Neurophysiology: Neural Signals and Seizure Disorders

Neurophysiology: Neural Signals

Clinical Case: Sheila (Page 2)

Sheila sustained a leg cut after falling in her English garden, which was cleaned and stitched in the ER.
Three days later, she returned with facial ache and difficulty opening her mouth, indicating a worsening condition.
She complained of diffuse pain and appeared unwell.
Within 24 hours, her condition deteriorated further, developing jaw stiffness and severe back and limb spasms, leading to her transfer to ICU.
This case highlights a severe neurological condition, likely tetanus, impacting neuromuscular function.

The Big Picture: Nerve Cells (Page 3)

Nerve cells, or neurons, are the fundamental units of the nervous system.
Key components include parts of neurons, the synapse, synaptic cleft, neuronal membrane, and ion channels.
The synaptic cleft is a 5 nm gap between neurons.

Simple Ion Forces Permit Electrical Signaling (Page 4)

Semipermeable membrane: Acts like a screen door, allowing some substances to pass while blocking others.
Diffusion: Ions flow from areas of high concentration to low concentration, moving along their concentration gradient.
Electrostatic pressure: Ions flow towards oppositely charged areas, following an electrical gradient.

The Resting Potential (Page 5)

Neurons as batteries: Neurons store electrical charge to be utilized when necessary.
Measurement: A reference electrode (outside axon) and a recording electrode (inside axon) connected to an amplifier measure the potential difference.
Microelectrode insertion: When a microelectrode enters a cell, the internal potential drops from 0 mV to a negative value.
Resting potential value: Typically ranges from -60mV to -90mV inside the axon, relative to the outside.

Cell Membrane and Ion Channels (Page 6)

Cell membrane: A lipid bilayer that repels water.
Ion channels: Proteins that span the membrane, allowing ions to pass in and out.
Gated channels: Open and close in response to:
- Voltage changes
- Chemicals
- Mechanical action
Ions are surrounded by water and thus require specific channels to cross the cell membrane.

Origin of the Resting Membrane (Equilibrium) Potential (Page 7)

Impermeability to large proteins: Neuronal membranes are not permeable to large, negatively charged proteins, which remain inside the cell.
Selective permeability to potassium (K^{+}): Neurons are selectively permeable to K^{+} ions, allowing them to enter and leave the cell freely at rest. No other ion behaves this way.
Electrostatic pressure: At rest, K^{+} ions move into the negatively charged interior of the cell due to this pressure.
Concentration gradient: As K^{+} ions accumulate inside, they also diffuse out along their concentration gradient.
Equilibrium: K^{+} reaches equilibrium when the rate of ion movement out of the cell is balanced by the rate of ion movement into the cell.

Resting Membrane Potential and the Sodium-Potassium Pump (Page 8)

Sodium-Potassium Pump (Na+/K+ pump): Actively pumps Na^{+} ions out of the cell and K^{+} ions into the cell.
This pump is crucial for maintaining the resting potential, compensating for ion leakage.
Slight Na^{+} permeability: The membrane is slightly permeable to Na^{+} ions, which slowly leak into the cell at rest.

Distribution of Ions Inside and Outside a Neuron (Page 9)

Outside cell: Many Na^{+}, few K^{+}, many Cl^{-}, many Ca^{2+}, few proteins.
Inside cell: Few Na^{+}, many K^{+}, few Cl^{-}, few Ca^{2+}, many proteins.
The movement of these ions through channels across the lipid bilayer creates electrical gradients.

Tetrodotoxin (Fugu Poisoning) (Page 10)

Tetrodotoxin (found in Fugu, 河豚) blocks nerve action.
Mechanism: It binds to and blocks the pores of voltage-gated sodium (Na^{+}) channels in neuron membranes, preventing Na^{+} influx.
Case example: A 32-year-old man experienced tingling in his tongue and right mouth, followed by a 'light feeling,' anxiety, and 'thoughts of dying' after consuming fugu. He then felt weak and collapsed, demonstrating the severe neurological effects.

How is this Stored Charge Used? (Page 11)

The stored charge (resting potential) is used to generate two main types of electrical signals:
- Graded potentials
- Action potentials
The axon hillock is a critical region where these signals are integrated.

Graded Potentials (Page 12)

Location: Occur primarily in dendrites and the cell body.
Propagation: As graded potentials spread across the membrane, they diminish in amplitude, similar to ripples in a pond. They are not regenerative.
Effect of ion injection: Injecting negative ions makes the inside of the cell more negative (hyperpolarization).

Graded Potentials Transform to Action Potentials (Page 13)

Threshold: If a sufficiently strong graded potential causes the membrane potential at the axon hillock to reach a specific threshold, it triggers an action potential.
Action potential characteristics: The inside of the cell briefly becomes positive (depolarization), and this signal sweeps unidirectionally down the axon to its terminal.

All-or-None Property of the Action Potential (Page 14)

Analogy: Similar to a rifle firing—a neuron fires at its full amplitude, or it does not fire at all.
Stimulus strength detection query: The question 'then how do we detect different stimulus strengths?' implies that stimulus strength is encoded by the frequency or pattern of action potentials, not by their amplitude.

Summary of Neural Information Flow (Page 15)

Input: Information enters the nerve cell at the synaptic site on the dendrite.
Graded potentials: Start in the dendrites and soma.
Action potential initiation: The action potential starts at the axon hillock.
Propagation: Propagated action potentials leave the soma-dendrite complex to travel down the axon.
Output: Information is carried via axon branches to axon terminals to other cells.

Ionic Basis of Action Potential – Step by Step (at the Axon Hillock) (Page 17-18)

Initial Depolarization: Voltage-gated Na^{+} channels open in response to an initial local depolarization (e.g., from graded potentials reaching threshold).
Rapid Depolarization (Rising Phase): More voltage-gated Na^{+} channels open, leading to a massive influx of Na^{+} ions into the cell. The membrane potential rapidly depolarizes, becoming positive, typically reaching +40 mV.
Na^{+} Channel Inactivation: Voltage-gated Na^{+} channels quickly inactivate and close.
K^{+} Channel Opening (Falling Phase): As the inside of the cell becomes very positive, voltage-gated K^{+} channels open.
Repolarization and Hyperpolarization: K^{+} ions, now driven by both concentration and electrical gradients, rapidly move out of the cell. This efflux of positive charge causes the membrane potential to repolarize and often slightly hyperpolarize (overshoot the resting potential).
Restoration of Resting Potential: The voltage-gated K^{+} channels close, and the Na^{+}/K^{+} pump and leak channels restore the membrane to its resting potential.

At peak: The concentration gradient pushing Na^{+} ions into the cell is momentarily balanced by the positive charge inside the cell driving them out.

Refractory Periods (Page 19-20)

Absolute Refractory Phase (AR): During this period, no amount of stimulation, regardless of strength, can produce another action potential. This is because the voltage-gated Na^{+} channels are inactivated. The inactivation gate acts like a 'deadbolt' on the apartment door, locking during this phase.
Relative Refractory Phase (RR): Following the absolute refractory phase, a stronger-than-normal stimulus is required to produce an action potential. This is due to some Na^{+} channels recovering from inactivation and the continued efflux of K^{+} causing hyperpolarization.

Action Potentials are Regenerated Along the Axon (Page 21)

Action potentials travel in one direction (unidirectionally) down the axon.
This is ensured by the refractory state of the membrane region that has just undergone depolarization, preventing the signal from propagating backward.

Conduction Speed: Myelin vs. Unmyelinated Axons (Page 22)

Unmyelinated axons (Continuous conduction): Action potentials are generated sequentially along every segment of the axon membrane. This is a slower process.
Myelinated axons (Rapid saltatory conduction): Myelin, an insulating sheath, wraps around the axon, interrupted by small gaps called Nodes of Ranvier.
- Action potentials 'jump' from one Node of Ranvier to the next, regenerating only at these nodes where Na^{+} channels are concentrated.
- This 'saltatory' (jumping) conduction significantly increases the speed of nerve impulse transmission.

Periodic Paralysis (Page 23)

A condition caused by a genetic defect in the Na^{+} channel in muscle cells.
This highlights the critical role of ion channel function in muscle excitability.

At the Synapse: Electrical and Chemical Signals (Page 24)

The synapse is the specialized junction where the electrical signal (action potential) from one neuron is transmitted to another, often via a chemical signal.

Sequence of Transmission at Chemical Synapses (Page 25, 27, 29)

Action Potential Arrival: An action potential travels down the axon and reaches the axon terminal (presynaptic terminal).
Ca^{2+} Influx: The depolarization caused by the action potential opens voltage-gated calcium (Ca^{2+}) channels, allowing Ca^{2+} ions to enter the presynaptic terminal.
Neurotransmitter Release: The influx of Ca^{2+} triggers synaptic vesicles (containing neurotransmitters) to fuse with the presynaptic membrane and release their neurotransmitter cargo into the synaptic cleft.
Neurotransmitter Binding and Postsynaptic Potentials: Neurotransmitters diffuse across the cleft and bind to specific postsynaptic receptors on the dendrite or cell body of the postsynaptic neuron.
- Excitatory Postsynaptic Potential (EPSP): A small, local depolarization of the postsynaptic membrane, making the cell interior less negative (more positive). This pushes the cell closer to its threshold for firing an action potential. EPSPs typically result from the influx of Na^{+} ions.
- Inhibitory Postsynaptic Potential (IPSP): A small, local hyperpolarization of the postsynaptic membrane, making the cell interior more negative. This pushes the cell further away from its threshold, inhibiting action potential generation. IPSPs typically result from the influx of Cl^{-} ions or efflux of K^{+} ions.
Presynaptic Autoreceptor Binding (Modulation): Some neurotransmitters may bind to presynaptic autoreceptors located on the axon terminal that released them. This binding usually provides negative feedback, decreasing further neurotransmitter release (Page 29).
Neurotransmitter Inactivation (Termination of Signal): After binding, neurotransmitters are rapidly inactivated to prevent continuous stimulation of the postsynaptic cell. This occurs via two main mechanisms:
- Degradation: Enzymes in the synaptic cleft break down the neurotransmitter.
- Reuptake: Neurotransmitters are actively transported back into the presynaptic terminal or glial cells.

Neurotransmitter Vesicles (Page 26)

Neurotransmitters are stored in synaptic vesicles within the presynaptic terminal, ready for release.

EPSPs and IPSPs are Integrated by the Axon Hillock (Page 28)

The axon hillock acts as an integrator, summing up all the excitatory (EPSPs) and inhibitory (IPSPs) inputs received by the dendrites and cell body.
This process is metaphorically described as 'Dendrites vote, and the axon hillock decides.' If the net sum of potentials reaches the threshold at the axon hillock, an action potential is triggered.

Neurotransmitter Reuptake (Page 30)

Mechanism: Specialized reuptake transporters on the presynaptic nerve terminal actively pump neurotransmitters (e.g., Serotonin/5-HT, Noradrenaline) from the synaptic cleft back into the presynaptic neuron.
Enzymatic breakdown (within the cell): Once reuptaken, neurotransmitters can be repackaged into vesicles or degraded by intracellular enzymes like Monoamine Oxidase (MAO) or Catechol-O-methyltransferase (COMT).
Pharmacological relevance: Drugs like SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors), such as venlafaxine, block these reuptake transporters, increasing the concentration of neurotransmitters in the synaptic cleft and prolonging their action.

Neurotransmitter Degradation (Page 31)

Mechanism: Enzymes in the synaptic cleft directly break down neurotransmitters.
Example: Acetylcholinesterase (AChE) is an enzyme that breaks down the neurotransmitter Acetylcholine (ACh) in the synaptic cleft.
AChE inhibition: Inhibitors of AChE (e.g., organophosphate pesticides like Raid) prevent the breakdown of ACh, leading to prolonged muscle contraction and various toxic effects.

Electrical Synapses (Page 32)

Direct ion flow: In electrical synapses, ions flow directly from one neuron to an adjacent neuron through large channels called gap junctions, with no time delay.
Historical context: This mechanism supports some of Golgi's earlier ideas about neuronal connectivity.
Benefits: Electrical synapses offer several advantages:
- Faster transmission: Eliminating the chemical mediator significantly speeds up signal propagation.
- Synchronization: Allows for rapid and synchronized activity among populations of neurons.
- Energy saving: Does not require the synthesis, storage, and release of neurotransmitters.

Review of Neural Signal Flow (Page 33)

Neurotransmitter is released from the presynaptic neuron.
This opens ion channels (e.g., Na^{+} channels) in the postsynaptic membrane.
A depolarizing current (EPSP) is created in the postsynaptic neuron.
This current passively flows down to the axon hillock.
If the threshold is reached, an action potential is triggered at the axon hillock.
The action potential is conducted down the axon to the presynaptic terminal.
The cycle then continues, transmitting information throughout the nervous system (e.g., from toe to brain or brain to toe).

Ligands (Page 34)

Definition: Ligands are molecules that fit precisely into specific receptors, acting like a 'lock-and-key' mechanism, to either activate or block them.
Endogenous ligands: Produced within the body, such as neurotransmitters and hormones.
Exogenous ligands: Originate from outside the body, including drugs and toxins.

Acetylcholine Receptor Example (Page 35)

Structure: The Acetylcholine (ACh) receptor, shown as a ligand-gated ion channel, has a specific binding site for ACh.
Function: When ACh binds to its site, it causes a conformational change that opens a gate, allowing ions (e.g., Na^{+}) to flow into the intracellular space across the neuronal membrane.

Number of Receptors in a Neuron Varies Over Time (Page 36)

Dynamic regulation: The number of receptors on a neuron can change rapidly, particularly during development, in response to drug use, and during learning processes.
Up-regulation ('sensitization'): An increase in the number of receptors. For example, nicotine receptors may up-regulate when someone starts smoking, leading to increased sensitivity to nicotine.
Down-regulation ('tolerance'): A decrease in the number of receptors. For instance, chronic use of benzodiazepines (e.g., Valium) can cause their receptors to down-regulate, leading to tolerance and reduced drug efficacy.

Why Should I Care? (Clinical Relevance) (Page 37)

Understanding neuron facts has practical applications, particularly in treating neurological disorders.
Antiepileptic drugs: Carbamazepine, Phenytoin, Lamotrigine, and Valproate are medications used to treat seizures.
Mechanism of action: These drugs often work by modulating ion channels, particularly Na^{+} channels. For example, some may prolong the inactivation state of Na^{+} channels or prevent them from staying open too long, thereby stabilizing neuronal membrane excitability that is disrupted in seizure disorders.

Electroencephalogram (EEG): Recording of Brain Activity (Page 38)

Definition: An EEG is a functional test that records the electrical activity of the brain using electrodes placed on the scalp.
Normal EEG: Shows characteristic wave patterns, which differ between brain hemispheres (e.g., Fp2-F4, F4-C4 represent right hemisphere; Fp1-F3, F3-C3 represent left hemisphere).
Waveforms vary in amplitude (200 imes 10^{-6} V shown) and frequency (relative to 1 s time markers).

Seizure Disorders: Tonic-Clonic Seizure (Page 39-40)

Generalized convulsions: Characterized by abnormal electrical activity spreading throughout the entire brain.
Characteristic movements: Involve both tonic (sustained stiffening of muscles) and clonic (rhythmic jerking) contractions, leading to a whole-body convulsion.
Post-seizure state: A seizure is typically followed by a period of confusion and sleep (postictal state).
EEG example: The provided EEG segment shows a 'Tonic-clonic seizure' pattern, distinguishable from normal EEG activity.

Seizure Disorders: Absence Seizure (Petit-Mal) (Page 41)

Brain activity: Brain waves show generalized rhythmic activity, but only for a few seconds at a time.
Frequency: Can occur hundreds of times a day.
Clinical presentation: No unusual muscle activity, except for stopping ongoing activity and staring blankly during the brief seizure.
Memory: Events that occur during the seizure are not remembered by the individual.

Seizure Disorders: Focal Seizures (Partial) (Page 42)

Limited involvement: Do not involve the entire brain; instead, they start in one specific area.
Symptoms: May manifest as jerking of only one side of the body or other localized symptoms, depending on the brain region affected.
Awareness levels:
- Focal Seizure – normal awareness: The individual remains fully conscious and aware during the seizure.
- Focal Seizure – impaired awareness: The individual's awareness or consciousness is altered or lost during the seizure.
EEG: Shows abnormal activity localized to the originating area of the brain.

Seizure Disorders: Myoclonic ('Muscle Jerk') Seizures (Page 43)

Characteristics: Involve rapid, brief contractions (jerks) of muscles.
Distribution: These contractions typically occur at the same time on both sides of the body.

Categories of Seizures - Summary (Page 44)

Partial (Focal) Onset: Seizures originating in a localized area of the brain.
- Focal seizures (aware): Consciousness is preserved.
- Focal seizures (awareness impaired): Consciousness is altered or lost.
Generalized Onset: Seizures involving both hemispheres of the brain from the outset.
- **Motor seizures:
  - Myoclonic seizures:** Brief, shock-like jerks of a muscle or group of muscles.
  - Tonic-clonic seizures (grand-mal): Involve stiffening (tonic) and rhythmic jerking (clonic) of the body.
- **Nonmotor seizures:
  - Absence seizures (petit-mal):** Brief lapses in awareness, often appearing as staring spells.