CNS/PNS

Organization of the CNS and PNS

• CNS includes the brain and spinal cord; PNS includes cranial and spinal nerves and their receptors

• Divisions:

  • Somatic Nervous System: sensory neurons for skin, muscles, joints; sends motor (efferent) impulses to skeletal muscle; somatic sensory nerves carry touch, pressure, temperature, pain

  • Autonomic Nervous System: sympathetic, parasympathetic, and enteric subdivisions; involuntary innervation of various organ systems

Cells of the CNS: Neurons and Neuroglia (Glial Cells)

• CNS is derived from 2 primary cell types: Neurons & Neuroglial (Glial) Cells

Neurons

• Basic functional cell of CNS

• Structure: cell body (perikaryon), dendrites, and a single axon

• Axon emerges from the cell body at the axon hillock; may branch to form collateral nerves distal to the cell body

• Varied size/shape; classified as pseudounipolar (unipolar), bipolar, multipolar

• Pseudounipolar neurons have one cytoplasmic process that exits the cell and divides into 2 branches: one dendrite-like branch and one axon-like branch; present in dorsal root ganglia and cranial ganglia; enables sensory impulses to travel from dendrite directly to axon without passing through the cell body

• Sensory neurons (e.g., dorsal root ganglion nerves) are pseudounipolar

Unipolar, Pseudopolar, Bipolar, Multipolar (structure-based summaries)

• Unipolar: one process from cell body; primary afferents of spinal and some cranial nerves; most common in CNS of invertebrates

• Pseudounipolar: two distinct processes (axon and dendrite) from the cell body; sensory neurons in dorsal root ganglia and retina-like structures

• Bipolar: two distinct processes (one axon, one dendrite) from the cell body; examples: retina, olfactory system

• Multipolar: many dendritic processes, single axon; most common neuron type in brain; motor neurons and interneurons

Neuroglial (Glial) Cells

• Smaller than neurons; outnumber neurons; lack dendrites and axons; do not participate in neuronal signaling directly

• Roles:

  • Maintain proper ionic environment

  • Modulate electrical conduction

  • Control reuptake of neurotransmitters

  • Repair after injury

• Four CNS glial cell types:

  • Astrocytes: most abundant; provide structural support; regulate metabolic/nutritive functions

  • Oligodendrocytes: form myelin sheath in brain and spinal cord; insulation; limited capacity to regenerate after injury

  • Microglia: smallest neural cell; migrate to injury/degeneration sites; phagocytose debris

  • Ependymal cells: line roof of the 3rd and 4th ventricles and central spinal canal; form choroid plexus which secretes CSF

Myelin and Nodes of Ranvier

• Myelin increases impulse conduction velocity and reduces axon size requirements

• Unmyelinated axons conduct at a rate roughly proportional to the square root of the diameter

• In the PNS, myelin is formed by Schwann cells; internodal segments are myelinated; gaps (1 mm apart) are the nodes of Ranvier

• Saltatory conduction: impulses jump from node to node, greatly increasing conduction velocity compared to non-myelinated segments

Blood-Brain Barrier (BBB)

• BBB isolates CNS extracellular compartment from intravascular compartment

• CNS endothelial cells form tight junctions, preventing polar/substrate passage

• BBB can be disrupted by trauma, hemorrhage, ischemia, mass lesions; also by hyperosmolar solutions used to deliver chemotherapy

• Newborns: BBB not fully developed; kernicterus risk with hyperbilirubinemia

• Practical notes: delivery of chemotherapeutics via BBB disruption can be intentional in treatment contexts

CNS Anatomy: Cerebral Structures

• Cerebral hemispheres contain: cerebral cortex, hippocampal formation, amygdala, basal ganglia

• Four major lobes per hemisphere:

  • Frontal: motor control

  • Parietal: pain, touch, limb position

  • Temporal: auditory cortex

  • Occipital: visual

• Cerebral Cortex: outer 3-mm layer; highly convoluted to increase surface area; gyri and sulci; medial longitudinal fissure divides hemispheres

• Lateral fissure (Sylvian fissure) and central sulcus divide into four lobes; central sulcus separates frontal and parietal lobes

• Brodmann’s areas (approx. 50 areas):

  • Areas 1, 2, 3: primary somatosensory area (somatosensory cortex)

  • Areas 5 & 7: somatosensory association area

• Temporal lobe: separated from others by Sylvian fissure; visual cortex located in occipital lobe; calcarine fissure houses primary visual cortex

• Corpus callosum: major commissural fiber bundle linking left and right hemispheres

• Basal ganglia: movement regulation; amygdala: emotional behavior and stress responses; hippocampal formation: memory and learning

• Diencephalon: thalamus (sensory integration to cortex) and hypothalamus (master neurohumoral organ)

Subcortical Structures and Limbic System

• Basal ganglia: movement regulation

• Amygdala: emotions, pain response, appetite, stress responses (stress eating)

• Hippocampal formation: memory formation and learning

• Diencephalon: thalamus and hypothalamus emphasized above

• Limbic connections influence behavior, emotion, and autonomic responses

Brainstem and Reticular Activating System (RAS)

• Brainstem components: midbrain, pons, medulla

• Reticular Activating System (RAS): maintains consciousness, arousal, and alertness

• Pons: anterior to cerebellum; connects medulla and midbrain; contains CN V and CN VII nuclei

• Medulla: contains ascending/descending tracts; respiratory and cardiovascular control centers; CN IX, X, XI, XII nuclei; vomiting, coughing, swallowing centers

Cerebellum and Cerebellar Functions

• Cerebellum: convoluted surface; outer gray matter, inner white matter

• Coordinates voluntary muscle activity; integrates information from CNS and PNS

• Outputs to cerebral cortex and lower motor neurons to maintain muscle tone and balance

Cerebral Physiology: EEG Rhythms and Arousal

• RAS stimulation increases alertness; diffuse stimulation can wake sleep

• EEG wave types and associations:

  • Delta waves: deep sleep or deep anesthesia

  • Theta waves: physiologic sleep, general anesthesia in adults, hyperventilation in awake children

  • Alpha waves: resting wakefulness with eyes closed or during sedation

  • Beta waves: activated CNS during mental concentration or light anesthesia

Meninges and Spinal Spaces

• Meninges: three layers

  • Dura mater: thick; overlies brain structures; innervation by C1-C3 and trigeminal nerve

  • Arachnoid mater: thin, avascular; subdural space is potential space between dura and arachnoid; injections here can cause patchy blocks; hematomas risk if vessels damaged

  • Pia mater: delicate, adherent to brain/spinal cord; subarachnoid space between arachnoid and pia

• Subarachnoid space contains CSF; spinal subarachnoid space extends to around S2-S3

• Epidural space: outside dura but within spinal canal; contains venous plexus and fat; depth to epidural space ~3-8 cm; negative pressure; contains connective tissue and nerve roots; largest gap at L2-L3 (~4-6 mm)

Cerebrospinal Fluid (CSF)

• CSF compartments: ventricles, cisterns, subarachnoid space

• Total adult CSF volume ≈ $150 ext{ mL}$; replaced every 3-4 hours

• Specific gravity ≈ 1.002–1.009; pH ≈ 7.32

• Isotonic with plasma; composition: higher Na+, Cl-, Mg2+; lower K+, Ca2+, HCO3-, glucose

• Produced by choroid plexus of ependymal cells at ~$30 ext{ mL/hour}$; rate ~ 0.5 mL/min

• CSF circulation route: lateral ventricles → foramen of Monro → 3rd ventricle → aqueduct of Sylvius → 4th ventricle; exits via foramina of Magendie and Luschka into subarachnoid space; cisterna magna; absorbed by arachnoid villi into superior sagittal sinus

• Entire CSF volume is replaced ~every 3-4 hours; normal hydrostatic pressure ~$5-15 ext{ mmHg}$

Spinal Cord Anatomy and Physiology

• Spinal cord protected within vertebral column; typically 24 articulating vertebrae with 9 fused in the sacrum/coccyx

• Conus medullaris: tapered end of the spinal cord; in adults ends at about L1; neonates end around L3

• Spinal nerves: 31 pairs (C1–C8, T1–T12, L1–L5, S1–S5, Co1)

• Cauda equina: nerve roots below conus medullaris; travel in vertebral canal before exiting at their respective foramina

• Spinal canal dimensions vary by level; width greatest around L5 (~27 mm) foramen openings; canal widths given for thoracic, cervical, and lumbar regions

• Meningeal coverings of peripheral nerves merge with epineurium as they exit; nerve roots travel in subarachnoid space before exiting

Spinal Cord Internal Organization

• Gray matter in H-shaped region contains ventral (anterior) horns, dorsal (posterior) horns, and lateral horns (intermediolateral columns between T1–L2)

• Rexed laminae (I–X):

  • Laminae I–VI: dorsal horn; sensory input processing; laminae V, VI contain many interneurons

  • Lamina VII–IX: ventral horn; motor neurons and interneurons for motor function

• White matter: organized into dorsal, lateral, and ventral columns; ascending sensory tracts and descending motor tracts

• Interneurons and projection neurons traverse and cross to contralateral sides via various routes; many tracts cross near level or below (e.g., decussation patterns)

• Intermediolateral horns: origin of preganglionic sympathetic neurons (T1–L2)

Dorsal Columns vs Anterolateral System (Pain/Temperature/Touch)

• DCMLS (dorsal column–medial lemniscal system): fast, highly localized touch, vibration, proprioception, two-point discrimination; large, myelinated fibers; spatial orientation preserved

  • Pathway: dorsal root ganglion → dorsal column (fasciculus gracilis medially for lower body; fasciculus cuneatus laterally for upper body) → medulla (nucleus gracilis and nucleus cuneatus) → decussation in medulla (internal arcuate fibers) → medial lemniscus → thalamus (VPL) → somatosensory cortex

• ALS (anterolateral system): slower, pain, temperature, crude touch; smaller myelinated fibers; less precise localization

  • Pathway: nociceptors/thermoreceptors → dorsal root ganglion → dorsal horn (Lissauer’s tract) → second-order neurons cross in ventral commissure → ascend in anterolateral or spinothalamic tracts → thalamus (VPL/VPM) → cortex

• Key contrasts: speed, localization, and fiber size/myelination determine modality and velocity of conduction

Peripheral Nervous System (PNS)

Somatic Nervous System (SoNS)

• Controls voluntary body movements via skeletal muscles; includes sensory neurons for skin, muscles, joints; efferent nerves control skeletal muscles

• Motor fibers arise from ventral horn; exit via ventral roots; join with sensory fibers to form mixed spinal nerves; motor and sensory components separate at their target site

• Includes spinal nerves, cranial nerves, and association nerves

Cranial Nerves (PNS)

• 12 pairs; mix of sensory, motor, and both functions

• CN I (Olfactory) and CN II (Optic) are not true cranial nerves in some classifications

• Six orbital muscles and their innervation:

  • Superior rectus: look up; CN III (oculomotor)

  • Inferior rectus: look down; CN III

  • Medial rectus: look inward; CN III

  • Lateral rectus: look outward; CN VI (abducens)

  • Superior oblique: intorsion/depression; CN IV (trochlear)

  • Inferior oblique: extorsion/elevation; CN III

• Six cranial nerves with predominantly sensory functions: CN V (trigeminal), CN VII (facial), CN VIII (vestibulocochlear)

• CN V branches: ophthalmic (sensory), maxillary (sensory), mandibular (sensory + motor for mastication)

• CN VII: facial expression, taste anterior tongue; lacrimal/salivary glands

• CN VIII: hearing and balance

• CN IX: taste posterior tongue; carotid body/sinus afferents

• CN X: autonomic control of gut, heart, larynx/pharynx; swallowing

• CN XI: spinal accessory; neck/shoulder movement

• CN XII: hypoglossal; tongue movement

Special Cranial Nerves and Head Innervation

• CN I and CN II are not always considered true cranial nerves in some texts

• Six orbital muscles and their innervation listed above

• Trigeminal nerve (CN V) sensory to face; motor to muscles of mastication

• Facial nerve (CN VII) motor to facial muscles; taste anterior tongue; lacrimal/salivary glands

• Vestibulocochlear (CN VIII): hearing and balance

• Glossopharyngeal (CN IX) and Vagus (CN X): pharyngeal/laryngeal control; autonomic functions

• Accessory (CN XI): shoulder/neck movements; hypoglossal (CN XII): tongue movements

Autonomic Nervous System (ANS)

• Controls involuntary visceral functions

• Subdivisions: Sympathetic (SNS), Parasympathetic (PNS), Enteric (ENS)

• SNS and PNS are functionally antagonistic

• Two-neuron chain: preganglionic (originates in CNS) and postganglionic (targets organ)

• Brainstem-origin autonomic fibers arise from brainstem nuclei; sacral roots contribute to lower GI and GU innervation

Vasculature of the CNS

• The brain receives ~% of CO: about 15% or ~50 mL per 100 g per minute

• Two arterial circulations: Carotid arteries (anterior circulation) and Vertebral arteries (posterior circulation)

• Circle of Willis provides collateral connections;, but limited mixing under normal conditions

• Major feeders: internal carotid arteries (anterior circulation) and vertebrobasilar system (posterior circulation)

• After entering skull, carotids bifurcate into anterior and middle cerebral arteries; communicants provide connections via anterior communicating artery and posterior communicating arteries

• Vertebral arteries join to form basilar artery near the pons; supply brainstem, cerebellum, occipital and temporal lobes, spinal cord cervical region, inner ear

• Venous drainage via internal jugular veins

• Circle of Willis enables collateral flow during occlusion of major vessels; stump pressure can guide carotid endarterectomy decisions

• Normal stump pressure > $60 ext{ mmHg}$ is generally acceptable; readers should note variability

Spinal Cord Blood Supply

• Two arterial sources: anterior spinal arteries (75%) and posterior spinal arteries (25%), branches of vertebral arteries

• Radicular arteries (segmental arteries) enter via intervertebral foramina; give rise to anterior and posterior radicular arteries along nerve roots

• Blood supply is segmental; interruptions at a given level may cause ischemia if a single source dominates that segment

• Artery of Adamkiewicz (great radicular artery): usually enters from left side at around T7; supplies the lower thoracic and lumbosacral cord

• Ischemia to spinal cord segments poorly supplied by alternate sources can cause paraplegia

Physiology: Resting Membrane Potential and Action Potentials

• Resting membrane potential (RMP) arises from ionic gradients and selective permeability

• Ionic distribution: $[K^+]{in} ext{ higher}$, $[Na^+]{out} ext{ higher}$; ~10x more Na+ outside, ~10x more K+ inside

• Key drivers:

  • K+ leak channels establish a resting deficit of positive ions inside the cell

  • Na+/K+-ATPase maintains ionic gradients

• RMP range: $-60 ext{ to } -90 ext{ mV}$

• Action potentials initiated when a threshold stimulus increases Na+ permeability, leading to rapid Na+ influx and depolarization

• Threshold potential affected by pH, PO2, PCO2; alkalosis increases excitability; hypoxemia/acidosis depress excitability

• Repolarization driven by opening of K+ channels and closing of Na+ channels; return to RMP; absolute refractory period with Na+ channels closed; relative refractory period later

• Na+-K+-ATPase pump helps reestablish ionic gradients after action potential

Synaptic Transmission and Neurotransmitters

Synaptic Transmission Basics

• Neuron-to-neuron communication occurs at synapses (pre- and postsynaptic neurons)

• Synaptic cleft separates neurons

• Can be electrical or chemical; majority are chemical with neurotransmitter release

• Mechanism: depolarization triggers Ca++ influx at presynaptic terminal; vesicles fuse and release neurotransmitter into synaptic cleft; transmitter binds postsynaptic receptors

• Neurotransmitter effects: excitatory if they increase Na+ permeability or depolarize; inhibitory if they increase Cl- permeability or hyperpolarize

• Some transmitter effects are immediate; others involve second messengers (cAMP, GMP)

Neurotransmitters: Categories

• Acetylcholine (ACh): excitatory; widespread; CNS, NMJ, all autonomic preganglionic fibers, postganglionic parasympathetic fibers; choline acetyltransferase (CAT) synthesizes ACh; degraded by acetylcholinesterase

  • Receptors: nicotinic (autonomic ganglia, NMJ) and muscarinic (smooth/cardiac muscle, glands)

• Biogenic amines: Epinephrine, Norepinephrine, Dopamine, Serotonin, Histamine

  • Synthesis from phenylalanine/tyrosine; adrenal medulla secretes Epi (75%) and Norepi (25%)

  • Reuptake terminates effects; MAO and COMT metabolize

  • Dopamine: inhibitory in CNS, especially basal ganglia; regulates mood and reward pathways; acts via adenylate cyclase

  • Norepinephrine: high in RAS and hypothalamus; inhibitory to cortex; arousal modulation

  • Serotonin: mood and behavior; histamine: hypothalamus/RAS regulator; both involve second messengers (cAMP)

• Amino acids: Glutamate (excitatory; NMDA, AMPA, kainate receptors), GABA (inhibitory; GABA-A and GABA-B), Glycine (inhibitory; spinal cord)

• Neuropeptides: Substance P, opioids (endorphins, enkephalins, dynorphins, endomorphins); complex modulation of pain; opioid receptors mu, kappa, delta

• Nitric oxide: gaseous neuromodulator/second messenger

• General notes:

  • Release is Ca++-dependent; vesicle fusion and transmitter release require Ca++ influx

  • Receptors mediate immediate or delayed effects via second messengers

Acetylcholine (ACh) in detail

• Synthesis: from acetyl-CoA and choline; stored in vesicles; release enhanced by Ca++ influx

• Breakdown: acetylcholinesterase converts ACh to acetate and choline (reuptake of choline)

• Receptors:

  • Nicotinic: ionotropic; in autonomic ganglia, NMJ, adrenal medulla

  • Muscarinic: metabotropic; smooth/cardiac muscle and glands

• ACh pathways: important in CNS nuclei and ventral horn motor neurons; collateral connections to Renshaw cells

Catecholamines and Serotonin

• Dopamine: predominant in basal ganglia; inhibitory via adenylate cyclase

• Norepinephrine: high in RAS; inhibitory to some cortical circuits

• Epinephrine: primarily peripheral; CNS roles

• Serotonin: mood/behavior modulation; multiple receptor subtypes

• Histamine: hypothalamic/RAS regulation

Glutamate and GABA/Glycine

• Glutamate: primary excitatory transmitter in CNS; NMDA/AMPA/kainate receptors allow Na+ and Ca++ influx; critical for learning/memory and pain processing

• GABA: major inhibitory transmitter; GABA-A receptor opens Cl- channels → hyperpolarization

• Glycine: primary inhibitory transmitter in spinal cord; also used clinically in TURP irrigation considerations

Neuropeptides and Substance P

• Substance P: excitatory in pain pathways; NK-1 receptor activation contributes to nociception

• Opioids: μ, κ, δ receptor subtypes elicit spinal and supraspinal analgesia; effects on mood, respiration, miosis, euphoria/dysphoria, dependence

Pain Pathways and Opioids

• Dual pain pathways: fast (Aδ) and slow (C fibers)

• Aδ fibers: first pain; sharp, well-localized

• C fibers: second pain; dull, diffuse, long-lasting

• Primary afferents reside in dorsal root ganglia; synapse in dorsal horn

• Major neurotransmitters in pain pathways:

  • Aδ: glutamate (acts on AMPA/NMDA receptors)

  • C fibers: substance P (acts on NK-1 receptors)

• Gate control theory: interneurons in substantia gelatinosa (Lamina II of dorsal horn) modulate pain transmission; enkephalinergic interneurons inhibit substance P release

• Opioid receptors: mu, kappa, delta; various sites and effects on analgesia, respiration, mood, and dependence

Sensory Pathways

General Principles

• Afferent (sensory) pathways carry pain, temperature, pressure, touch, vibration, proprioception, and special senses

• Receptors types:

  • Exteroceptors: near skin/oral mucosa; proprioceptors in deeper tissues

• First-order neurons synapse in dorsal root ganglia; second-order neurons cross and ascend to thalamus; third-order neurons project to somatosensory cortex

Pain and Temperature Pathways (ALS vs DCMLS as contrasts)

• Head pain/temperature pathways synapse in trigeminal ganglion; ascend via CN V pathways to thalamus and cortex

• Pain and temperature from trunk/extremities travel via dorsal roots to dorsal horn; cross via ventral commissure; ascend via lateral spinothalamic tract

• Crude touch/pressure from extremities travel via ventral spinothalamic tract and dorsal columns for more precise modalities

• Dermatome organization: key landmarks (e.g., nipple T4, umbilicus T10, clavicle C4, etc.)

Proprioception, Vibratory Sense, and Discriminative Touch

• Proprioceptive fibers of face synapse in mesencephalic nucleus; trunk/limbs ascend via dorsal columns (fasciculus gracilis and fasciculus cuneatus)

• First-order neurons rise in DRG; medullary nuclei for dorsal columns; second-order neurons decussate to form medial lemniscus; thalamus (VPL) and then postcentral gyrus

• Lateral vs medial tracks: dorsal column (DCMLS) carries fast, well-localized touch; ALS carries slower pain/temperature/crude touch

Motor Pathways

Corticospinal Tract (Pyramidal Tract)

• Originates from upper motor neurons in the precentral gyrus (frontal lobe)

• Travels through internal capsule; decussates in the medullary pyramids (~90% cross) to form the lateral corticospinal tract; continues to SC and synapses with lower motor neurons in ventral horn

• A minority (~10%) continues as ventral corticospinal tract; fibers cross later at the level of the synapse

• Function: voluntary motor control of trunk and limbs; lower motor neurons innervate skeletal muscles

Corticobulbar Tracts (Cranial Nerve Motor Control)

• Originate from UMNs in cortex; synapse with brainstem nuclei to supply cranial nerves

• Include pathways to CN III, IV, VI, VII, IX–XII; control muscles of head and neck

Subcortical Motor Areas

• Basal ganglia, red nucleus, substantia nigra, reticular formation, Luys’ nucleus, etc.

• Lesions produce movement disorders (Parkinson disease, Huntington chorea) due to disruption of modulating motor tone

SSEP (Somatosensory Evoked Potentials) and Anesthesia Considerations

• SSEP: evoked potentials elicited by repetitive stimulation; used to monitor integrity of specific neural pathways and cerebral oxygenation

• EEG vs SSEP: EEG is a spontaneous signal; SSEP is a stimulus-evoked response (amplitude in microvolts, 10–200 μV range typical vs EEG in mV range)

• Anesthetic considerations:

  • Neuromuscular blocking agents (NMB) dampen waveform

  • Etomidate and ketamine can increase amplitude

  • Volatile anesthetics and N2O depress waveform

  • Hypothermia increases latency of responses

Quick Reference: Key Numerical and Conceptual Points

• Resting membrane potential: $V_{rest} \,\approx\,-60 \,\text{to}\,-90\, \text{mV}$

• CSF total volume: $ext{CSF} \approx 150\ \text{mL}$; turnover every 3–4 hours

• BBB normal stump pressure for carotid procedures: > $60\ \text{mmHg}$ (approximate value; variability exists)

• CSF production rate: $\approx 30\ \text{mL/hour}$

• Spinal canal dimensions vary by level; width ~17–27 mm depending on region

• Conus medullaris ends around: adults $\approx L1$; neonates $\approx L3$

• Myelination and conduction velocities: Aα fibers (fastest, $60–120\ \text{m/s}$); Aβ similar; Aδ (5–25 m/s); C fibers slow (0.7–2.0 m/s) depending on fiber type

• Major cranial nerves with mixed functions: CN V, CN VII, CN IX–X, CN XI, CN XII (see detailed function lists above)

• Dermatome landmarks: Clavicle C4; Umbilicus T10; Nipples T4; Xiphoid T6; Perineum S2–S5

• DCMLS vs ALS: DCMLS transmits fast, highly localized touch/vibration/proprioception; ALS transmits pain/temperature/crude touch with less precision

Connections to Practice and Real-World Relevance

• BBB integrity is critical in neurosurgery and anesthesiology for safe drug delivery and pressure management

• Understanding spinal tracts helps localize lesions and interpret intraoperative neurophysiological monitoring (SSEP)

• Knowledge of cranial nerves and autonomic pathways informs airway management, anesthesia depth, and risk for respiratory compromise

• Neurotransmitter systems underpin pharmacologic strategies (e.g., analgesia, anesthesia agents, antiemetics, and mood regulation)

• Pain pathway modulation (gate control) illustrates why certain nonpharmacologic therapies (e.g., distraction, acupuncture) can alter pain perception

References to Foundational Principles and Ethical/Practical Implications

• Structure-function relationships: neuron morphology and glial support directly influence signaling, repair, and disease outcomes

• Blood supply, BBB, and CSF dynamics underlie safety considerations in neurosurgery and anesthesia (drugs crossing BBB, intracranial pressure management)

• Pain pathways and opioid pharmacology require careful balancing of analgesia with respiratory and CNS depressant risks

• Ethical implications include ensuring patient safety when manipulating cerebral physiology (e.g., deliberate BBB disruption for chemotherapy) and respecting neurocognitive outcomes in anesthesia planning