The Nervous System

Ischemic Stroke — Subtypes & Workup

• Thrombotic — clot forms locally, usually over a ruptured atherosclerotic plaque, commonly in the MCA
• Embolic — a clot travels from elsewhere (atrial fibrillation, carotid stenosis, endocarditis, or a DVT crossing a patent foramen ovale) and can affect multiple vascular territories at once
• Hypoxic/hypoperfusion — global reduction in blood flow or oxygenation (e.g., cardiac arrest, intraoperative hypotension); preferentially injures watershed zones
• Irreversible neuronal injury begins after roughly 5 minutes of ischemia; the hippocampus, neocortex, cerebellar Purkinje cells, and watershed zones are the most vulnerable regions
• Workup — noncontrast CT first, to exclude hemorrhage before giving tPA (ischemic changes may not show on CT for 6–24 hours); diffusion-weighted MRI can detect ischemia within minutes
• Treatment — IV tPA within 3–4.5 hours of clear symptom onset (if no hemorrhage/bleeding risk) and/or mechanical thrombectomy for large-vessel occlusion; secondary prevention with antiplatelets and risk-factor control
• Transient ischemic attack (TIA) — a brief, fully reversible deficit with a negative MRI, most resolving within 15 minutes; amaurosis fugax (transient monocular vision loss) is a classic presentation from retinal artery emboli

Stroke Syndromes by Vessel

Common Brain Lesion Localization

Aphasia Subtypes

Decorticate vs. Decerebrate Posturing

Intracranial Aneurysms

• Saccular (berry) aneurysm — occurs at Circle of Willis bifurcations, most commonly the ACom–ACA junction; risk factors include hypertension, smoking, ADPKD, and Ehlers–Danlos syndrome; usually silent until rupture causes subarachnoid hemorrhage, but can also cause symptoms by direct compression — an ACom aneurysm can compress the optic chiasm (bitemporal hemianopia), and a posterior communicating artery aneurysm classically compresses CN III (ipsilateral blown pupil, ptosis, "down and out" eye)
• Charcot–Bouchard microaneurysm — small-vessel aneurysm associated with chronic hypertension, the source of most hypertensive intraparenchymal hemorrhages; too small to be seen on angiography

Intracranial Hemorrhage — Beyond Epidural/Subdural

• Subarachnoid hemorrhage — usually from trauma or a ruptured aneurysm/AVM; presents as the "worst headache of my life," with bloody or xanthochromic (yellow) CSF on lumbar puncture; vasospasm 3–10 days later can cause delayed ischemic infarction, for which nimodipine may improve outcomes; raises the risk of subsequent hydrocephalus
• Intraparenchymal hemorrhage — most often from chronic hypertension causing rupture of Charcot–Bouchard microaneurysms, classically in the putamen/basal ganglia, followed by the internal capsule, thalamus, pons, and cerebellum; also caused by amyloid angiopathy (recurrent lobar hemorrhage in older adults), AVMs, or vasculitis

Other Localized Pain & Trauma Syndromes

• Thalamic pain syndrome — neuropathic pain (burning, allodynia, hyperalgesia) that develops days to years after a thalamic (often lacunar or PCA-territory) stroke
• Phantom limb pain — burning/electric pain referred to an amputated limb, thought to reflect cortical reorganization of the primary somatosensory map
• Diffuse axonal injury — shearing of white matter tracts from rapid acceleration-deceleration (e.g., motor vehicle collision); often causes coma or a persistent vegetative state, with scattered punctate hemorrhages on MRI

Fever vs. Heat Stroke

Watershed Zones

• Border regions between the territories of two major arteries (classically ACA–MCA and MCA–PCA) that receive the least redundant blood supply
• Vulnerable to hypoperfusion injury (systemic hypotension, cardiac arrest, severe blood loss) rather than to focal vessel occlusion
• ACA–MCA watershed infarct — proximal upper and lower limb weakness with sparing of the face/hands, classically described as a "man-in-a-barrel" presentation

Blood Supply to the Brain

Venous Drainage

• Superficial cerebral (bridging) veins drain into the superior sagittal sinus
• Superior sagittal sinus and inferior sagittal sinus converge with the great cerebral vein into the straight sinus
• Straight and sagittal sinuses drain into the transverse sinus → sigmoid sinus → internal jugular vein
• The cavernous sinus receives the superior ophthalmic vein and communicates with the venous system near the pituitary
• Venous (dural) sinus thrombosis presents with signs of raised ICP — headache, seizures, papilledema, and focal deficits — and is associated with hypercoagulable states (pregnancy, oral contraceptive use, factor V Leiden)

Cerebral Perfusion & Intracranial Pressure

• Cerebral perfusion pressure (CPP) = mean arterial pressure (MAP) − intracranial pressure (ICP); a CPP of zero means no cerebral perfusion → coma or brain death
• Cerebral blood flow is tightly autoregulated and driven primarily by PCO2 — hyperventilation lowers PCO2, causing vasoconstriction that reduces cerebral blood flow and ICP (a maneuver sometimes used for acute cerebral edema)
• Severe hypoxia (e.g., high altitude) triggers cerebral vasodilation and can itself raise cerebral blood flow enough to cause edema
• Cushing reflex — the triad of hypertension, bradycardia, and respiratory depression that occurs as a physiologic response to rising ICP

Contents of the Cavernous Sinus

• Located lateral to the pituitary fossa/sphenoid sinus, on either side of the sella turcica
• Structure running centrally through the sinus, surrounded by sympathetic fibers
  • Internal carotid artery
• Structures embedded in the lateral dural wall
  • Oculomotor nerve (CN III)
  • Trochlear nerve (CN IV)
  • Ophthalmic and maxillary divisions of the trigeminal nerve (V1, V2)
• Abducens nerve (CN VI) runs freely within the sinus lumen alongside the carotid artery — this positioning makes CN VI especially vulnerable to compressive or thrombotic cavernous sinus lesions
• Clinical relevance — cavernous sinus thrombosis or a mass in this region can produce a combination of ophthalmoplegia (III, IV, VI), facial sensory loss (V1/V2), and proptosis

Classic Spinal Cord Lesion Patterns

Conus Medullaris vs. Cauda Equina Syndrome

• Both are surgical emergencies from compression (disc herniation, tumor, trauma) near the end of the spinal cord, presenting with radicular low back pain, saddle/perianal numbness, and bladder/bowel dysfunction
• Conus medullaris syndrome — compression of the terminal spinal cord itself → typically symmetric weakness with upper motor neuron (spastic) features
• Cauda equina syndrome — compression of the lumbosacral nerve roots below the cord → typically asymmetric weakness with lower motor neuron (flaccid) features

Cortical Lesion Correlates

Sensory Receptor Types

Ascending Sensory Pathways

Trigeminothalamic Pathway

• Carries pain and temperature sensation from the face — the facial counterpart of the spinothalamic tract
• Receives input from fast (A-delta) and slow (C) pain fibers via free nerve endings

Dermatome Landmarks

• C2 — posterior scalp ("cervical cap")
• C4 — top of the shoulders (a useful marker for the level of a high spinal cord injury affecting respiration)
• T4 — nipple line
• T7 — xiphoid process
• T10 — umbilicus
• L1 — inguinal ligament ("L-one, inguinal")
• L4 — kneecaps
• S2, S3, S4 — genital/perianal region — "S2, 3, 4 keeps the penis off the floor" (erection and continence)

Corticospinal Tract (Descending Motor)

• Mediates voluntary movement of striated (skeletal) muscle
• Lesion above pyramidal decussation (UMN) → contralateral spastic paresis, positive Babinski
• Lesion below decussation (UMN, in cord) → ipsilateral spastic paresis, positive Babinski
• Lesion of the LMN itself → flaccid paralysis with fasciculations

Corticobulbar Tract & Facial Innervation

• Descends from motor cortex to synapse on the facial motor nucleus (CN VII)
• Upper face muscles (frontalis, orbicularis oculi) receive bilateral cortical input → spared in unilateral (UMN) cortical lesions
• Lower face muscles receive only contralateral input → affected in unilateral cortical lesions
• A complete LMN facial lesion (Bell palsy) affects both upper and lower face on the ipsilateral side, unlike a cortical (UMN) lesion

Cerebellar Pathway

• Controls posture, balance, muscle tone, and coordination
• Dominant tract: dentatothalamic, originating in the dentate nucleus, relayed through the ventrolateral thalamic nucleus to motor cortex
• Deep cerebellar nuclei, lateral to medial — dentate, emboliform, globose, fastigial
• Medial structures (vermis, fastigial/globose/emboliform nuclei) control axial and proximal limb muscles bilaterally; lateral structures (hemispheres, dentate nucleus) control distal limb movement and motor planning ipsilaterally
• Unilateral cerebellar (vestibulocerebellar) lesions cause ipsilateral deficits — patient falls toward the lesion side (positive Romberg-type finding)
• Bedside tests — rapid alternating movements (dysdiadochokinesia), finger-to-nose and heel-to-shin (dysmetria/intention tremor), and gait assessment

Muscle Spindles vs. Golgi Tendon Organs

• Muscle spindles — sense muscle length; arranged in parallel with extrafusal fibers; serve as the afferent limb of the myotactic (deep tendon/stretch) reflex
• Golgi tendon organs — sense muscle tension; arranged in series with extrafusal fibers

Deep Tendon, Superficial & Primitive Reflexes

Glial Cells & the Blood–Brain Barrier

• The blood–brain barrier restricts free diffusion of most water-soluble and large molecules into brain tissue, formed by three cooperating structures
  • Tight junctions between capillary endothelial cells
  • A surrounding basement membrane
  • Pericytes
  • Astrocyte foot processes ("end-feet") that envelop the capillary
• Only small, lipophilic, or actively transported molecules cross readily — this is why drugs like levodopa (transported) work centrally while carbidopa (not transported) stays peripheral
• The barrier is incomplete at a few "circumventricular organ" sites that must sense or secrete into the blood directly, e.g., the area postrema (vomiting center, senses circulating toxins), the posterior pituitary (hormone release into blood), and the OVLT (senses plasma osmolarity) — these regions are also where CNS infections/tumors can more easily seed

Myelination

• CNS myelination performed by oligodendrocytes
  • One oligodendrocyte extends processes to myelinate multiple axons simultaneously
• PNS myelination performed by Schwann cells
  • Each Schwann cell myelinates only a single axon segment
• Timeline: myelination starts around month 4 of gestation and continues until roughly age 2

Neuron Basics: Action Potentials & Nerve Injury

• Resting membrane potential is maintained because the neuronal membrane is far more permeable to K⁺ than Na⁺ at rest
• Depolarization — voltage-gated Na⁺ channels open once threshold is reached, and Na⁺ rushes in
• Repolarization — Na⁺ channels inactivate, voltage-gated K⁺ channels open, and K⁺ flows out
• Hyperpolarization — K⁺ channels close slowly, producing a brief dip below resting potential before the Na⁺/K⁺ pump restores baseline
• Myelin dramatically speeds conduction by enabling saltatory conduction — the action potential "jumps" between the high-Na⁺-channel-density nodes of Ranvier instead of propagating continuously

Vomiting Center & Chemoreceptor Trigger Zone

• The nucleus tractus solitarius (medulla) coordinates the vomiting reflex, integrating input from the chemoreceptor trigger zone (CTZ), the GI tract (via vagal afferents), the vestibular system, and higher cortical centers
• The CTZ sits in the area postrema, outside the blood–brain barrier, so it can directly sample circulating drugs/toxins — this is why chemotherapy and other bloodborne emetogens trigger vomiting through it
• Five receptor types converge on the CTZ/vomiting center: dopamine (D2), serotonin (5-HT3), neurokinin (NK1), histamine (H1), and muscarinic (M1)
• Pharmacologic correlate — D2/5-HT3/NK1 antagonists (e.g., ondansetron) treat chemotherapy-induced vomiting; H1/M1 antagonists treat motion sickness, and H1 antagonists are also used for hyperemesis gravidarum

Peripheral Nervous System Origin

• PNS components (peripheral nerves, autonomic ganglia, sensory ganglia) arise from neural crest cells
• Neural crest derivatives relevant to the PNS
  • Schwann cells
  • Pseudounipolar sensory neurons of dorsal root and cranial nerve ganglia
  • Multipolar neurons of autonomic ganglia
• Neural crest also produces structures classically excluded from the PNS proper
  • Pia mater and arachnoid mater (leptomeninges)
  • Melanocytes
  • Chromaffin cells of the adrenal medulla (epinephrine-secreting)

Spinal Cord Positional Change

• At birth the conus medullaris (caudal tip of cord) sits at vertebral level L3
• Differential growth of the vertebral column relative to the cord causes an apparent "ascent"
• Adult resting level of the conus medullaris is L1
• Clinical relevance: this is why lumbar puncture is performed below L2 to avoid cord injury

Cranial Nerve Overview

Cranial Nerve Nuclei & Brainstem Organization

• CN nuclei sit in the brainstem tegmentum, organized by level — midbrain (III, IV), pons (V, VI, VII, VIII), medulla (IX, X, XI, XII), with the spinal portion of XI arising from the upper cervical cord
• Within the brainstem, sensory (alar-plate-derived) nuclei lie lateral and motor (basal-plate-derived) nuclei lie medial — the same dorsal/ventral logic as the spinal cord
• Exit pattern rule of thumb: 4 nerves exit above the pons (I, II, III, IV), 4 exit from the pons (V, VI, VII, VIII), and 4 exit from the medulla (IX, X, XI, XII); the purely medial (motor) nuclei are III, IV, VI, and XII

Extraocular Muscles

Pupillary Light Reflex Pathway

• Bilateral projection from the pretectal nucleus to both Edinger–Westphal nuclei is what produces the consensual light reflex — light in one eye constricts both pupils

Pupil & Gaze Syndromes

Visual Field Defects by Lesion Site

• Optic nerve transection — complete monocular blindness
• Optic chiasm (e.g., pituitary tumor) — bitemporal hemianopia
• Optic tract — contralateral homonymous hemianopia
• Temporal (Meyer) loop lesion — contralateral upper quadrantanopia ("pie in the sky")
• Parietal radiation lesion — contralateral lower quadrantanopia
• Occipital cortex (with macular sparing) — contralateral homonymous hemianopia, macula spared due to dual blood supply

Lens Disorders & Refractive Errors

Retinal Disorders

Papilledema, Leukocoria & Uveitis

• Papilledema — bilateral optic disc swelling with blurred margins from raised ICP; results from impaired axoplasmic flow along the optic nerve
• Leukocoria — loss/whitening of the red reflex in a child; always warrants urgent workup for retinoblastoma or congenital cataract
• Uveitis — inflammation of the uveal tract (anterior = iritis, posterior = choroiditis/retinitis); may show hypopyon (pus layering in the anterior chamber); associated with sarcoidosis, Behçet syndrome, juvenile idiopathic arthritis, and HLA-B27–associated disease

Eyelid & Conjunctival Disorders

Glaucoma Pharmacotherapy

Nystagmus Direction Patterns

Taste, Vestibular, and Auditory Pathways

• Taste — anterior 2/3 tongue via CN VII (chorda tympani), posterior 1/3 via CN IX, epiglottic region via CN X → solitary nucleus → VPM thalamus → parietal cortex
• Vestibular hair cells — semicircular canals sense angular acceleration; utricle and saccule sense linear acceleration
• Vestibular signals reach the vestibular nuclei of the low pons, which then project to
  • The spinal cord — postural reflexes
  • The cerebellum — coordination and balance
  • The thalamus — conscious spatial orientation
  • CN III, IV, and VI via the medial longitudinal fasciculus (MLF) — this is the circuit that generates nystagmus
• Auditory pathway is bilaterally represented beyond the cochlear nuclei, so a one-sided central lesion typically does not cause hearing loss — only a cochlear nerve lesion causes ipsilateral deafness
• Cochlear tonotopic organization
  • Base of the cochlea (nearest the oval window) — sensitive to high-frequency sounds
  • Apex of the cochlea (near the helicotrema) — sensitive to low-frequency sounds, owing to progressive thickening of the basilar membrane

See: Cortical Localization & Long Tracts → Muscle Spindles vs. Golgi Tendon Organs

Ear Anatomy & Sound Transduction

• Outer ear collects and channels sound waves to the tympanic membrane; the middle ear's ossicular chain conducts and mechanically amplifies that vibration
• The middle ear connects to the nasopharynx via the eustachian tube, which equalizes pressure across the tympanic membrane — dysfunction here underlies most middle-ear disease
• Inner ear cochlea is fluid-filled and tonotopically organized: high frequencies are detected near the base (stiff, narrow membrane), low frequencies near the apex (wide, flexible membrane, close to the helicotrema)

Outer & Middle Ear Infections

Hearing Loss — Causes & Bedside Testing

Vertigo — Peripheral vs. Central

• Benign paroxysmal positional vertigo (BPPV) — displaced otoconia (canalith debris) in a semicircular canal; brief (<1 minute) episodes triggered by head position change; diagnosed with the Dix–Hallpike maneuver, treated with canalith repositioning (Epley maneuver)
• Ménière disease — endolymphatic hydrops (excess inner-ear fluid) producing the classic triad of episodic vertigo, sensorineural hearing loss, and tinnitus
• Vestibular neuritis — presumed postviral inflammation of the vestibular nerve; sudden, sustained vertigo without hearing loss

Meningeal Layers (outside → in)

• Dura mater — tough outer connective tissue layer; epidural bleeds classically involve the middle meningeal artery after temporal bone fracture
• Arachnoid mater — thin, avascular layer; bridging veins cross the subdural space and are vulnerable to shear injury
• Pia mater — thin, highly vascular layer adherent to brain/cord surface
• Subarachnoid space contains CSF and terminates around vertebral level S2
• Lumbar puncture is performed within the subarachnoid space, typically L3–L4 or L4–L5

Epidural vs. Subdural Hematoma

Ventricular System & CSF Circulation

• CSF is produced by the choroid plexus, found in all four ventricles, at a fairly constant rate regardless of intracranial pressure
• The cerebral aqueduct (of Sylvius) is the narrowest point in the pathway and the most common site of congenital obstructive hydrocephalus
• Final reabsorption into venous blood occurs at the arachnoid granulations, which project into the superior sagittal sinus

Hydrocephalus Classification

• Communicating (non-obstructive) — CSF flows freely but reabsorption at arachnoid granulations is impaired
• Non-communicating (obstructive) — physical blockage along the ventricular system, e.g., at the foramen of Monro, cerebral aqueduct, fourth ventricle outlets, or foramen magnum

Cerebrovascular Disease

Seizure Classification

• Every seizure passes through up to three phases — an aura (early warning, e.g., an odd smell/taste), the ictal period (first symptom to end of seizure activity), and a postictal period of gradual recovery

• Focal seizures most commonly originate in the medial temporal lobe; a focal seizure can also spread and become a generalized tonic–clonic seizure ("secondary generalization")
• Status epilepticus — continuous (≥5 min) or repeated seizures without return to baseline consciousness between them; a medical emergency treated with IV benzodiazepine
• Common causes of new-onset seizures shift with age — children/young adults: genetic, developmental, infectious (including febrile), or traumatic causes; adults 18–65: trauma, infection, tumor, stroke, or metabolic derangement; adults over 65: stroke and neurodegenerative disease rise to the top of the list

Antiepileptic Mechanisms & Toxicity

Basal Ganglia Circuitry

• Direct pathway (net effect: facilitates movement) — cortex excites the striatum (glutamate) → striatum inhibits the internal globus pallidus (GPi) via GABA → less GPi inhibition of the thalamus → thalamus is disinhibited → increased cortical activation and movement
• Indirect pathway (net effect: suppresses movement) — cortex excites the striatum → striatum inhibits the external globus pallidus (GPe) → GPe normally inhibits the subthalamic nucleus (STN), so less GPe activity disinhibits the STN → STN excites the GPi → more GPi inhibition of the thalamus → reduced movement
• Dopamine from the substantia nigra pars compacta (nigrostriatal pathway) binds striatal D1 receptors to stimulate the direct pathway and D2 receptors to inhibit the indirect pathway — the net effect of dopamine is to promote movement
• Clinical correlate — Parkinson disease (dopamine loss) shifts the balance toward the indirect pathway → bradykinesia/rigidity; Huntington disease (early loss of indirect-pathway striatal neurons) shifts the balance toward the direct pathway → chorea (excess movement)

Degenerative Diseases

Antiparkinsonian Pharmacology

• Levodopa — dopamine precursor that crosses the blood-brain barrier; causes on-off fluctuations with chronic use
• Carbidopa — peripheral DOPA decarboxylase inhibitor, reduces systemic conversion, does not cross the BBB itself
• Selegiline/rasagiline — selective MAO-B inhibitors
• Bromocriptine, pramipexole, ropinirole — dopamine receptor agonists
• Benztropine — antimuscarinic, helps tremor/rigidity but not bradykinesia
• Amantadine — increases dopamine release and blocks reuptake; mainly used to reduce levodopa-induced dyskinesia; toxicity includes peripheral edema and livedo reticularis
• Entacapone/tolcapone — COMT inhibitors that block peripheral (and, for tolcapone, central) breakdown of levodopa, extending its effect

Alzheimer, ALS & Huntington Drug Therapy

Demyelinating Diseases

Diseases Causing Dementia

Meningitis by Age Group

CSF Profile by Etiology

• Organisms with a thick capsule visible on India ink prep suggest Cryptococcus neoformans — think HIV-associated immunocompromise
• Adults with cell-mediated immune deficiency are at increased risk for Listeria meningitis
• Predisposing factors for pneumococcal meningitis: sinusitis/otitis, sickle cell disease, alcoholism, meningeal trauma, and terminal complement (C5–C8) deficiency

CNS Tumors in Adults

CNS Tumors in Children

Synaptic Physiology

Autonomic Receptor Effects

GABA-A Receptor Pharmacology

• GABA synthesized from glutamate by glutamate decarboxylase (requires pyridoxal phosphate, vitamin B6)
• GABA-A is a ligand-gated chloride channel — opening hyperpolarizes the neuron
• Benzodiazepines increase the frequency of channel opening
• Barbiturates increase the duration of channel opening — this is why barbiturate overdose is more dangerous (greater maximal chloride flux)

Neurotoxin Mechanisms

Dopaminergic Pathways

Neurotransmitter Changes with Disease

Local Anesthetics

• Two structural classes — esters (benzocaine, chloroprocaine, cocaine, tetracaine) and amides (bupivacaine, lidocaine, mepivacaine, prilocaine, ropivacaine)
• Mechanism — block voltage-gated Na⁺ channels from the inner (cytoplasmic) side of the axonal membrane; most effective against rapidly firing/small fibers
• Often co-administered with epinephrine, which prolongs the block by causing local vasoconstriction and slowing systemic absorption
• In infected (acidic) tissue, anesthetics stay charged and can't penetrate the membrane as well, so more drug is needed for adequate anesthesia
• Order of sensory loss — pain first, then temperature, then touch, then pressure
• Adverse effects — CNS excitation/seizures, cardiovascular toxicity (notably bupivacaine), arrhythmias (cocaine), methemoglobinemia (benzocaine, prilocaine)

General Anesthetics

• CNS-active anesthetics must be lipid-soluble (to cross the BBB) or be actively transported
• Lower blood solubility (e.g., nitrous oxide) → faster induction and recovery; higher lipid solubility (e.g., isoflurane) → greater potency
• MAC (minimum alveolar concentration) is the dose that prevents movement in 50% of subjects to a noxious stimulus — potency is inversely related to MAC (potency = 1/MAC)

Neuromuscular Blocking Drugs

• Used for surgical paralysis or mechanical ventilation; act selectively at nicotinic Nm receptors of the neuromuscular junction
• Depolarizing — succinylcholine is a strong Nm agonist that causes sustained depolarization and blocks further contraction; early "Phase I" block has no antidote and is worsened by cholinesterase inhibitors, while a later "Phase II" block can be reversed by them; risks include hyperkalemia and malignant hyperthermia
• Nondepolarizing — atracurium, cisatracurium, pancuronium, rocuronium, and vecuronium competitively block Nm receptors; reversed with sugammadex or a cholinesterase inhibitor (e.g., neostigmine, usually paired with an anticholinergic like glycopyrrolate to blunt muscarinic bradycardia)

Malignant Hyperthermia

• Rare, life-threatening hypermetabolic reaction to potent inhaled anesthetics or succinylcholine in susceptible individuals (RYR1 or DHPR receptor mutations)
• Massive sarcoplasmic reticulum Ca²⁺ release → sustained muscle contraction, hypercapnia, tachycardia, rigidity, rhabdomyolysis, hyperthermia
• Treatment — dantrolene, a ryanodine receptor antagonist

Skeletal Muscle Relaxants

Opioid Analgesics

• Act as agonists at μ (β-endorphin), δ (enkephalin), and κ (dynorphin) opioid receptors — close presynaptic Ca²⁺ channels and open postsynaptic K⁺ channels, reducing synaptic transmission and release of ACh, norepinephrine, serotonin, glutamate, and substance P
• Full agonists — morphine, meperidine, methadone, codeine (a prodrug), fentanyl
• Partial agonist — buprenorphine; mixed agonist/antagonists — butorphanol, nalbuphine (cause less respiratory depression than full agonists but can precipitate withdrawal in a patient already on a full agonist, and are not easily reversed by naloxone)
• Antagonists — naloxone (acute overdose reversal), naltrexone/methylnaltrexone (relapse prevention, peripheral effects)
• Clinical use — moderate-to-severe pain, cough suppression, antidiarrheal (loperamide, diphenoxylate), acute pulmonary edema, opioid use disorder maintenance (methadone, buprenorphine/naloxone)
• Adverse effects — nausea, pruritus (histamine release), constipation, respiratory depression, miosis (except meperidine, which causes mydriasis); tolerance does not develop to miosis or constipation

Tramadol & Capsaicin

• Tramadol — a very weak opioid agonist that also inhibits norepinephrine/serotonin reuptake; used for chronic pain, but lowers the seizure threshold and carries a serotonin syndrome risk
• Capsaicin — desensitizes nociceptive fibers by depleting substance P; used topically for musculoskeletal and neuropathic pain

Thalamic Relay Nuclei

Hypothalamic Nuclei & Function

Limbic System

• Coordinates emotion and instinctual behavior, broadly summarized as the "five F's"
  • Feeding
  • Feeling (emotional processing)
  • Fighting
  • Fleeing
  • Sexual activity ("mating")
• Regulated primarily through the hypothalamus and autonomic nervous system
• Core anatomic components
  • Anterior nucleus of the thalamus
  • Cingulate gyrus
  • Mammillary bodies
  • Septal area
  • Hippocampus — memory consolidation
  • Amygdala — fear processing and emotional salience; bilateral destruction produces Klüver–Bucy syndrome
• These structures interconnect through the Papez circuit (hippocampus → mammillary bodies → anterior thalamic nucleus → cingulate gyrus → back to hippocampus), the classic anatomic substrate for emotional memory

See: Degenerative, Demyelinating & Dementing Diseases → Basal Ganglia Circuitry

Nonpharmacologic Modalities

• Classical conditioning — a natural reflex is paired with a neutral stimulus until the stimulus alone triggers the response
• Operant conditioning — behavior frequency is shaped by reinforcement (positive, negative, continuous, fixed, or variable schedules)
• Systematic desensitization — pairs relaxation with graded exposure to a feared stimulus; used to treat phobias
• Cognitive therapy — restructures distorted negative thought patterns; effective for depression and anxiety
• Electroconvulsive therapy — rapid-acting treatment for severe/refractory major depression; retrograde amnesia is the main side effect
• Psychoanalysis — Freudian model of id (drives), ego (reality-testing), and superego (conscience)

Eating Disorders

Drugs of Abuse — Intoxication vs. Withdrawal

Schizophrenia Spectrum

• Core diagnostic features: hallucinations (usually auditory), delusions, disorganized speech/behavior, and negative symptoms (flat affect, avolition)
• Requires at least 1 month of active symptoms with functional impairment for 6 months
• Dopamine excess theorized to underlie positive symptoms
• Brief psychotic disorder — under 1 month; schizophreniform — 1 to 6 months; schizoaffective — psychosis plus a mood disorder
• Delusional disorder — fixed, non-bizarre delusions (beliefs that could plausibly happen) without hallucinations; overall functioning and behavior remain largely intact aside from the delusion itself

Antipsychotic Pharmacology

• Typical (first-generation) antipsychotics block dopamine D2 receptors
  • High potency (haloperidol) — more extrapyramidal symptoms, fewer anticholinergic effects
  • Low potency (chlorpromazine) — more anticholinergic/antihistaminergic/alpha-blocking effects, fewer EPS
• Atypical antipsychotics (clozapine, olanzapine, risperidone, quetiapine, aripiprazole) — lower EPS risk but weight gain and metabolic effects; clozapine carries agranulocytosis risk requiring blood monitoring
• Extrapyramidal symptom timeline: acute dystonia (days) → akathisia (weeks) → bradykinesia (months) → tardive dyskinesia (months–years, often irreversible)
• Neuroleptic malignant syndrome — rigidity, hyperthermia, autonomic instability; treated with dantrolene and immediate drug discontinuation

Mood Disorders & Antidepressants

• Major depressive disorder — at least 2 weeks of depressed mood/anhedonia plus associated neurovegetative symptoms, summarized by the mnemonic SIG E CAPS
  • Sleep disturbance
  • Interest loss (anhedonia)
  • Guilt
  • Energy loss
  • Concentration difficulty
  • Appetite change
  • Psychomotor agitation or retardation
  • Suicidal ideation
• Decreased norepinephrine and serotonin are implicated; decreased REM latency is a classic finding
• Atypical depression — hypersomnia, weight gain, mood reactivity; responds well to MAOIs
• Seasonal affective disorder — light-deficiency-related winter depression, treated with light therapy
• Postpartum depression — depressive symptoms persisting beyond 2 weeks after delivery, occasionally lasting over a year; managed the same as standard MDD
• Dysthymia — a milder, chronic form of depression meeting fewer diagnostic criteria but persisting for at least 2 years

Other Neuropsychiatric Disorders

Anxiety Disorders

• Panic disorder — discrete episodes of intense anxiety with palpitations, chest pain; associated with mitral valve prolapse
• Generalized anxiety disorder — persistent worry for over 6 months; SSRIs and buspirone are first-line
• PTSD — follows trauma; hypervigilance, flashbacks, nightmares
• OCD — recurrent intrusive thoughts and compulsive behaviors; SSRIs and clomipramine are effective
• Phobias — irrational situational fear; treated with systematic desensitization; propranolol helps physical symptoms

Other Psychiatric Drugs

Defense Mechanisms

Personality Disorders

Cluster A — "Weird" (odd, eccentric)

Cluster B — "Wild" (dramatic, erratic)

Cluster C — "Worried" (anxious, fearful)

Sleep Stages (EEG Correlates)

• Slow-wave (N3) sleep is when night terrors, sleepwalking, and bedwetting occur
• REM sleep occurs roughly every 90 minutes and features rapid eye movements, skeletal muscle atonia, penile erections, and most vivid dreaming
• Serotonin from the raphe nuclei helps initiate sleep; the reticular activating system maintains wakefulness
• Aging reduces N3 (slow-wave) sleep and increases nighttime awakenings

Factors Affecting Sleep Architecture

• Alcohol, benzodiazepines, and barbiturates all reduce N3 and REM sleep (benzodiazepines are used therapeutically for sleepwalking/night terrors, which arise from N3)
• Depression classically reduces N3 sleep, increases REM sleep and shortens REM latency, and causes repeated nighttime and early-morning awakenings
• Narcolepsy is marked by shortened REM latency — REM intrudes abnormally early, including at sleep onset
• REM sleep behavior disorder — loss of the normal muscle atonia of REM leads to dream enactment (often violent movements/vocalization); strongly associated with Lewy body dementia and Parkinson disease, sometimes preceding the motor diagnosis by years

Sleep Disorders

Neural Tube → CNS

Congenital Malformations

Neonatal & Birth-Related Cranial Injuries