongly associated with stroke)

• Hypertension (half of all stroke patients had documented hypertension)

• Smoking (doubles the risk of stroke—including marijuana)

• Alcohol & drug abuse

• Obesity and sedentary behaviour (often through blood pressure and cholesterol)

• Inflammation (infection has been shown to sometimes trigger strokes)

post stroke recovery

Neurons that die are not replaced with new ones, their functions are taken over by other cells

• Whole brain areas can change function as stroke victims recover in a process called neuroplasticity

 immeditatly after stroke, large area of brain that doesn't work anymore

• Therefore whatever it was controlling doesn't work as well

• Over time, brain area controlling different things shifts, cell change what they're connected to (neuroplasticity)

traumatic brain injury

Traumatic Brian Injuries (TBIs) cause damage to the brain through several ways:

• Tissue is damaged by direct damage to cell bodies at injury location (‘gray matter damage’)

• Vascular damage (leading to haemorrhagic strokes

• Finally axon damage (‘white matter damage’) can disconnect neurons from each other

secondary injury of brain damage

After an traumatic brain injury (TBI), there is a period that the injury seems to spread--this is called the ‘secondary injury cascade’

• Whereas the primary injury is physical tissue damage, the secondary injury is biochemical damage

• This is the result of both vascular disruptions and the neuronal network being knocked out of balance

• After TBI, important ions (Ca+, K+) and nutrients (glutamate, glucose) are out of balance

• Combined with altered blood flow causes the metabolic changes of brain cells to become self- destructive

this happens in many brain diseases, including after a stroke

the stroke penumbra

Penumbra: An area outside of the original stroke location that slowly dies off (the secondary injury for stroke)

• Also caused by ion imbalances that lead to excitotoxicity

• most drugs target stopping prgression of penumbra, rather than initial injury

EXCITOTOXICITY AFTER A STROKE OR TBI

Immediate:

• ↓ATP stores

• ↑Lactic acid

Seconds to minutes

• Ion balance cannot be maintained

• ↑[NA+]i

• ↓[K+]i

• ↑[Ca2+]i

• ‘anoxic depolarization’ - this ion imbalance excites cells

• Oxygen-depleted mitochondria begin making free radicals (reactive oxygen species, ROS)

excitotoxicity spreads

Dying neurons over-excite the downstream neurons until they start dying as well,

Due to depolarisation of neuron, generates action potentials down to other neurons, over exciting downstream neurons and causing spreading damage

free radiacal general

• Reactive oxygen species (ROS)/‘Free Radicals’ are generated in the mitochondria and cytosol of neurons with too much calcium (Ca2+)

• When the amount of ROS outweighs the cell’s antioxidant molecules, this is called oxidative stress

• Any molecule hit by a ROS can be destroyed

• Pores open the mitochondria, which leads to a cascade that can lead to cell death (apoptosis)

too much glutamate over excites neurons, causes influx of calcium, and too much calcium causes generation of free radicals

reducing the penumbra

You have a few hours to prevent the damage from stroke to get worse

Blocking the channels that lead to excitation (block glutamate receptors

• NMDA for Ca2+

• AMPA for Na+

Stimulating the channels that lead to inhibition (GABA is inhibitory receptor)

• GABA for Cl-

treatment strategies for stroke

1. Reperfusion

2. Reducing excitotoxicity

3. Manage risk factors

4. Rehabilitation

reperfusion

• get blood flow back: thrombolytic drugs

• prevnet excessive movement

reducing excitoxicity

Correcting ion imbalances: Na+, Ca2+ channel blockers

• Reducing excitability: glutamate channel blockers

• Reducing oxidative stress: antioxidant drugs

manage risk facotors

Antihypertensive therapy

• Glucose management

• Antiplatelet therapy

rehabilitation

• physical therapy

• speech therapy

alzheimers disease prevalence

1 in 6 people over age 60 will have AD by 2030, potentially becoming 1 in 3 (over 60) by 2050

• AD is the 7th leading cause of death globally

•  not increase of incidence in younger people, cases are increasing because people are living longer, not because becoming more prevalent

amyloid beta (AB) plaques

• Amyloid Precursor Protein (APP) is cleaved by two secretase enzymes to make Aβ

• Aβ proteins misfold and clump together into insoluble oligomers and then plaques

• Aβ oligomers inhibit neuron communication and health

the cleaving is a normal process, but if amyloid beta not cleared out, can misfold and cause plaques

tau tangles

• After Aβ triggers neurodegeneration, tau pathology begins in late AD

• Tau proteins (tubulin associated unit) are modified and dissociate from microtubules

• They disrupt function and can spread from neuron to neuron through synapses

• Clump together into ‘neurofibrillary tangle

Tau tangles can jump thru synapse to spread neuron to neuron, therefore alzheimers disease is able to spread thru the brain

 Tau tangles cause other tau proteins to be modified

brain areas affected in alzheimers

First areas affected: Areas important for creating new memories and retrieving old memories

• entorhinal cortex and hippocampus

Then spreading to the neocortex, including prefrontal cortex (executive function), parietal cortex (attention), and visual cortex (vision)

amyloid cascade hypothesis

Amyloid β aggregation is the cause of all other pathologies in AD

• Aβ plaques directly affect neuronal health and activity, causing

• inflammation

• tau protein aggregation

Aβ plaques and tau protein tangles can spread from neuron to neuron, killing them (neurodegeneration)

AD is progressive

 biomarkers in blood can allow for detection of abnormal amyloid beta levels before cognitive symptoms show

• The disease can begin in the brain ~20 years before

  symptoms show

  • Earlier to give treatment, the more the treatment can help

AD therapeutics

Blocking Aβ production:

• β-secretase and γ-secretase inhibitors

• Unfortunately, did not work well

Targeting Aβ directly

• Anti-Aβ antibodies (immunotherapy) to flag them for the body’s immune system

• Inhibitors for plaque formation

treatments cant completlty eliminate AB, as is needed in brain

major mental illnesses

Major depressive disorder (MDD)

• Anxiety Disorders

• Schizophrenia

• Bipolar disorder

• Attention Deficit Hyperactivity Disorder (ADHD)

very hard to study, and hard to find animal models for study

• because onset is young, DALYs are much higher, mean can have larger impact of quality of life

major depressive disorder (depression)

~5% of adults (4% of male-identified, 6% of female-

identified) experience depression

Symptoms include:

• Depressive ‘episodes’: periods of symptoms that can alleviate on their own

• Poor concentration

• Hopelessness

• Little pleasure in doing things

• Feeling tired

• Disrupted sleep

biological determinants of depression

• Physical health conditions

• Brain derived neurotrophic factor (BDNF) -    neurotrophic: helps neurons grow

• Genetic polymorphisms relating to major histocompatibility complexes (MHCs) and tryptophan metabolism

• Inflammation

• Gut microbiome (inflammation)

• HPA axis dysfunction

psychological determinants of depression

• Negative self-concept

• Sensitivity to rejection

• Neuroticism

• Rumination

• Negative emotionality

• Meta-emotions (e.g. guilt about anger)

social determinants

• Oppression

• Sociodemographics

• Social support

• Food security

• Adverse childhood experiences

• Bullying

• Violent crime exposure

• Migrant status

• Literacy

estimating genetic heritability: twin studies

   using identical vs fraternal twins, can determine to which degrees environment vs genes affects disease probability of development

Schizophrenia: 41-61% of identical twins

develop it if their twin has it

• Heritability: 81%

Depression:

• Heritability:

• Male-identified: 29%

• Female-identified: 42%

brain derived neurotrophic factor (BDNF)

Important molecule to promoting neuron growth and proliferation in development

• Both a between-cell signalling molecule (neurotransmitter) and a within-cell signalling molecule

• Promotes neuroplasticity—changes in neuron structure that allow for learning, help break out of rumination

neuroplasticity and rumination

depending on size of post-synaptic neuron or amount of receptors, changes response of post-synaptic neuron

• Neuroplasticity makes post synaptic neuron have more strength

• In rumination, want post0synaptic neuron to have less receptors/be smaller, make a weaker signal to prevent rumination

mechanism of antidepressants

 for every antidepressant given, all cause increase in BDNF signalling, sometimes by 50% or doubling it.

• Did not know increase bdnf when approved for patients, but just has

evidence linking BDNF and depression

   correlational evidence, but potentially evidence for how BNDF helps depression

• All antidepressants increase BDNF on average

• People that had a larger decrease in symptoms had more BDNF

• People that did not respond to antidepressants had stable BDNF

exercise promotes BDNF levels

BDNF levels can be measured in the blood serum, which correlates with BDNF release in the brain

• BDNF concentration drastically increases from physical exercis

serotonin and depression

Evidence shows that depression is NOT caused by a deficiency of serotonin

• The ‘chemical imbalance’ (i.e. serotonin) theory of depression is incorrect However, serotonin- promoting drugs help depression symptoms