Lecture 1: Brain Damage and Neurodegeneration

Types of Brain Injury

congenital, acquired, traumatic, non-traumatic, open head, closed head

Congenital Brain Injury

present at birth; occurs before/around birth

What causes congenital brain injury?

genetic factors affecting neurodevelopment; prenatal or birth related trauma

Example of congenital brain injury

congenital Zika syndrome

Virus causing a congenital brain injury

Zika virus

Who does Zika syndrome lead to?

severe impairment of neurodevelopment in parts of brain

5 main problems of Zika syndrome

1- microcephaly (small head size) w/ partially collapsed skull

2- decreased brain tissue w/ distinct pattern of calcium deficits

3- damage in back of eye w/ specific scarring pattern, increased pigment

4- extreme muscle tone, restricts movements

5- limited range of motion in joints, clubfoot

Non- Traumatic Brain Injury

happened over period of time, even if short; complicated symptoms

Non- Traumatic Brain Injuries

stroke, infections, tumours, hypoxia/anoxia

What type of disorder is a stroke?

cerebrovascular

Thrombolysis

clot busting treatment for strokes

Main causes of strokes

• cerebral haemorrhage

• cerebral ischaemia

Cerebral haemorrhage

blood (often from aneurysm) exposed to neural tissue, causing damage bc toxic salts in blood causing death. neurones not getting what they need bc blood not where it is supposed to be

Aneurysm treatment

• if spotted before rupture, can sometimes be treated, e.g. by clipping blood vessel

• that involves surgery so sometimes monitoring is only course

• prevention of bursting: maintain low bp, avoid strenuous activity

Cerebral ischaemia

lack of oxygen/glucose leads to excitotoxicity and neuronal cell death

How is cerebral ischaemia caused?

interruption of the blood supply to a part of the brain due to blockages of a blood vessel

What causes blood vessel blockages?

plugs: thrombus, embolus

cardiovascular disease: atherosclerosis

• two regions of clot: core, punmbra

• core centred around blockage in blood vessel; struggling to get oxygen/glucose

• penumbra less effected

• clot busting drugs/insertions moving clot out of way unlikely to save tissue in a core, but can restore blood supply and function to penumbra and minimise damage to quality of life

How quickly does clot busting need to be done?

4 hours

Goal of treatment after stroke

reduce penumbra by reopening blocked blood vessel

Traumatic brain injury

• sudden and bad happening

• specific in focus or widespread

• can affect brain tissue directly or indirectly by damaging the blood supply (circulatory) system

• closed or open injury

• aka intracranial injury

Coup injury

primary injury

Contrecoup injury

secondary injury

Closed head injury + why important

• no penetration of skull

• important bc skull protective and damage can cause swelling, infection, etc

What acts as cushion for brain?

• brain floats in cerebrospinal fluid

Explain process of closed head injury

• excess force, brain swish forwards and smacks skull and swish back and impacts on skull, damaging areas of brain

• damage can diffuse and be widespread

Why are normal forces applied to skull not problematic?

brain floats in cerebrospinal fluid; acts as cushion

Dementia Pugilistica

Punk Drunk Syndrome

Punk Drunk Syndrome

Dementia Pugilistica

Cause of punch drunk syndrome

• powerful, repeated blows to the are head non-conducive to long term brain health

• damage neural tissue, connections, health of tissue

• cumulative structural damage occurs → dementia symptoms

What may dementia pugilistica lead to?

some evidence may lead to neurodegenerative diseases like PD, AD

Open head injury

• skull not intact

• objects penatrating skull and entering brain

• damage to the skull → bone fragments → damage brain tissue

Consequences of open head injury

• damage can be localised but risk of complications (bleeding, infection, swelling) → wider damage

• if brain swells, can put pressure on edges and botton of brain bc skull doesn’t flex

Examples of brain diseases

• cerebrovascular diseases (incl. stroke)

• cancer

• epilepsy

• infections

• other movement disorders

• psychiatric / mental disorders

• Alzheimer’s disease

• Parkinson’s disease

• dementias

Neural changes in Alzheimer’s disease

• diffuse changes in brain structure and volume associated with widespread neuronal loss

• large areas, lots diff parts of brain, can reduce overall brain volume

Neural changes in Parkinson’s disease

• mainly attributable to a single type of neuron in specific brain region

• primarily affects globus pallidus in basal ganglia

What neuron does PD affect, and where is this neuron?

globus pallidus , located in basal ganglia

Predominant symptom type in AD

cognitive symptoms, esp early stages

Predominant symptom type in PD

motor symptoms, esp early stages

Neurotransmitter changes associated with AD

• loss of acetylcholine

→ other proteins accumulate too

Neurotransmitter changes associated with PD

• loss of dopamine

→ loss of neurons that release dopamine

First person to describe PD + what they said

• James Parkinson, 1755-1824

• 1817: ‘Essay on the Shaking Palsy’

% of the population with PD

• 0.5%

• 1-2% of elderly population

Cause of PD

• idiopathic disease

• each case has own origins

• no discovered single cause

One of most studied, common, best understood movement disorders

Parkinson’s disease

How did Parkinson define PD?

“... involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported, with a propensity to bend the trunk forward, and to pass from walking to a running pace, the senses and intellects being uninjured”

What is missing from Parkinson’s definition of PD?

cognitive effects

Symptoms of PD

• paucity of spontaneous movement

• bradykinesia

• akinesia

• increased muscle tone

• resting tremor

• shuffling gate and flexed posture

• impaired balance

• mask like expression

• impaired intiiation of/selection of movements

Paucity of spontaneous movement

Insufficiency of movement

Bradykinesia

very slow movements

Akinesia

no movements

Increase muscle tone

Rigidity

Common resting tremor in PD

‘pill-rolling’

What can help with movements in PD?

certain cues/contexts

What is the problem with movement in PD?

problem w initiation/selection of movement, not movement pathways themselves. problem turning on pathways. circuits functional, initiation not.

Why might putting your foot in front of someone with PD, or lines on the floor, help them walk?

• visual trigger

• provides cue to help initiation of movement

• movement circuits fine

Is PD the first example of a brain disorder resulting from deficiency of a single neurotransmitter?

Yes

Pathway of the brain where there is a lack of dopamine in PD?

the nigrostriatal dopamine pathway

Location of the nigrostriatal dopamine pathway

Basal ganglia

% of brain’s dopamine located in basal ganglia

80%

Where are PD brains deficient in dopamine?

in the nigrostriatal dopamine pathway in the basal ganglia in the striatum

1960s, PD shown to be the result of…

degeneration of dopaminergic neurons within the substantia nigra pars compacta

Describe what image shows

• substantia nigra = dark substance = dopamine cells

• dopamine cells die off, absent

• degeneration of dopaminergic neurons within substantia nigra pars compacta

Describe the diagram

• normal brain

• motor cortex sends commands fairly directly down motor systems

• muscles → movements

• another system- basal ganglia- responsible for inhibiting motor output

• basal ganglia enables controlled movements, in orderly fashion

• cleanly selects sequences of movement, dedicates self to sequence

• BG quiets everything, lets winning motivation take control of motor system

• dopamine allows BG inhibition to be reduced

Function of basal ganglia

inhibit motor output

Detail: function of basal ganglia

• inhibits motor output

• allows controlled use of motor system

• stops motor system doing too many things at once

• controlled movements in orderly fashion

• cleanly select sequence of movement

• quiets everything down, lets winning motivation control motor system

• dopamine allows basal ganglia inhibition to be reduced

Describe

• Parkinson’s disease brain

• basal ganglia can’t excessively inhibitory bc dopamine cells died so nothing to reduce basal ganglia inhibition

• → results in tremors and freezing

• explains why need additional triggers to get over inhibitions

Role of dopamine in basal ganglia

dopamine allows basal ganglia inhibition to be reduced

How to stop the basal ganglia from being stuck in ‘on’ - inhibition- mode?

• lesion globus pallidus (relevant part of BG)

• symptoms reduce/disappear

• not satisfactory treatment option in humans, mostly
  

  

Mechanisms/approaches of/to treatment for PD

• enable BG to be ‘off’ sometimes

• replace lost dopamine

• surgical intervention

Treatment methods for PD

• pharmacology

• surgery: lesion

• deep brain stimulation (DBS)

• stem cell transplantation (developing currently)

Pharmacological treatments of PD

• Levo Dopa

• Apomorphine

• Deprenyl

• Cannabis ?

Why can’t you just dose PD patients with dopamine?

• dopamine doesn’t cross the BBB

• even if could cross BBB, could go to wrong area of brain anyway

Leva Dopa

• dopamine precursor

• treatment for PD

• aim to replace lost dopamine

Dopamine precursor

• Levodopa

• synthesised from amino acid tyrosine

• can cross BBB and convert into dopamine

Apomorphine

• dopamine agonist

• treatment for PD

• activate dopamine receptors

Deprenyl

• monoamine agonist

• monoamine → serotonin/dopamine

Monoamines

• class of neurotransmitters and neuromodulators derived from aromatic amino acids

• amino acids include tyrosine, tryptophan, phenylalanine

• derived from aromatic amino acids by action of aromatic amino acid decarboxylase enzymes

• contain one amine group (NH2) attached to small carbon atom that is a part of a benzene ring

Cannabis

• potential treatment for PD

• dopamine agonist

• seems effective in some cases, not overall backed up by larger scale studies compared to other drugs

Surgical intervention for PD

• lesion inhibitory output structures (GPi, STN)

• surgically damage problem/output BG structures

→ only in very severe cases, very difficult in humans

STN

subthalamic nucleus

Subthalamic nucleus

• important modulator of basal ganglia output

• recieves major afferents from cerebral cortex, globus pallidus exterus, thalamus, brainstem

• projects mainly to both segements of globus pallidus, substantia nigra, striatum, brain stem

GPi

globus pallidus internus

Globus pallidus internus

• medial aspect of putamen

• function: control conscious and propioceptive movements

• subcortical nuclei

• inhibitory output in basal ganglia

Two subcortical nuclei that provide inhibitory output in basal ganglia

STN = subthalamic nucleus

GPi = globus pallidus internus

surgical intervention for PD

lesioning globus pallidus internus and/or subthalamic nucleus

stops inhibitory output of basal ganglia

Electrical stimulation of basal ganglia

Deep brain stimulation (DBS)

Deep brain stimulation (DBS)

• targets same sites as lesion (GPi, STN) but with electrical current tuned to shut them down → inhibit output

• reversable / controllable / adjustable

• DBS rapidly becoming more effective

What does this show?

• DBS

• deep brain stimulation

• treatment of PD

• inhibits output of globus pallidus internus and subthalamic nucleus via electrical current

How is DBS carried out?

• tiny electrodes surgically implanted in brain

• electrodes connected via subcutaneous wire to a neurostimulator/or two implanted under skin near clavicle

DBS lead

• thin, insulated, coiled wire

• end in 1.5mm electrode

• deliver stimulation to targeted area (GPi, STN)

Neurostimulator

• pace-maker- like device

• contains battery and circuitry to generate electrical signals

• electrical signals delivered by leads to targeted structures deep in brain

Extension

• in DBS, an insulated wire that connects the lead to the neurostimulator

Developing treatments aiming to replace lost DA cells?

• initial indications of success for fetal/stem cell transplantation have not been underpinned in longer, larger trials

• esp in terms of balancing risks

Dementia

a chronic or persistent disorder of the mental processes caused by brain disease or injury and marked by memory disorders, personality changes, and impaired reasoning

Alzheimer’s disease

a disease that causes dementia, accounting for 2/3 of dementia cases

Types of dementia

• vascular dementia

• dementia w/ Lewy bodies

• frontotemporal dementia

• mild cognitive impairment

• posterior cortical atrophy

• primary progressive aphasia

Incidence of AD: 65+ y/o

10%

Incidence of AD: 85+ y/o

35%

Symptoms of AD

• memory loss

• selective decline in memory

• deficits in attention

• personality changes