PBL 4- Epilepsy Flashcards
What makes up myofilaments
Myofilaments: - Contain protein ○ Actin ○ Tropomyosin ○ Troponin - Thick Filaments Myosin
What happens at the neuromuscular junction?
- Ach released at NMJ
- AP generation in muscle cell
- Ca influx
- Myosin-actin interaction
Contraction occurs
What is the A-motorneuron?
Where are they located?
What is the structure?
- Large diameter myelinated
- Final neurons located in the ventral horn of the spinal cord
- Their axons form the ventral root
What is a motor unit?
- The smallest functional unit for movement
- Consists from:
○ Single a-motor neuron
○ Its axon
Plus all the muscle fibres innervated by the neuron
- Consists from:
What is a motoneuron pool?
A group of neurons (a column) that innervate one muscle
What is The neuromuscular junction
- The synapse between the motoneuron axon terminal and the muscle fibre
The arrival of the action potential along the neuron to the terminal causes release of a neurotransmitter
What degrades/ rate limits the Ach in the NMJ?
- Cholinesterase
What kind of receptors bind Ach in the NMJ?
Nicotinic ion channels
What allows the muscle to be a “smooth” contraction?
- Temporal summation of action potential leads to tetanus
Ceases when stimulation ceases or when fatigue begins
Drugs that effect the neuromuscular junction
- Curare ○ ACH receptor blocker ○ Results in Paralysis of the muscle - Physotigmine ○ cholinesterase inhibitor ○ potentiates effects of Ach ○ Muscle spasm at overdose - Organophosphates ○ Cholinesterase inhibitor - Botox ○ Ach Release Blocker Results in paralysis of muscle
Which Motor Neurone innervates a muscle spindle/ intrafusal fibres?
- Gamma motor neuron
Intrafusal
Which motor neuron innervates an extrafusal fibre
Alpha motor neurons
What does a Golgi tendon do?
Detects tension
What does a muscle spindle do?
Detects changes in muscle length
What is a reflex?
- Responses to sensory stimuli without participation or contribution of consciousness
What are the key features of a motor reflex?
- They are elementary acts of behaviour
- Stimulation of a given output produces determined and predicted output
- Performed without conscious control
- In a reflex the afferent input strictly determines output- there is NO contribution of will.
Where is the primary motor cortex located?
- M1
- Area 4
Pre central gyrus
- Area 4
What are Betz cells?
- Pyramidal cell neurons in the primary motor cortex
- Send axons down the corticospinal tracts to the anterior horn cells of the spinal cord
- Lie in the deep area of the cortex
Responsible for initiating voluntary and conscious movement.
Damage to the capsula interna would result in what clinical signs?
Paralysis and sensory loss on the CONTRALATERAL side
Why does the membrane potential occur?
Separation of oppositely charged ions
What is responsible for the membrane potential?
- Inside is negative compared to outside
- Determined by the concentration gradient of Potassium
Loss of K results in a negative charge
- Determined by the concentration gradient of Potassium
What ensures that the membrane potential remains constant?
Active transport pumps (Na/K ATPase) ensure that the electrochemical equilibrium does not occur
What is a nerve terminal?
A secretory machine that is dedicated to rapid rounds of NT release
What is hyperpolarisation?
A refractory period where no new action potential can be granted
What ion causes the depolarisation phase?
Na influx
What ion causes the repolarisation phase?
K efflux
What causes hyperpolarisation?
- Inhibitory post synaptic potential
- Prevents excitation or terminates action potential
- Restores voltage to original value
- Cell becomes more negative inside
Through influx of CL- and Efflux of K+
What causes Depolarisation?
- Excitatory post synaptic potential
- Cell becomes less negative inside
- Influx of NA and Ca
No potassium leaving the cell
Different broad types of Ion Channel types
- Voltage-gated
- Ligand-gated (extracellular ligand)
- Ligand-gated (intracellular)
Mechanically gated
Voltage Gated ion channels
What are they made from?
How are they gated?
What type of signal do they give?
- Pore forming proteins
- Gated: opening is voltage dependent
○ Flow is according to pre-existing electrochemical gradients - High flow selectivity
- High throughput
○ Thousands of ions flow per second
○ Large and brief electrical signal - High variety
Complex range of signals
- Gated: opening is voltage dependent
Domains of voltage gated Na, Ca and K
- S4 family = the pore forming subunit
- Built on a motif of 6 TM (S1-S6) segments
- S4 = the Voltage sensor
- Pore Loop domain = S5-S6
Forms complex with auxiliary sub units
What is the purpose of the auxillary sub units of a voltage channel?
- They are associated with the channel
- Modulate gating, kinetics, intracellular trafficking, current amplitude
How are voltage gated channels modulated?
- Voltage
○ Activation and inactivation kinetics depending on cell type and channel sub type- Activation gate
○ Responds to voltage changes - Inactivation Gate
○ Na channels - close the gate - Auxilary subunits
- Protein phosphorylation/dephosphorylation
○ Action of protein kinases and phosphatases
○ Na phosphorylation slows its inactivation - Binding of toxins and drugs
Ion channel subtype specificity
- Activation gate
Voltage gated K channels
- Involved in the REPOLARISATION phase
- Terminates action potential
Rate of closing affects excitability ( ability to rapidly fire)
- Terminates action potential
Therapeutic targets for K channels?
- When action potential firing is decreased in CNS depression
○ K channel inhbitors- When pathological hyperexcitability
K channel activators
- When pathological hyperexcitability
Voltage Gated Calcium Channels
How is it classified?
What role does it have
how is it modulated?
- Classification is according to the Alpha 1 subtype
- Critical role in NT release, synaptic plasticity and PAIN
Complex modulation
- Critical role in NT release, synaptic plasticity and PAIN
Therapeutic targets for N-type calcium channels
- Associated with Pain
- Opiates
Derivatives of conotoxins= analgesics
- Opiates
Voltage Gated Na channels Describe the gates How is it regulated? What role does it have? How does it appear in the different phases of the AP?
- Has 2 gates
- Activation gate
- H = Inactivation gate
- Regulated by Phosphorylation
- Opening is responsible for the rising phase of the action potential
- In the repolarisation phase the activation gate is open but the inactivation gate is closed
- Resting = activation is closed and inactivation is open
Depolarisation phase = both open
Clinical significance of Na channels
- Important in transduction of noxious signals -> pain pathways
- Local anaesthetics like lidocaine block Na conductance by binding to the inner portion of the Na channel
- Targets for many epileptic drugs
Targets for many toxins
Tetrodotoxins
- TTX- producing bacteria
- Prevent the Na flow
○ Bind to the outside of pore independent of voltage status- alpha subunit
Most Na channels in CNS and PNS are TTX sensitive
- Prevent the Na flow
Voltage gated Chloride channels
General structure
what role does it have?
- 9 proteins- glial and neuronal
- Has two pores
- Channels are arranged as dimers
- Separate (fast) or common gating - opening/closing of 2 pores
Alterations associated with juvenile epileptic syndrome, gliomas.
Ionotropic receptors
- Not a transporter
- If no ligand they are closed
- Multimeric protein
Opening typically requires binding of more than one neurotransmitter molecule
What are the types of Ionotropic Neuro transmitters
- Excitatory ○ Nicotinic (Ach, Da, NE) ○ 5HT3 (5HT) ○ AMPA, NMDA (Glutamate) - Inhibitory GABA a (GABA)
GABA a Receptors
What type of receptors?
role?
- Ligand gated ion channels
- Responsible for hyperpolarisation (CL influx, K efflux = decreased depolarisation)
Terminates or prevents initiation of action potential
- Responsible for hyperpolarisation (CL influx, K efflux = decreased depolarisation)
Cation-selective ligand gated ion channels
What type of receptors?
- Neuronal ACH receptors
- Glutamate NMDA (NA and Ca)
Glutamate AMPA (Na)
- Glutamate NMDA (NA and Ca)
What happens in Seizure initiation?
- Burst of action potentials called a paroxysmal depolarising shift
Abnormal and excessive synchronisation of neighbouring populations of cortical cells
How is a Seizure propagated?
How is it mediated?
- Ie partial seizure that spreads
- Activation of nearby neurons
- Loss of surrounding Inhibition
- Aberrant excitability associated with epileptic discharge mediated by voltage gated and ligand gated ion channels
May also be a result of genetic defects in channels
What are the Key features of seizure generation
- TOO MUCH EXCITATION
○ Leads to sustained, overt depolarisation and excessive discharge
○ Mediated by ions - inward NA and Ca currents
○ Mediated by NT - Glutamate- TOO LITTLE INHIBITION
○ Leads to defects in hyperpolarisation
○ Mediated by ions : inward CL and outward K
Mediated by NT = glutamate
- TOO LITTLE INHIBITION
What is the paroxysmal depolarisation shift?
- Characteristic sustained depolarisation with repetitive spiking (burst firing)
Occurs synchronously in a large group of neurons
Role of channels in epilepsy
Voltage gated NA and CA channels are major AED targets
○ Inhibitors of these inhibit high frequency repetitive spiking
GABA a receptors = second major AED targets
○ Drugs that ENHANCE INHIBITION are used as anticonvulsants
○ Prevent AP propagation and seizure spread
○ Phenobarbitol
○ Inhibitors of GABA degradation or reuptake
Others
○ Antagonists of NMDA receptors- to prevent excitation
○ Activators of voltage gated K channels
Blockers are powerful convulsants
Describe general Brain metabolism/ energy requirements
- The brain depends on a large and stable blood supply
- It has no effective way to store oxygen or energy
- High metabolic demand is met by a high blood flow to deliver energy substrates and oxygen
Local blood flow rates vary depending on neuronal activity
What is the main source of ATP for neurons?
Mitochondrial oxidative Phosphorylation
Why is ATP so important in the brain?
- Maintains Ion gradients
- If you lose ATP there is an inhibition of the Na, K ATPase pump
- Destruction of ion gradients
Results in energy failure and neuronal death
What is Phosphocreatine?
- Can be used transiently to regenerate ATP
- Used under ANAEROBIC conditions
- Used in skeletal muscle and brain
- Used when:
○ Intense muscular effort or neuronal demand
A decrease in phosphocreatine is seen prior to a decrease in ATP in anaerobic conditions because brain would utilise pcr as needed
What is The blood brain barrier:
- Specialised system of capillary endothelial cells
- Enclosed by end feet of astrocytic cells
- Separates circulating blood and CSF
- Is a physical and metabolic barrier
- Protects brain from harmful substances while supplying required nutrients
- Tight junctions disrputed in many CNS pathologies
- Provides the rate limiting factor in permeation of drugs
Molecular trafficking through BBB
ie how to things go through the BBB?
- Paracellular pathway
○ Through the tight junctions
○ Small, water soluble- Transcellular
○ Lipid soluble
○ Usual pathway for drugs - Transport proteins
○ Glucose, amino acids, nucleotides
○ Also has efflux transporters
Cyclosporin a
- Transcellular
Glucose and the brain Use: Storage: Transport: How can it go wrong?
Use:
- In the fed state glucose is the main fuel for the brain - Brain completely oxidises glucose to CO2 and water - Required for normal brain function and development
Storage:
- No storage of glycogen in neurons - Some glycogen stores in astrocytes
Glucose transport:
- facilitated diffusion - GLUT 1 transporter = BBB endothelial cells and astrocytes - GLUT 3 transporter = Neuronal specific - High affinity and high capacity glucose transport (facilitated diffusion)
How it can go wrong?
- GLUT1 deficiency syndrome- defective glucose transport across BBB- low glucose in CSF in presence of normal glycaemia
○ Infantile seizures and developmental delay
Abnormal expression and/or activity of GLUT1 in chronic epilepsy = decreased glucose uptake
What is GLUT1?
Glucose transporter in BBB endothelial cells and astrocytes
What is GLUT 3?
Neuronal specific glucose transporter
What is the glucose transporter for BBB endothelial cells?
GLUT1
What is the neuronal specific glucose transporter?
GLUT 3
When are alternative brain fuels used?
- When energy demands exceed glucose supply brain can utilise lactate and ketone bodies
- During:
○ Development
○ Hypoglycaemia (Ketones)
○ Starvation
Situations of intense neural activity
- During:
Ketone Bodies Where are they produced? How are they utilised? What is their importance How can this be used clinically?
Produced:
- In the liver in response to starvation
Utilisation:
- Up regulation of transport across BBB during starvation
Importance:
- Development
Uses:
A ketogenic diet can be an effective treatment of epileptic seizures in GLUT 1 deficiency syndrome- will use ketones rather than glucose
Oxidative phosphorylation
Is oxygen required?
What is the process?
Oxygen:
- Necessary for this process
Process:
- Glucose metabolised to pyruvate via glycolysis
- Pyruvate is then completely oxidised in the mitochondria to CO2
Produces a lot of ATP
Anaerobic glycolysis
Is oxygen required?
What is the process?
Oxygen :
- Used when oxygen is limiting
Process:
Cells redirect the pyruvate generated by glycolysis away from mitochondrial oxidative phosphorylation by generating lactate
What is Aerobic Glycolysis
- Conversion of glycose to lactate when oxygen is PRESENT
- Much less efficient than oxidative phosphorylation for generating ATP
Process can exist in tumours - Warburg effect
- Much less efficient than oxidative phosphorylation for generating ATP
Lactate What are its uses? When does it increase in its use? What is the role of the neuron? sources of lactate?
Uses: - Underlies the energetics of diverse brain activities ○ Long term memory function ○ Sensory processing ○ Pathophysiological conditions
- Increases in response to: ○ Hypoglycaemia ○ Ischaemic events ○ Stress - Could be present in the resting brain however research isnt sure
Role of neurons:
- Can transport and oxidise lactate
Sources of lactate when brain activity is increased:
- Net influx of lactate from blood to brain - via lactate transporters
- Increase in local aerobic glycolysis (increased neuronal/astrocyte glucose uptake)
- Astrocyte- neuron lactate shuttle hypothesis
○ Lactate generated from astrocyte glycogen breakdown
Transported into neurons for use
What is the response to falling plasma glucose?
- Prolonged and severe hypoglycaemia is rare in humans
The brain is very tolerant to changes in glucose
What happens in the Early stages of hypoglycaemic coma
What does the EEG show?
What changes do you see in oxygen, energy, phosphocreatine and ATP levels?
- Normal oxygen and energy levels
- Oxygen consumption continues
- Eeg shows slow waves and polyspikes
- Levels of phosphocreatine and ATP remain NORMAL unless there is respiratory depression
What happens in Prolonged and severe Hypoglycaemia?
- Some loss of ATP = approximately 25-30% of control levels
- There is not a complete energy loss
- loss of ATP correlates with onset of flat (isoelectric) EEG
- Neuronal damage results from oxidative stress
- Neuronal death takes several hours
Mechanisms for damage/death:
Increased neuronal release of glutamate leads to oxidative stress
What is Oxidative stress:
When does it occur?
what does it lead to?
- Results from imbalance between levels of reactive oxygen species ROS and antioxidants
- ROS such as peroxides and radicals are derived form inherent aerobic metabolism of oxygen
- Under normal circumstances cells are able to balance the production of oxidants and antioxidants resulting in the redox equilibrium
- Oxidative stress occurs:
○ Cells are exposed to excess levels of ROS and/or
○ As a result of antioxidant depletion - Leads to:
○ Mitochondrial damage
○ DNA damage
Ultimately leading to energy failure and death
Hypoxia Causes: Effects: Mechanisms to avoid metabolic failure? What is a clinical risk of treatment?
Causes:
- Systemic/local blood circulation defects eg Stroke
Effects:
- Not tolerated for long periods due to insufficient energy supply to brain
- Activation of short and long term adaptive mechanism
○ Activated by oxygen sensing systems
○ Activation depends on duration and severity of deprivation
○ Does this to avoid metabolic failure and risk of oxidation toxicity
Mechanisms to avoid metabolic failure:
○ Increase in local blood supply (autoregulation of cerebral blood flow, increases cardiac output, vasodilation)
○ Shut down of non-essential energy consuming mechanisms
○ Changes in gene transcription and protein synthesis to stimulate production of RBC and angiogenesis
Risk:
Excessive reoxygenation = risk of cell injury by increased inflammation and oxidative stress
How does energy failure occur in hypoxia/ischaemia?
- Lack of oxygen
- Utilisation of Phosphocreatine
- Rapid ATP exhaustion
- Blocking of ATPase (NA/K)
- Collapse of ion gradients
Rapid and large depolarisation
Events during brain ischaemia
- ATP failure
- Collapse of ion gradients
- Massive depolarisation due to influx of NA and CA and efflux of K
- Increased Glutamate released
- NMDA receptor activation
- Increased CA influx
Increased acidification (lactic acidosis)
Explain the link between Ischaemia and lactic acidosis
- The Ischaemic brain has no O2 so uses anaerobic glycolysis to meet the brains energy requirements
- This leads to production of lactate
- Excessive accumulation of lactate aggravates brain damage during ischaemia due to enhanced lactic acidosis
- The intensity will depend on glucose sotres
There is NO lactic acidosis in hypoglycaemia- THERE IS NO GLUCOSE PRECURSOR TO MAKE LACTATE
What are the secondary mechanisms of ischaemic cell death?
- intracellular calcium overload
○ Due to increased calcium influx from increased glutamate release
○ Oxidative and metabolic stress leading to cell death
○ This occurs via mitochondrial failure, disruption of cell membranes and changes in gene transcription- Inflammatory reactions
○ Microglia - Blood Vessel leakage
- Brain oedema
BBB breakdown
- Inflammatory reactions
What is the time course of hypoxic-ischaemic brain injury?
Immediate: 2-10 minutes
- Necrotic cell death
○ Due to Na overload and increased glutamate
Delayed: 6-72 hours - Delayed necrotic and apoptotic cell death ○ Ca overload and oxidative stress ○ Mitochondrial dysfunciton ○ Inflammation BBB failure
What brain sites are most vulnerable to cerebral ischaemia?
- Hippocampal CA1
All middle laminae of the cortex
Describe what happens to the brain metabolism during the ictal phase of a seizure:
- Increased metabolic rate (250%) = hypermetabolic
- Increased cerebral blood flow to supply glucose and nutrients
- Very small perturbation of tissue energy state and ion homeostasis (ATP remains stbale - 99%)
Increased lactate production during and as a result of a seizure (due to increased demands for glucose)
Describe the changes in metabolism during the INTERICTAL PERIODS of a seizure
- DECREASED requirement - lower than normal glucose uptake and blood flow
- Altered GLUT 1 expression at BBB endothelium
Decreased glucose uptake within epileptic areas/foci
- Altered GLUT 1 expression at BBB endothelium
What is 2DG?
- Assessment of brain glucose metabolism - indirect measure of neural activity
- It competes with glucose for entry into cell and accumulates
- It cannot be catabolised
PET scan with flurescent derivative ( 18F)FDG can identify low metabolism seizure sites in interictal period
What are the cellular events in response to an epileptic insult?
Repeated and prolonged seizures can lead to irreversible damage and cell loss and reorganisation of synaptic networks
First minute to hours after status epilepticus insult:
- Cell loss
- Hippocampal sclerosis
○ Excessive activation of excitatory glutamate receptors which results in glutamate excitotoxicity
○ Oxidative stress leads to damage of mossy cells and loss of GABAergic inhibition
- Astrocyte proliferation and dysfunction as a result of neuronal damage
- Inflammation and BBB failure
- Moderate lactate acidosis compared to ischaemia
Several hours to months after seizure insult - Disease progression - Long term damage - Chronic increase in calcium ○ Changes to gene expression initiating synaptic remodeling events ○ Eg neurogenesis - Acquired channel dysfunction BBB dysfunction
The links between BBB function and seizures?
- Seizures can cause BBB failure leading to BBB leakage
- BBB failure can lead to seizures
○ Acquired BBB defects such as head trauma and brain tumours
○ Multiple drug resistance can be due to defects in transporters in the BBB
○ Metabolic BBB defects such as GLUT1 deficiency syndrome
Systemic and immune triggers.
- BBB failure can lead to seizures
General function of areas of the brain
Cerebrum:
- Conscious thought processes
- Intellectual functions
- Memory storage and processing
Conscious and subconscious regulation of skeletal muscle contractions
General function of areas of the brain
Thalamus:
Relay and processing centres for sensory information
General function of areas of the brain
Hypothalamus:
- Center controlling emotions
- Autonomic functions
Hormone production
- Autonomic functions
General function of areas of the brain
Midbrain:
- Processing of visual and auditory data
- Generation of reflexive somatic motor responses
- Maintenance of consciousness
General function of areas of the brain
Pons:
- Relays sensory information to cerebrum and thalamus
Subconscious somatic and visceral motor center
General function of areas of the brain
Medulla oblongata:
- Relays sensory information to thalamus and to other portions of the brain stem
Autonomic centers for regulation of visceral function (cardiovascular, respiratory and digestive system activities)
General function of areas of the brain
Cerebellum:
- Coordinates complex somatic motor patterns
Adjusts output of other somatic motor centers in brain and spinal cord
Which brain areas are responsible for attention?
- Dorsolateral prefrontal cortex
- Ventrolateral prefrontal cortex
- Parietal cortex
- Dorsal anterior midcingulate cortex
- Striatum: caudate and putamen
- Cerebellum
If a patient showed Hemineglect- which lobe of the brain is effected?
Which side is most likely?
- Parietal association cortex
In particular the right hemisphere
What would deficits in the orbitofrontal cortex present as?
- Disinhibition
- Altered personality
- Lack of empathy
- Socially inappropriate behaviour
- Reactive aggression
Impaired “mind theory”
What would deficits in the Dorsolateral prefrontal cortex present as?
- Reduced attentional control
- Perseveration
- Impaired “executive” functions
Working memory , sequencing, planning, creativity, reasoning
What would deficits in the Medial prefrontal cortex present as?
- Decreased motivation
- Apathy
- Akinesia
- Impaired detection of mismatches or errors
What is consciousness?
- State of awareness of self and the environment (space/time)
- Being able to orientate and respond to new stimuli appropriately
- Arousal and wakefullness
○ Depends on the functioning of cerebral hemispheres and the reticular activating system of the brainstem - Content and cognition: emotions
○ Depends on a functioning cerebral cortex
○ Confusion, delirium, stupor - Unconsciousness is a lack of awareness/responsiveness
- Narrow meaning of consciousness = being awake
What is an EEG?
Minimal amount of electrodes?
Where does it get contributions from?
- Recording of electrical signals from the scalp
- Minimal electrodes is usually 18
- Waves come from synchronous contribution from a very large number of neurons
- Contributions from both post synaptic potentials (excitatory and inhibitory) and action potentials
- Cannot record EEG from a small amount or a single neuron
Types of brain waves from an EEG:
- Delta wave
○ Slow wave sleep
○ Coma
○ < 4hz- Theta
○ Drowsiness
○ 4-7 hz - Alpha
○ Relaxed wakefulness with CLOSED eyes
○ 8-15 hz - Beta
○ Active wakefulness
○ 16-30 hz - Gamma
○ Usually Artefact by muscular activity
○ 30-100 Hz
- Theta
What describe the waves seen in Slow wave sleep
- High amplitude and low frequency
- Synchronised EEG
Delta waves
- Synchronised EEG
Describe the waves seen in wakefulness
- High frequency and low amplitude
- Desynchronised EEG
Beta waves
- Desynchronised EEG
What brain waves would you see if you were awake with closed eyes?
Alpha waves
In Slow wave sleep- how to thalamic neurons fire?
- They fire in bursts
Frequency is the same as delta waves
In awake and REM sleep how do thalamic neurons fire?
- Neurons fire single spikes in alpha frequency
Excitatory influences are then transmitted to cortex via thalamo-cortical projections
Slow cortical waves are of what origin?
Thalamic
What is the difference between EEG and fMRI
EEG:
- based on direct measurements of electrical activity of electrical activity of the brain - Excellent temporal resolution - Poor spatial resolution
fMRI:
- Indirect measure- based on consequences of metabolic activation - Poor temporal resolution (few seconds to mins) - Good and improving spatial resolution
REM Sleep:
What are EEG waves like?
- Rapid eye movement
- EEG waves are similar to wakefulness
- Neurons fire single spikes in alpha frequency
What is the Lateral Reticular formation?
What is another name for it?
- Parvocellular
- Reflex connection to local cranial nerve nuclei
What is the medial Reticular formation?
What is another name for it?
- Magnocellular
- Neurons make long ascending and descending axons
- Involved in control of:
○ Movement
○ Posture
○ Pain
○ Autonomic function
○ Arousal
Noradrenergic neurons (In relation to arousal) Where are they located? Where do they project to? What is the function?
Location:
- Locus coeruleus - Ie bilaterally In the pons
Project to:
- The spinal cord to modulate autonomic reflexes and pain - To cerebrum: for vigilance and responsiveness to unexpected environmental stimuli and mood
Serotonergic neurons (In relation to arousal) Where are they located? Where do they project to? What is the function?
Located in:
- Raphe Nuclei - Midline along the brain stem
Project to:
- The spinal cord: modulation of AP, HR and Body temp - The Hypothalamus: modulation of AP, HR and Body temp - The Cerebrum: Mood and sleep/wake cycle
Cholinergic neurons (In relation to arousal)
Where are they located?
What is the function?
When are Ach levels high and low?
Located:
- Pons and Midbrain - Pontomesencephalotegmental complex - Basal nuclei
Function:
- Influence cortical arousal during waking states and dreaming (REM)
Ach Levels:
- High during wake and REM sleep - Low during Slow wave sleep
Histaminergic neurons (In relation to arousal)
Where are they located?
What is the function?
What effect to antihistamines have?
Located:
- Tuberal mamillary nucleus
Function:
- To help maintain arousal in forebrain
Antihistamines:
- Cause drowsiness if they cross the BBB
Orexin/Hypocretin neurons (In relation to arousal)
What is orexin?
What is the function?
What does a deficit cause?
It is an excitatory Neuropeptide
Function:
- It provokes wakefulness - Increaes thermogenesis - Increases appetite
Deficit:
- Causes Narcolepsy
Which brain structure modulates sleep?
Where is this located?
What are the functions?
Where does it project to and what role does this have?
The Suprachiasmatic Nucleus
- Located in the rostral part of the hypothalamus
Functions:
- Brains biological clock - Modulate via Retino-hypothalmic tracts - Output controls sleep onset and durations as well as associated bodily changes
Projects to:
Forebrain
- Attention - Emotions - Psychomotor performance
Pineal Gland
- Melatonin - Suppressed by light
Hypothalmaus
- Hormonal control - TH, GH, Cortisol - Metabolism - Orexin
Brainstem
- Sleep/arousal state - AP, HR, respiration
What does Melatonin do?
- Involved in light-induced entrainment of sleep cycle
- Secretion suppressed by light
What is Orexin?
Where is it produced?
What does it do?
- Neuropeptides
- Produced by dorsal hypothalamus
- Control appetite and arousal
- Works as a neurotransmitter
What cell groups are involved in the Ascending Arousal system?
What are the two main cholinergic pathways?
What is the end result?
- Monoaminergic cell groups involved:
○ Noradrenaline, serotonin- Cholinergic inputs from pedunculopontine and laterodorsal tegmental nuclei
Two main cholinergic pathways:
- To the intralaminar nuclei of the thalamus - this then projects widely to the cortex - To the lateral hypothalamic area to join with hypothalamic and basal forebrain cholinergic projections to cortex
Results in: massive diffuse cholinergic innervation of cortex
What is the inhibitory Surround?
What is the importance of this?
- When excitatory pyramidal neurons send projections to proximal neurons they also activate interneurons adjacent to them
- The interneurons are GABAeric and send inhibitory projections to surrounding neurons
- This creates an inhibitory surround
- The inhibitory surround prevents synchronisation of adjacent neurons
- This process is abnormal in epilepsy allowing synchronous firing of neurons
What are the characteristics of a partial seizure?
• Occur in a limited part of the cerebral hemisphere
• Preceded by an aura
• The part of the brain that is involve will determine the symptoms
○ Ie sensory cortex will produce sensory symptoms
○ Motor cortex will cause twitching or stiffening in the opposite side
○ Temporal lobe will cause: hallucinations of smell, taste or sound, dejavu or flashbacks, fear, nausea
• Simple = remains conscious
• Complex = consciousness is impaired- ability to respond or remember the event
○ Usually display automatisms such as lip smacking
○ Usually begin in the temporal lobe however can arise from anywhere
• Can spread to becomes secondarily generalised
What are the characteristics of a generalised seizure?
• Involved both sides of the brain from the beginning
• Consciousness is impaired immediately
• No recollections of the seizures
• Can begin as partial seizures that spread
• Subtypes
○ Tonic-clonic
○ Absences
○ Tonic
○ Myoclonic
○ Atonic
What are the characteristics of a tonic-clonic seizure?
- Lasts from a few seconds to 3-4 minutes
- Often the person bites or swallows his or her tongue and may have difficulty breathing- sometimes to the extent that cyanosis occurs
- Also signals transmitted from the brain to the viscera frequently cause urination and defecation
○ Stupor for many minutes after the seizure attack remains severely fatigued asleep for hours thereafter
• Initiation of a tonic-clonic seizure
□ Majority are idiopathic
□ Many have a hereditary predisposition to epilepsy (1 in 50-100)
□ Factors can increase the excitability of the abnormal epileptogenic circuitry enough to precipitate attacks
® Emotional stimuli
® Alkalosis caused by over breathing
® Drugs
® Fever
® Loud noises or flashing lights
□ Traumatic lesions in the brain cause excess excitability of local brain areas
What are the characteristics of absence seizures?
- Begin in childhood
- Last less than 10 seconds
- Sudden stare and loss of facial expression
- Possible rolling of eye upwards
- Rhythmic blinking
- Can be provoked by hyperventilation
- Seizure usually involves much or most of the thalamo-cortical activating system of the brain
What are the characteristics of Tonic Seizures?
- Brief generalised stiffening
- Last only seconds
- Often occur in sleep
- Common in those with intellectual disabilities
- Causes “drop attacks”
What are the characteristics of tonic seizures?
- Sudden loss of tone
- If sitting will cause “head nod”
- If standing will fall
What are the characteristics of myoclonic seizures?
• Appear like a sudden startle
• Brief (1 second or less) muscle contraction.
• Symptoms may occur in individual muscle or generalise to all muscle groups of the body
○ The latter can result in falling
• Associated with systemic diseases such as uraemia, hepatic failure, hereditary degenerative conditions
• Associated with mad cow disease
