3. Neurophysiology

Overview of Nervous System Function & Cellular Organization

• Central Function:

  • Responsible for gathering sensory information from internal and external environments.

  • Processes incoming sensory information and sends executive messages to appropriate effectors.

  • Controls and regulates virtually every other physiological system in the body.

• Structural Divisions:

  • Central Nervous System (CNS): Composed of the brain and spinal cord; acts as the primary integration center.

  • Peripheral Nervous System (PNS): Composed of all peripheral nerve fibers and ganglia.

  • Afferent Division: Sensory neurons carrying information from internal and external sensors to the CNS.

  • Efferent Division: Motor neurons carrying signals from the CNS out to target effectors in the periphery.

• Functional Control Principles:

  • Antagonistic Control: Dual regulation of organs where one branch increases function and another decreases function (e.g., decreasing vs. increasing heart rate).

  • Gut-Brain Axis: A standalone area of study focusing on bidirectional communication between the gastrointestinal tract and the CNS; approximately $90\%$ of the body's serotonin is synthesized in the gut.

• Primary Cell Types:

  • Neurons: Highly excitable cells capable of initiating and conducting electrochemical signals along their membranes.

  • Glial Cells: Non-excitable helper cells that provide crucial structural, metabolic, and functional support for neurons.

Neuronal Structure, Subtypes, and Axonal Transport

• Neuronal Functional Subtypes:

  • Sensory (Afferent) Neurons: Transport sensory inputs (somatic senses, vision, smell) toward the CNS integrating center.

  • Interneurons of CNS: Located entirely within the CNS; process, integrate, and excite or inhibit downstream target cells.

  • Efferent Neurons: Transport integrative output signals from the CNS out to peripheral effectors; possess long axons with axon collaterals and terminal trees.

• Structural Domains of a Neuron:

  • Dendrites:

  • Extensively branched structures designed to receive input signals from multiple presynaptic sources.

  • Possess specialized dendritic spines that significantly increase receptive surface area for picking up signals.

  • Cell Body (Soma): Contains the nucleus, rough endoplasmic reticulum, and mitochondria; serves as the metabolic center.

  • Axon Hillock:

  • Region where the single axon emerges from the cell body.

  • Serves as the integration site for incoming received signals and acts as the trigger zone for action potentials.

  • Characterized by decreased membrane capacitance and increased lipid bilayer conduction speed.

  • Axon:

  • Long process that processes and conducts signals over distances; branches into axon collaterals and synaptic terminals.

  • Synapse Mechanics:

  • Presynaptic Terminal: Delivers signals via synaptic vesicle fusion and neurotransmitter release into the synaptic cleft.

  • Postsynaptic Cell: Receives signals via specialized membrane receptors in the synaptic space.

• Axonal Transport Mechanisms:

  • Structural Microtubules (MT): Function as structural highways running along the entire length of the axon for vesicle and organelle transport.

  • Vesicle Dynamics: Organelles and vesicles synthesized in the cell body travel along MT highways to fuse with the terminal membrane.

  • "Kiss and Run" Transport: Synaptic vesicles touch the axon terminal membrane to release neurotransmitters, then detach to be degraded or reused.

Membrane Potential ($V_m$) and Electrochemical Equilibrium

• Biophysical Principles of $V_m$:

  • The plasma membrane acts as an electrical insulator separating extracellular fluid (ECF) from intracellular fluid (ICF).

  • ECF possesses a slight relative excess of cations ($+$).

  • ICF possesses a slight relative excess of anions ($-$, net negative interior).

  • Membrane Potential Difference ($V_m$): The electrical disequilibrium existing across the plasma membrane due to uneven distribution of ions between ECF and ICF.

• Measurement of $V_m$:

  • Absolute $V_m$: Direct measurement of exact localized charge differences across the lipid bilayer.

  • Relative $V_m$: Measures internal charge relative to an extracellular saline bath ground/reference electrode set at $0\,mV$.

  • Standard Resting Membrane Potential ($V_m$): Baseline resting state is $-70\,mV$.

• Dynamics of Potential Changes:

  • Depolarization: Membrane potential becomes less negative (more positive) than resting potential (e.g., moving toward $0\,mV$ or $+30\,mV$).

  • Repolarization: Membrane potential returns back toward resting potential.

  • Hyperpolarization: Membrane potential becomes more negative than resting potential (e.g., dropping to $-80\,mV$ or $-100\,mV$).

• Generation of Electrochemical Gradients:

  • Resting State Model: ECF ($Na^+$ and $Cl^-$) and ICF ($K^+$ and large impermeable organic anions $A^-$) begin in charge neutrality.

  • Insertion of $K^+$ Leak Channels: $K^+$ diffuses out down its steep concentration gradient.

  • Charge Separation: Impermeable $A^-$ remains inside, creating a growing negative charge interior.

  • Opposing Forces: The negative interior creates an electrical gradient attracting $K^+$ back into the cell, opposing the outward concentration gradient until equilibrium is reached.

• Quantitative Ion Dynamics and Nernst Equation:

  • Equilibrium Potential ($E_{ion}$): The membrane potential at which electrical and chemical concentration forces on a specific ion are equal and opposite (no net flux).

  • Equilibrium Potential Values:

  • Potassium ($E_{K^+}$): $-90\,mV$

  • Sodium ($E_{Na^+}$): $+60\,mV$

  • Chloride ($E_{Cl^-}$): $-63\,mV$

  • Calcium ($E_{Ca^{2+}}$): $\approx +120\,mV$

  • Nernst Equation (at $37^\circ\text{C}$):     $E_{ion} = \left(\frac{61}{z}\right) \times \log\left(\frac{[ion]_{out}}{[ion]_{in}}\right)$

  • Normal Physiological Ion Concentrations (Table 8-2):

  • Potassium ($K^+$): Extracellular = $5\,mM$ (normal range: $3.5-5\,mM$); Intracellular = $150\,mM$; $E_{K^+} = -90\,mV$.

  • Sodium ($Na^+$): Extracellular = $145\,mM$ (normal range: $135-145\,mM$); Intracellular = $15\,mM$; $E_{Na^+} = +60\,mV$.

  • Chloride ($Cl^-$): Extracellular = $108\,mM$ (normal range: $100-108\,mM$); Intracellular = $10\,mM$ (normal range: $5-15\,mM$); $E_{Cl^-} = -63\,mV$.

• Resting Permeabilities & Goldman-Hodgkin-Katz (GHK) Equation:

  • Resting Permeability Hierarchy: $P_K > P_{Cl} > P_{Na} > P_{Ca}$.

  • High baseline resting permeability to $K^+$ is due to high expression of constitutively open $K^+$ leak channels, drawing baseline $V_m$ close to $E_{K^+}$.

  • Goldman-Hodgkin-Katz (GHK) Equation:     $V_m = 61 \times \log\left(\frac{P_K [K^+]_{out} + P_{Na} [Na^+]_{out} + P_{Cl} [Cl^-]_{in}}{P_K [K^+]_{in} + P_{Na} [Na^+]_{in} + P_{Cl} [Cl^-]_{out}}\right)$

  • GHK Permeability Shifts:

  • Increasing $K^+$ permeability (or decreasing $Na^+$ permeability) repolarizes or hyperpolarizes $V_m$ toward $-90\,mV$.

  • Increasing $Na^+$ permeability (or decreasing $K^+$ permeability) depolarizes $V_m$ toward $+60\,mV$.

• Maintenance of Resting Potential:

  • Ion concentration gradients are actively maintained by the $Na^+-K^+$ ATPase pump, pumping 3 $Na^+$ out for every 2 $K^+$ brought into the cell.

Signal Integration: Graded Potentials vs. Action Potentials

• Graded Potentials:

  • Definition: Local potential changes proportional in amplitude to the strength of the initiating stimulus.

  • Location: Usually occur in dendrites and cell body.

  • Channel Types: Triggered by mechanically, chemically, or voltage-gated ion channels.

  • Signal Dynamics: Decremental conduction; signal strength weakens exponentially with distance from origin due to charge leaking across the membrane ("ripples in water").

  • Subthreshold Stimuli: Weak stimuli cause localized depolarizations that attenuate below threshold ($-55\,mV$) by the time they reach the axon hillock, failing to trigger an action potential.

  • Suprathreshold Stimuli: Strong stimuli generate sufficient initial depolarization so that the potential reaching the axon hillock remains at or above $-55\,mV$, triggering an action potential.

• Summation Mechanisms:

  • Spatial Summation: Simultaneous postsynaptic potentials originating from multiple distinct synapses combine at the trigger zone.

  • Temporal Summation: Rapid successive input signals originating from a single synapse piggyback on top of one another to reach threshold.

  • Excitatory Post-Synaptic Potentials (EPSPs): Depolarizing potential shifts caused primarily by $Na^+$ influx.

  • Inhibitory Post-Synaptic Potentials (IPSPs): Hyperpolarizing potential shifts caused by $K^+$ efflux or $Cl^-$ influx.

  • Synaptic Inhibition Control:

  • Global Synaptic Inhibition: An inhibitory neuron targets the cell body or dendrites, hyperpolarizing the axon hillock and preventing action potential generation entirely across all downstream terminals.

  • Selective Synaptic Inhibition: An inhibitory neuron selectively targets one specific collateral branch of an axon terminal, preventing neurotransmitter release at that single target while leaving other branches active.

Action Potential Mechanics, Kinetics, and Propagation

• Characteristics of Action Potentials:

  • Regenerating electrical signals of uniform strength that travel unidirectionally from the trigger zone to axon terminals.

  • All-or-None Phenomenon: Once threshold ($-55\,mV$) is reached, an action potential fires at fixed amplitude regardless of stimulus magnitude beyond threshold.

• Sequential Phases and Ion Fluxes:

  1. Resting State: $V_m$ sits at $-70\,mV$.

  2. Threshold Reached: Suprathreshold signal depolarizes trigger zone to $-55\,mV$.

  3. Rising Phase (Depolarization): Voltage-gated $Na^+$ channels open rapidly $\rightarrow$ massive $Na^+$ influx $\rightarrow$ membrane potential overshoots to $+30\,mV$.

  4. Peak Phase: Voltage-gated $Na^+$ inactivation gates close; voltage-gated $K^+$ channels finish opening.

  5. Falling Phase (Repolarization): Rapid $K^+$ efflux repolarizes membrane back toward negative potential.

  6. Undershoot (Hyperpolarization): Voltage-gated $K^+$ channels are slow to close, allowing continued $K^+$ efflux so $V_m$ approaches $-90\,mV$.

  7. Restoring Baseline: $K^+$ channels close, and leak channels alongside $Na^+-K^+$ ATPase restore resting potential to $-70\,mV$.

• Voltage-Gated Channel Kinetics:

  • $Na^+$ Activation Gate: Fast to open.

  • $Na^+$ Inactivation Gate: Slow to close.

  • $K^+$ Activation Gate: Slow to open and slow to close.

  • Positive Feedback Loop: Depolarization opens fast $Na^+$ activation gates $\rightarrow$ $Na^+$ enters cell $\rightarrow$ further depolarization $\rightarrow$ opens more $Na^+$ activation gates. This cycle is capped at $+30\,mV$ when the slow $Na^+$ inactivation gate closes.

• Refractory Periods:

  • Absolute Refractory Period: Duration during the rising and early falling phase where no second AP can be triggered, regardless of stimulus strength, because $Na^+$ channels are inactivated.

  • Relative Refractory Period: Duration following the absolute period where $Na^+$ channels have reset to original closed positions, but $K^+$ channels remain open; a larger-than-normal suprathreshold stimulus can initiate a new AP.

• Effects of Clinical Perturbations (Hyperkalemia):

  • Hyperkalemia: Increased extracellular $K^+$ concentration ($[K^+]_{out}$).

  • Math Application (Nernst Equation): Elevating extracellular $K^+$ from $5\,mM$ to $6\,mM$ shifts $E_{K^+}$ from $-90\,mV$ to $-85\,mV$:     $E_{K^+} = 61 \times \log\left(\frac{6}{150}\right) = -85\,mV$

  • Physiological Impact: Depolarizes baseline resting potential closer to threshold, increasing neuronal excitability and causing detrimental cardiac/neurological instability.

• Comparative Overview (Table 8.3):

  • Graded Potential: Input signal; located in dendrites and cell body; uses mechanically, chemically, or voltage-gated channels; involves $Na^+$, $K^+$, $Ca^{2+}$; depolarizing or hyperpolarizing; variable strength, can summate; no threshold required.

  • Action Potential: Regenerating conduction signal; located from trigger zone through axon; uses voltage-gated channels; involves $Na^+$ and $K^+$; depolarizing only; all-or-none phenomenon, cannot summate; requires threshold stimulus ($-55\,mV$); limited by refractory periods.

• Action Potential Propagation Dynamics:

  • Unmyelinated Axon Propagation: Continuous conduction; local $Na^+$ influx diffuses laterally in both directions. Upstream membrane is in absolute refractory period, preventing backward propagation and forcing unidirectional signal movement.

  • Myelinated Axon & Saltatory Conduction:

  • Myelin Sheath: Insulator formed by Schwann cells (PNS) or Oligodendrocytes (CNS) wrapped in multiple layers; prevents current leakage.

  • Nodes of Ranvier: Unmyelinated gaps ($1-1.5\,mm$ spacing) densely populated with voltage-gated $Na^+$ and $K^+$ channels.

  • Saltatory Conduction: Action potential jumps from node to node, significantly increasing conduction velocity.

  • Demyelinating Pathology: Demyelinating diseases (e.g., Multiple Sclerosis, ALS) cause current leakage, slowing conduction velocity and causing motor/sensory dysfunction.

Synaptic Function, Neurotransmitters, and Glial Cells

• Synaptic Transmission Mechanics:

  • Electrical Synapses: Direct movement of ions via gap junctions; extremely fast charge change.

  • Chemical Synapses: Unidirectional transmission via chemical neurotransmitters.

  • Steps of Chemical Transmission:

  1. Action potential depolarizes the axon terminal membrane.

  2. Depolarization opens voltage-gated $Ca^{2+}$ channels; $Ca^{2+}$ enters the cell down its electrochemical gradient ($E_{Ca^{2+}} = +120\,mV$).

  3. Calcium entry triggers exocytosis of synaptic vesicle contents via docking proteins.

  4. Neurotransmitter diffuses across the synaptic cleft and binds to receptors on the postsynaptic cell.

  5. Neurotransmitter binding initiates a response in the postsynaptic cell.

• Stimulus Frequency Coding:

  • Weak stimulus $\rightarrow$ low action potential frequency $\rightarrow$ minimal neurotransmitter release.

  • Strong stimulus $\rightarrow$ high action potential frequency $\rightarrow$ increased neurotransmitter release.

• Neurotransmitter Inactivation & Signal Termination:

  • Reuptake: Active transport of intact neurotransmitter back into presynaptic terminals (for recycling/reuse) or surrounding glial cells (converted to precursors).

  • Enzymatic Destruction: Specific enzymes in the synaptic cleft degrade neurotransmitters into inactive components.

  • Diffusion: Passive diffusion away from the synaptic cleft into blood vessels (where they can function as neurohormones).

• Postsynaptic Receptor Types:

  • Ionotropic Receptors: Ligand-gated ion channels; fast response ($\approx 1\,ms$).

  • Metabotropic Receptors: G-protein coupled receptors; slower, longer-lasting responses (hundreds of $ms$).

• Glial Cell Diversity and Functions (Figure 9.2):

  • Central Nervous System (CNS) Glia:

  • Ependymal Cells: Create functional barriers between fluid compartments; act as neural stem cell sources.

  • Astrocytes: Help form the blood-brain barrier (BBB); take up $K^+$, water, and neurotransmitters; secrete neurotrophic factors; supply substrates for ATP production.

  • Microglia: Specialized immune cells acting as scavengers to clear debris.

  • Oligodendrocytes: Form myelin sheaths around CNS axons.

  • Peripheral Nervous System (PNS) Glia:

  • Schwann Cells: Form myelin sheaths around PNS axons; secrete neurotrophic factors.

  • Satellite Cells: Support cell bodies within peripheral ganglia.

Central & Peripheral Nervous System Architecture

• Brain Structures and Functional Specializations:

  • Executive Function & Personality: Cerebral cortex / frontal lobe centers.

  • Vision: Primary visual cortex.

  • Language & Hearing: Auditory cortex and specialized speech areas.

  • Motor Coordination & Balance: Cerebellum.

  • Autonomic & Life Support Centers: Medulla oblongata and pons (blood pressure, respiration, urinary bladder control).

• Functional Roles of the Hypothalamus (Table 9.2):

  1. Activates Sympathetic Nervous System: Controls catecholamine release from adrenal medulla; maintains blood glucose via endocrine pancreas; stimulates shivering and sweating.

  2. Maintains Body Temperature.

  3. Controls Body Osmolarity: Motivates thirst and drinking behavior; stimulates vasopressin secretion.

  4. Controls Reproductive Functions: Directs oxytocin secretion; directs FSH and LH release via anterior pituitary trophic hormones.

  5. Controls Food Intake: Stimulates satiety center and feeding center.

  6. Interacts with Limbic System: Influences behavior and emotions.

  7. Regulates Cardiovascular Control Center: In medulla oblongata.

  8. Secretes Trophic Hormones: Controls hormone release from anterior pituitary gland.

• Cerebral Vasculature & Blood-Brain Barrier (BBB):

  • Vasculature: Circle of Willis provides a circular anatomical configuration of cerebral arteries allowing collateral blood rerouting if a vessel becomes occluded.

  • Blood-Brain Barrier Properties:

  • Formed by tight junctions between endothelial cells lining cerebral blood vessels.

  • Permeable to: Small, lipid-soluble/lipophilic molecules (alcohol, nicotine, anesthetics, psychoactive drugs), small essential gases ($O_2$, $CO_2$), and specific nutrients transported via specialized membrane transport proteins (glucose, specific amino acids, vitamins, hormones).

  • Impermeable to: Large molecules (proteins, antibodies), hydrophilic water-soluble substances without transporters, pathogens, bacteria, viruses, and most therapeutic drugs/antibiotics.

• Neural Reflex Pathways:

  • Simple Neural Reflex: Sensory input $\rightarrow$ Integration in CNS $\rightarrow$ Motor system output $\rightarrow$ Physiological response/behavior (e.g., monosynaptic knee-jerk reflex without brain involvement).

  • Complex Integration: Incorporates cognitive systems, limbic inputs, and behavioral state modulation.

• Peripheral Nervous System (PNS) Organization:

  • Somatic Motor Pathways: Single neuron extending directly from CNS to skeletal muscle target; releases Acetylcholine (ACh) onto nicotinic cholinergic receptors.

  • Autonomic Pathways: Two-neuron chain consisting of a preganglionic neuron (CNS to ganglion) synapsing onto up to 32 postganglionic neurons (ganglion to target tissue).

• Autonomic Nervous System (ANS) Divisions:

  • Sympathetic Division ("Fight or Flight"): Active during high activity or stress. Uses ACh at ganglion (nicotinic receptor) and Norepinephrine (NE) at target tissue (adrenergic receptors: $\alpha_1, \alpha_2, \beta_1, \beta_2, \beta_3$).

  • Parasympathetic Division ("Rest and Digest"): Active during quiet daily activities. Uses ACh at ganglion (nicotinic receptor) and ACh at target tissue (muscarinic receptor).

  • Adrenal Sympathetic Pathway: Modified sympathetic ganglion where preganglionic neurons innervate the adrenal medulla, triggering secretion of Epinephrine (E) directly into the blood.

• Comparative ANS Target Organ Responses (Page 66 Table):

  • Pupil of Eye: Sympathetic dilates ($\alpha$); Parasympathetic constricts.

  • Salivary Glands: Sympathetic secretes mucus and enzymes ($\alpha, \beta_2$); Parasympathetic secretes watery fluid.

  • Heart: Sympathetic increases rate and force of contraction ($\beta_1$); Parasympathetic slows rate.

  • Arterioles & Veins: Sympathetic constricts ($\alpha$) or dilates ($\beta_2$); Parasympathetic has minimal direct innervation.

  • Lungs (Bronchioles): Sympathetic dilates ($\beta_2$); Parasympathetic constricts.

  • Digestive Tract: Sympathetic decreases motility and secretion; Parasympathetic increases motility and secretion.

  • Exocrine Pancreas: Sympathetic decreases enzyme secretion ($\alpha$); Parasympathetic increases enzyme secretion.

  • Endocrine Pancreas: Sympathetic inhibits insulin secretion ($\alpha$); Parasympathetic stimulates insulin secretion.

  • Adrenal Medulla: Sympathetic secretes catecholamines.

  • Kidney: Sympathetic increases renin secretion ($\beta_1$).

  • Urinary Bladder: Sympathetic causes urinary retention ($\alpha, \beta_2$); Parasympathetic stimulates release of urine.

  • Adipose Tissue: Sympathetic stimulates fat breakdown ($\beta_3$).

  • Sex Organs: Sympathetic induces ejaculation ($\alpha$); Parasympathetic induces erection.

Clinical Neurophysiology: Stroke & Aphasia Management

• Pathophysiology of Stroke:

  • Ischemic Stroke ($85\%$ of cases): Occurs when flow in a cerebral vessel is disrupted or blocked by atherosclerotic plaques on which thrombi (clots) form, depriving tissue of $O_2$ and nutrients (halting ATP synthesis) and risking permanent neurological disability.

  • Hemorrhagic Stroke ($15\%$ of cases): Occurs when a cerebral vessel ruptures, causing internal bleeding, rapid accumulation of intracranial pressure (ICP), severe mechanical damage, and risk of fatal brain herniation.

• B.E. F.A.S.T. Acute Screening Mnemonic:

  • Balance: Sudden loss of balance or severe vertigo.

  • Eyes: Sudden double vision, blind or blurry spot, or visual field loss.

  • Face: Unilateral facial droop or asymmetry on smile.

  • Arm: Unilateral arm/leg weakness or motor drift.

  • Speech: Slurred speech, aphasia (impairments to speech, reading, or writing).

  • Time: Call emergency medical services immediately.

• Specific Cortical Speech Regions and Aphasia Syndromes:

  • Broca's Area:

  • Anatomical Location: Left inferior frontal gyrus (opercular and triangular parts; Brodmann areas 44 & 45).

  • Vascular Supply: Superior Division (M2 segment) of Middle Cerebral Artery (MCA).

  • Clinical Presentation (Broca's Expressive Aphasia):

    • Non-fluent, effortful speech with impaired articulation and telegraphic syntax using informational content words (e.g., "Dorm… sleep… campus… run… lecture… late.").

    • Preserved auditory comprehension for simple language.

    • Impaired repetition and naming abilities.

    • Patients retain insight into their deficit and experience significant frustration.

  • Associated Deficit: Contralateral face and arm motor weakness due to proximity to motor cortex.

  • Wernicke's Area:

  • Anatomical Location: Posterior superior temporal gyrus (Brodmann area 22) adjacent to primary auditory cortex in dominant hemisphere.

  • Vascular Supply: Inferior Division (M2 segment) of Middle Cerebral Artery (MCA).

  • Clinical Presentation (Wernicke's Receptive Aphasia):

    • Fluent, volumetric speech lacking meaningful semantic content ("word salad", paraphasias, neologisms; e.g., "The clock is reading my blue pencil because the class was very running today.").

    • Markedly impaired auditory comprehension and reading.

    • Impaired repetition.

    • Anosognosia: Patient completely lacks insight into their language deficit.

  • Associated Deficit: Motor weakness is typically absent.

• Emergency Ischemic Stroke Management Guidelines:

  1. Intravenous (IV) Thrombolysis:

  • Agents: Alteplase or Tenecteplase.

  • Window: Administered within 4.5 hours of symptom onset for acute ischemic stroke without hemorrhage confirmed on CT.

  • Contraindications: Active bleeding, recent major surgery, severe hypertension.

  1. Endovascular Thrombectomy (EVT):

  • Procedure: Physical clearing of clot using a catheter to restore blood flow.

  • Indication: Large Vessel Occlusion (LVO) in anterior circulation (e.g., proximal MCA).

  • Window: 6 to 24 hours from onset in patients exhibiting penumbral tissue mismatch on perfusion neuroimaging.

  1. Hemodynamic and Support Care:

  • Blood Pressure: Maintain blood pressure below $185/110\,mmHg$ prior to thrombolysis; avoid aggressive BP lowering in acute phase.

  • Hemorrhage Management: Reversal of anticoagulation, blood pressure control, Intracranial Pressure (ICP) management, and neurosurgical decompressive craniectomy if severe.