NeuroPsych 1 - Mi

What are the initial assessment and workup steps (6) for a patient with suspected acute stroke (ischemic or hemorrhagic)?

• 1) Recognize stroke symptoms (BE FAST):

  • B: Balance difficulties

  • E: Eyes (vision changes)

  • F: Facial droop

  • A: Arm/extremity weakness

  • S: Speech difficulties

  • T: Time (call 911 immediately)

• 2) Stabilize/Assess the patient (ABC(D))

  • Assess ABCs (airway, breathing, circulation [BP, HR], dextrose/glucose levels)

  • Provide O2 if hypoxic and establish IV access

• 3) Obtain labs

  • STAT CBC, coagulation studies, Chem-7

  • Platelets (low platelets may contraindicate thrombolysis)

  • Weight (for weight-based TNK/tPA dosing)

  • 12-lead ECG

• 4) Assess stroke severity (NIHSS)

  • 11 items (0-4 points each)

  • The higher the score = more severe the impairment

    •  0 – no stroke

    •  1-4 – minor stroke

    •  5-15 – moderate stroke

    • 16-20 – moderate to severe stroke

    •  >20 severe strokes

      • Good predictor of patient outcomes: 

        • <6 good outcome, >16 high likelihood of death

• 5) CT/CTA

  • CT: differentiates between hemorrhagic vs ischemic (sees whether there is bleeding/hemorrhage or not)

  • CTA (CT with contrast): maps out the brain vasculature, looking for clots/lesions

    • Can determine large vessel occlusions (LVO)

• 6) Review history

  • Determine last known well (LKW) to assess eligibility for IV thrombolysis (typically within 4.5 hours).

  • Wake-up stroke: LKW is generally when the patient was last normal before sleeping.

  • Review anticoagulant use (warfarin, DOACs) and bleeding risk.

  • Review Alzheimer's medications (lecanemab/donanemab) due to increased hemorrhage risk.

What medications should you look out for in a patient's PMH for stroke? Why?

• Anticoagulant use (warfarin, DOACs)

  • If they are on an anticoagulant, don't give thrombolytics for stroke

  • For warfarin, monitor INR to determine (INR must be ≤1.7)

    • Thrombolytics have the highest bleeding risk (which is why they are only used for emergencies)

  • If the patient has not taken an anticoagulant in 48 hours, they are more eligible 

    • Can check INR for DOAC use (will show any variation in bleeding risk, just not as accurate/reliable as warfarin)

• Alzheimer's medications (lecanemab/donanemab) due to increased hemorrhage risk.

All may increase bleeding risk if tNK/tPA are used

What is the pathophysiology and what are the common causes of ischemic stroke?

• MOA: Blocked blood flow to part of the brain → inadequate oxygen delivery

• Common causes

  • Atherosclerotic ~20% → decrease blood flow

  • Small vessel disease (lacunar) ~25%

  • Cardiogenic embolism ~20% → afib (Without appropriate anticoagulant treatment)

  • Cryptogenic ~30% → unknown

  • Other causes ~5% → drugs: cocaine, meth = vasoconstriction

How is acute ischemic stroke managed (dose, monitoring) based on time since symptom onset?

• ≤4.5 hours: IV thrombolysis (if eligible)

  • Alteplase (tPA): 0.9 mg/kg IV (max 90 mg)

    • 10% IV bolus over 1 minute, then 90% infused over 1 hour.

  • Tenecteplase (TNK): 0.25 mg/kg IV (max 25 mg) as a single bolus over approximately 5 seconds.

  • BP before treatment: ≤185/110 mmHg.

  • BP after treatment: ≤180/105 mmHg for 24 hours.

  • Monitor closely in a stroke unit/ICU for at least 24 hours.

  • Avoid antiplatelets and anticoagulants for the first 24-48 hours.

• Beyond 4.5 hours (without thrombolysis):

  • Evaluate for large vessel occlusion (LVO) → CTA, and mechanical thrombectomy eligibility (selected patients up to 24 hours)

    • Removal of stationary clot

  • Allow permissive hypertension to maintain cerebral perfusion

    • Generally avoid BP lowering unless >220/120 mmHg.

    • If treatment is needed, lower BP by approximately 15% during the first 24 hours.

  • After 24 hours, consider restarting oral antihypertensives when neurologically stable.

What are the BP goals and IV antihypertensive options (+their dosing/limitations) for acute ischemic stroke?

• Goals

  • BP before tPA/tNK treatment: ≤185/110

  • BP after tPA/tNK treatment: ≤180/105 for 24-48 hour

    • Increased risk for hemorrhaging if above this target range

  • No thrombolysis: Permissive HTN up to 220/120

    • If above: Reduce BP by ~15% in first 24 hours

• Treatment options:

  • IV labetolol 5-20mg over 1-2 min q15 min

    • Non-selective BB: will lower both BP and HR

    • Hold for HR <55

  • IV Clevidipine 1-2mg/hr infusion

    • DHP CCB: will lower BP but not HR

    • Use if labetalol fails to control BP after 3 doses and/or HR <55

    • Titrate by 2mg/hr q5min PRN to max of 21mg/hr

  • IV Nicardipine 5mg/hr infusion

    • DHP CCB: will lower BP but not HR

    • Titrate by 2.5mg/hr q15min PRN to max of 15mg/hr

What are the limitations of giving tPA/tNK?

• Must be given ≤4.5 hours of stroke onset

• Head CT scan without evidence of hemorrhage

• Max weight for both tPA/tNK = 100kg for dosing

  • DO NOT GIVE tNK over 25mg or total tPA over 90mg

• Labs:

  • BP ≤185/110

  • Platelet count above 100,000/mm3

  • Avoid DDI (other drugs that can increase bleeding risk) → INR ≤1.7

  • Glucose >50

• Age ≥ 18 years

What are the primary and secondary prevention methods for stroke?

• Primary:

  • Stop smoking

  • Manage HTN, HLD, DM

  • Increase physical activity + weight loss

  • Manage afib

    • Anticoagulants reduce the risk of stroke by 70%

• Secondary

  • Afib → DOAC/warfarin

  • Non afib related

    • Aspirin 50-325mg PO QD or

    • Clopidogrel 75 mg PO QD or

    • (Aggrenox) Aspirin/dipyridamole 25/200 mg PO BID

    • Cilostazol 100 mg PO BID

  • For smaller strokes (NIHSS ≤3), DAPT may be indicated

    • ASA + clopidogrel for 21-90 days, then single agent

    • Start DAPT within 24-48 hours

  • Lipids

    • High statin therapy (Atorvastatin 80mg PO QD)

    • Dose + effect independent of LDL level

      • After 5 years decrease in the risk of fatal and non-fatal stroke, CV events, and an increase in ICH (intracerebral hemorrhage)

Anticoag should not be started until at least 24 hours after tPA administration and repeat CT confirms no bleeding.

What is the pathophysiology and common causes of hemorrhagic stroke?

• MOA: Mechanical injury due to edema

  • Blood vessel ruptures → bleeding into/around the brain

  • Increased intracranial pressure (ICP) + swelling of the brain = increased mass

  • Reduced cerebral perfusion (ischemia)

  • Cerebral herniation

• Common causes:

  • Hypertension

  • Older age (risk doubles q10 years after 35)

  • Cerebral angiopathy (vessel weakening)

  • Drugs (cocaine, amphetamines)

  • Brain tumors

  • Arteriovenous malformations

  • Asian > AA > MA > White

What are the main components (5) of medical management for hemorrhagic stroke?

• 1) Stabilization/supportive care:

  • ABCs, intubation if necessary

  • Manage blood glucose, fever, hydration, and DVT prophylaxis.

• 2) BP control:

  • Goal: SBP 140–160 mmHg

  • IV labetalol, nicardipine, or clevidipine.

  • Avoid hypotension and excessive BP reduction to preserve cerebral perfusion.

• 3) Anticoagulation reversal:

  • Warfarin, Factor Xa inhibitors,Dabigatran, Heparin/enoxaparin

• 4) Reduce elevated intracranial pressure (ICP) :

  • Mannitol

  • Hypertonic saline

• 5) Seizure management:

  • Acute seizures (treatment): Benzodiazepines.

  • Antiseizure medications (PPX): Levetiracetam, phenytoin, or valproate when indicated (depends on type of seizure).

What surgical interventions may be used for hemorrhagic stroke, and what is their purpose?

• Cerebellar decompression

  • Creates more space for a swollen cerebellum → relieves increased ICP and prevents brainstem compression/herniation

• Hematoma evacuation 

  • Surgically removes a collection of blood (hematoma) to reduce mass effect and pressure on surrounding brain tissue

• Ventriculostomy

  • Places a catheter in the brain ventricle to drain blood and reduce ICP

• Open craniotomy

  • Opens part of the skull to directly access the brain to evacuate a hematoma or control bleeding

What supportive care measures are recommended for both ischemic and hemorrhagic stroke?

• 1) Blood glucose control:

  • BG >140 mg/dL in the first 24 hours is associated with worse outcomes.

  • BG >200 mg/dL increases the risk of ICH following tPA.

  • Goal: 140–180 mg/dL

  • Treatment: Insulin (IV reg insulin in critical → basal + correctional insulin for stable)

    • Avoid oral antihyperglycemics in acute management.

    • Avoid hypoglycemia.

• 2) Temperature management:

  • Avoid hyperthermia (>38°C), which worsens neurologic injury.

  • Treat fever with acetaminophen (Tylenol).

  • Monitor for infection, especially pneumonia.

• 3) IV fluid management:

  • Maintain adequate hydration and cerebral perfusion.

  • Avoid dextrose-containing IV solutions unless needed to treat hypoglycemia.

• 4) DVT prophylaxis:

  • Immobility increases venous stasis, contributing to Virchow's triad:

    • Venous stasis

    • Endothelial injury

    • Hypercoagulability

  • Use intermittent pneumatic compression devices in immobilized patients.

  • Consider pharmacologic prophylaxis (UFH/LMWH) when safe, accounting for stroke type and bleeding risk.

What conditions or medications can mimic stroke symptoms?

• Hypoglycemia: Can cause confusion, weakness, and focal neurologic deficits resembling stroke.

• Hyperglycemia (DKA): Can cause altered mental status and neurologic symptoms resembling stroke.

• Compazine (prochlorperazine): Can cause acute dystonia, characterized by sudden, painful, involuntary muscle spasms that may resemble neurologic deficits.

Rank antithrombotic medications from highest to lowest bleeding risk.

Thrombolytics > Glycoprotein IIb/IIIa inhibitors > Anticoagulants >> P2Y12 inhibitors (prasugrel, ticagrelor, clopidogrel) > Aspirin

What are the four mechanisms that regulate substance transport across the blood-brain barrier (BBB)?

• 1) Cell membranes repel hydrophilic toxins

• 2) Tight junctions limit toxins from sneaking between cells into the brain (no paracellular diffusion)

• 3) Active transporters 

  • Influx transporters: SLC transporters

    • Solute carrier-mediated transport

      • Facilitated diffusion + secondary active transport

    • Bring in solutes/nutrients from circulation →  endothelial cells → brain

    • EX: GLUT-1, LAT-1

  • Efflux transporters: ABC transporters 

    • ATP-binding dependent primary active transport

    • Kick out toxins that don't belong in the brain

    • EX: P-glycoprotein (pgp)

• 4) Drug properties

  • Small (<400Da)

  • Lipophilic/nonpolar (less than eight hydrogen bonds) (less OH the better)

  • Charge (the less charge, the better)

  • LogBB is positive

    • LogBB = log(brain/(blood)

      • LogBB = negative number means that more of the drug exists in the blood > brain

      • LogBB = positive means more in the brain > blood 

        • +1 = 10x more drug in the brain than in the blood

  • Drug protein binding

    • Increased protein binding means decreased ability to get into the brain

  • Route of administration

    • Intracerebral (IC) delivery

What is the anatomy of the BBB?

• Made from 3 cell types

  • Endothelial cells (innermost):

    • Lining of the blood vessel

    • Have tight junctions

  • Pericyte (middle layer):

    • Intermediate layer embedded in basement membrane, just superficial to endothelial cells

  • Astrocytes (outer layer)

    • Wrap inner layers with foot processes (podocytes)

What does the Glasgow Coma Scale (GCS) assess, and how are scores interpreted?

Assesses level of consciousness using:

• Eye-opening (1–4)

• Verbal response (1–5)

• Motor response (1–6)

  • 13–15: Mild impairment

  • 9–12: Moderate impairment

  • 3–8: Severe impairment/coma

What factors determine DOAC (apixaban, rivaroxaban, dabigatran, edoxaban) dose adjustments?

• Apixaban: ≥2 of age ≥80, weight ≤60 kg, SCr ≥1.5 mg/dL

• Rivaroxaban: CrCl ≤50 mL/min

• Dabigatran: CrCl 15–30 mL/min

• Edoxaban: CrCl 15–50 mL/min

What are the two anatomical divisions of the nervous system, and how does their nomenclature differ?

• 1) Central Nervous System (CNS)

  • Consists of the brain and spinal cord.

  • Nucleus: Collection of neuron cell bodies in the CNS.

  • Tract: Bundle of axons in the CNS.

• 2) Peripheral Nervous System (PNS)

  • Consists of nerves and ganglia outside the CNS.

  • Ganglion: Collection of neuron cell bodies in the PNS.

  • Nerve: Bundle of axons in the PNS.

Compare the somatic (SNS) and autonomic (ANS) nervous systems in terms of function, motor/sensory innervation, and neurotransmitters.

• 1) Somatic Nervous System (SNS): Conscious control

  • Motor: CNS → skeletal muscles (voluntary movement).

  • Sensory: Skin, muscles, bones, joints → CNS.

  • Motor pathway: Single neuron from CNS to skeletal muscle (ACh).

• 2) Autonomic Nervous System (ANS): Unconscious control

  • Motor: CNS → smooth muscle, cardiac muscle, glands.

  • Sensory: Visceral organs → CNS.

  • Motor pathway: 2-neuron chain (preganglionic → postganglionic).

    • Sympathetic (SANS)

      • Acetylcholine as a preganglionic neurotransmitter

      • Norepinephrine as a postganglionic neurotransmitter

      • Longer postganglionic neuron

    • Parasympathetic (PANS)

      • Acetylcholine as a pre- and postganglionic neurotransmitter

      • Longer preganglionic neuron

Compare the motor and sensory neuron chains in terms of neuron number, location, and function.

• Motor pathway (descending):

  • 2-neuron system (upper and lower motor neurons).

    • Upper motor neuron: Descends through CNS white matter.

    • Lower motor neuron: Extends into the periphery to innervate skeletal muscle.

  • Function: CNS → muscle (movement).

• Sensory pathway (ascending):

  • 3-neuron system:

    • First-order neuron: Cell body in the dorsal root ganglion, receives peripheral sensory information.

    • Second-order neuron: Located in the spinal cord gray matter or brainstem.

    • Third-order neuron: Located in the thalamus, projects to the cerebral cortex.

  • Function: Peripheral receptors → CNS (sensation).

Compare gray and white matter in terms of composition, location in the brain vs. spinal cord, and function of the spinal cord horns.

• Gray matter

  • Neuron cell bodies and their support cells

• White matter

  • Axon segments and their support cells

• The arrangement differs from the brain to the spinal cord

  • Brain = gray external, white internal

  • Spinal cord = gray internal, white external

    • Divided into two grey matter horns 

      • Dorsal horn: sensory neurons

      • Ventral horn: motor neurons

What are the major components of a neuron and synapse, and how do they transmit nerve impulses?

• Neuron

  • Axon = long cytoplasmic extension

    • Often myelinated. Myelin restricts depolarization (+) of the membrane to the myelin sheath gaps

      • Causes jump from one node to the next (saltatory conduction) = faster conduction than non-myelinated axons

  • Cell body = cell body, contains nucleus and organelles

  • Dendrites = collects info to send to the nucleus

  • Use excitability to produce and move an AP (nerve impulse) along an axon → transmitted to another neuron or effector cell via a synapse

• Synapse

  • Axon terminal

    • Release neurotransmitter (NE or acetylcholine)

  • Travels to the postsynaptic cell

What are the meningeal layers of the brain?

• 1) Dura mater (outer)

  • Composed of two layers

    • Periosteal layer (outer)

    • Meningeal layer (inner)

  • Space between layers includes dural venous sinuses

    • Drains blood from the brain to the internal jugular veins in the neck (systemic circulation)

• 2) Arachnoid mater (middle)

  • Arachnoid trabeculae

    • Tread-like structures that connect the arachnoid mater with the pia mater

  • Arachnoid granulations

    • Projections of the arachnoid into the dural sinuses to recycle CSF

  • Held against the dura mater by the osmotic pressure of CSF

  • Separated from the pia mater by  the subarachnoid space (contains CSF)

• 3) Pia mater (inner)

  • Directly against the brain (very thin and permeable to water and small solutes)

  • Allows vessels to pass through and nourish the brain

  • Allows formation of perivascular spaces, which serve as the brain’s lymphatic system (drains excess fluid)

What are the source, location, functions, and flow pathway of cerebrospinal fluid (CSF)?

• Source: Choroid plexus (500mL produced per day)

  • Continuous to compensate for the amount resorbed into the systemic circulation

• Location: Cranial ventricles (hollow cavities within the brain where CSF is produced and circulated)

  • 1+2) Lateral ventricles (L+R)

    • Connect to the 3rd by the interventricular foramen (of Monro)

  • 3) Third ventricle

    • Connected to the 4th by the cerebral aqueduct (of Sylvius)

  • 4) Fourth ventricle

    • Surrounded by pons, medulla, cerebellum

    • Connected to the CSF space around the brainstem by the lateral aperture (foramen of Luschka)

• Function:

  • Provide buoyancy for the brain and CNS

  • Provide a medium for nutrients and electrolytes to be conveyed to the brain

  • Removed metabolic waste from the brain

• Flow

  • Choroid plexus in lateral ventricles → interventricular foramen (of Monro) - connection to → Third ventricle → cerebral aqueduct (of Sylvius) - connection to → fourth ventricle → lateral aperture (foramen of Luschka) - connection to → CSF space around brainstem + subarachnoid space around the CNS and/or central canal of spinal cord → arachnoid granulations → Dural venous sinuses → Resorbed into venous system through arachnoid granulations in skull (125-150mL in circulation at any time)

What are the functions of peripheral nerves, and how are spinal and cranial nerves classified?

• 1) Peripheral nerve functions

  • Sensory (afferent): Carries information toward the CNS.

  • Motor (efferent): Carries commands away from the CNS.

    • Somatic motor: Controls skeletal muscles.

    • Visceral/autonomic motor: Controls smooth muscle, cardiac muscle, and glands.

• 2) Spinal nerves

  • Mixed nerves containing both sensory and motor fibers.

  • Connect the spinal cord to the body.

    • Sensory: Body → spinal cord.

    • Motor: Spinal cord → body.

• 3) Cranial nerves (12 bilateral pairs)

  • 12 bilaterally paired cranial nerves, which primarily provide sensory and motor innervation to the muscles, skin, and glands of the head and neck

    • Sensory only: CN I, II, VIII

    • Motor only: CN IV, VI, XI, XII

    • Both sensory + motor: CN III, V, VII, IX, X

What are the functions and clinical applications of cranial nerve 2?

• 2: Optic - sensory 

  • Function: Vision 

    • Carries visual info from the retina → associated with occipital (primary visual cortex)

  • Clinical applications:

    • Optic neuropathies (ethambutol, PDE-5 inhibitors)

    • Glaucoma pharmacology to protect nerve

What are the functions and clinical applications of cranial nerve 3?

• 3: Oculomotor - sensory + motor

  • Function: Eye movement, Eyelid elevation (i.e., ptosis: eyelid drooping), pupil size + shape (CN 3 parasympathetics)

  • Nuclei is in mid-brain → part of brainstem

  • Clinical applications

    • Anticholinergic effects on eye = mydriasis (pupil dilation) → Acute angle-closure glaucoma

    • Cycloplegia (Loss of accommodation)

  • EX: The pupil (shape/size) and location will be off-center if not like that at baseline, and there will be pain when moving the eye around

    • Vertical gaze → eye ball move/skew

What are the functions and clinical applications of cranial nerve 5?

• 5: Trigeminal - sensory + motor

  • Function: Facial sensation + controls motor to muscles of mastication: pin pricking/light touch, 

    • Subdivided into three branches

      • CN V1 (Ophthalmic): sensation to upper face, orbit

      • CN V2 (Maxillary): sensation to midface, nasal cavity

      • CN V3 (Mandibular): sensation to lower face, oral cavity, motor masticatory muscles

  • Nuclei in midbrain, pons, medulla → brainstem

  • Clinical applications:

    • Trigeminal neuralgia (slight breeze = extreme pain)

      • Treated with anticonvulsants (carbamazepine and oxcarbazepine)

    • Masseter muscle spasms or impaired jaw movement.

What are the functions and clinical applications of cranial nerve 7?

• 7: Facial - sensory + motor

  • Function: Facial expression, taste (Anterior ⅔ of tongue), tears/saliva production

  • Clinical applications:

    • Bell’s palsy (lower motor neuron lesion, paralysis of the full ½ face)

      • Treatment with higher dose corticosteroids

      • Stroke (upper motor neuron lesion)

        • CAN move forehead (Forehead control - bilateral)

        • Eyeclosure

        • Contralateral lower facial weakness

What are the functions, associated nuclei, and clinical applications of cranial nerve 9?

• 9: Glossopharyngeal - sensory + motor

• Function: Swallowing + taste (posterior ⅓ of tongue) + Saliva production, BP sensation to middle ear

  • Gag reflex - most obvious

  • Pharynx

  • Dysphagia - but a lot of pts have GERD

• Nuclei in the lowest pons, mostly medulla → brainstem

• Associated nuclei

  • Spinal trigeminal nucleus (sensation from the middle ear, posterior tongue, and throat)

  • Inferior salivatory nucleus (saliva production)

  • Nucleus ambiguous (motor for swallow, reflexes, baroreception)

  • Solitary nucleus (taste and visceral sensation, HR/BP/respiration)

• Clinical applications:

  • Dysphagia, impaired gag reflex, and loss of posterior tongue sensation/taste.

What are the functions, associated nuclei, and clinical applications of cranial nerve 10?

• 10: Vagus 

  • Function: Swallowing, speech, parasympathetics

    • Hoarseness in the throat

    • Vocal cord paralysis is typically responsible for slurring of the speech

  • Nuclei in medulla → brainstem

  • Associated nuclei:

    • Spinal trigeminal nucleus (sensation from skull to ear)

    • Dorsal vagal nucleus (parasympathetics to thoracic + abdominal viscera)

    • Nucleus ambiguus (motor for swallow, reflexes, baroreception)

    • Solitary nucleus (taste, sensation from throat, baro/chemoreception)

  • Clinical applications:

    • Hoarseness or dysphonia due to vocal cord paralysis.

    • Dysphagia and impaired gag reflex.

    • Uvula deviation away from the side of a unilateral CN X lesion.

What are the functions and clinical applications of cranial nerve 12?

• 12: Hypoglossal - motor

  • Function: Strength of tongue/movement

    • Atrophy, tongue deviation

  • Nuclei in medulla → brainstem

  • Clinical applications

    • Tongue weakness, atrophy, and deviation.

    • Each side of the brain controls one side of the tongue

      • When the tongue deviates = CN XII lesion (indicates side of lesion = left leaning = left lesion)

What are the two main sources of cerebral arterial blood, and how do they form the Circle of Willis?

• Heart → aorta → subclavian artery → vertebral artery (L+R)

  • L+R v combine to form basilar artery

• Heart → aorta → common carotid artery → internal carotid artery (L+R)

• Both sources of blood combine to form the cerebral arterial circle (of willis)

  • Posterior communicating artery: 

    • Connects vertebral and internal carotid arteries on same side

  • Anterior communicating artery:

    • Connects between branches of left and right internal carotid arteries

Compare the vascular territories and characteristic stroke symptoms of the ACA, MCA, and PCA.

• Anterior cerebral artery (ACA)

  • Top side of the surface of the frontal/parietal cortex

  • Infarct symptoms: 

    • Motor/sensory loss to the opposite side of the stroke lower limb

    • Since the lower limb is not associated with any CN

• Middle cerebral artery (MCA)

  • Bottom sides of the frontal/parietal lobes and the top side of the temporal lobe

  • Infarct symptoms:

    • Weakness/paralysis on one side of the body (face/arm), speech difficulty, confusion, sudden loss of senses

    • Associated with CN V, VII,  and XII

• Posterior cerebral artery (PCA)

  • Bottom side of the temporal lobe and the occipital lobe

  • Infarct symptoms:

    • Complete loss of visual field on ONE HALF of each eye

      • This is because each part of the brain is responsible for one side of the eye (weird)

    • Associated with CN II

Infractions → associated with opposite side of stroke (damage to the cortical region and disrupts cortical control/processing of cranial nerve function

What are the primary functions of the cerebral lobes and corpus callosum?

• Frontal lobe - high-order processing

• Parietal lobe - sensory perception

• Temporal lobe - auditory processing and memory acquisition

• Occipital lobe - visual processing

• Insular lobe - homeostasis and emotion

• Corpus callosum - bridge between L+R cerebral hemispheres

Which arteries supply the cerebellum and brainstem?

• Cerebellum

  • PICA (Posterior Inferior Cerebellar Artery): Branches from the vertebral artery.

  • AICA (Anterior Inferior Cerebellar Artery): Branches from the basilar artery.

• Brainstem

  • Primarily supplied by branches of the vertebral and basilar arteries.

What is the monitoring process like if pt is given tPA/tNK/has an ischemic stroke?

• All patients given tPA or ischemic stroke need ICU-level monitoring. All patients should be monitored for:

  • Bleeding

  • Intracranial hemorrhage

  • Other bleeding: gums, epistaxis

  • Angioedema

• Monitoring frequency should be at least:

  • Q15min x2 hours after infusion, then

  • Q30min x6 hours, then

  • Q1hr until 24 hours post-infusion

• Other:

  • BP should be maintained <180/105 mmHg for 24 hrs.

  • No antiplatelets or anticoagulants for 24 hours

  • No poking (e.g., NG tubes, Foley catheters, IA lines)

  • Repeat CT scan at 24 hours before starting ASA or DVT prophylaxis

How efficacious is tPA/tNK?

About 30% of patients receiving tPA for stroke get better. However, 60% will not see any harm or benefit from this medication. The rest is gg.

How do you calculate CHA2DS2-VASc scores?

Risk factor	Points
C: Congestive heart failure	+1
H: Hypertension	+1
A₂: Age ≥75 years	+2
D: Diabetes mellitus	+1
S₂: Prior stroke/TIA/systemic thromboembolism	+2
V: Vascular disease (prior MI, PAD, aortic plaque)	+1
A: Age 65–74 years	+1
Sc: Sex category (female)	+1

Score of ≥ 2 (Men) or ≥ 3 (Women) → anticoag recommended

What are the mechanisms of action (MOA) and adverse effects (SE) of alteplase and tenecteplase?

• MOA:

  • Both: Bind to fibrin → convert plasminogen into plasmin → which breaks down fibrin and dissolves existing clots.

  • Tenecteplase: Modified alteplase with greater fibrin specificity, resistance to PAI-1 (enzyme that breaks down intrinsic tPA), and a longer duration of action.

• SE (Both):

  • Bleeding (major risk):

    • Intracranial hemorrhage (ICH)

    • Mucosal bleeding (gums, epistaxis)

  • Angioedema: Rapid swelling of the tongue/larynx, potentially causing airway obstruction.

What is the difference in MOA/SE between mannitol and hypertonic saline?

• Mannitol

  • MOA:

    • Decreases ICP through osmotic diuresis

    • Holds water in tubular lumen

    • Pulls water from intracellular compartments into the blood

      • Temporarily increases volume/dilutes blood

    • Freely filtered in kidneys, poorly or not reabsorbed

      • Aggressively increases urine output (if GFR is adequate)

      • Moves so fast that reabsorption of solutes is decreased

    • Concentrates blood as a result

  • SE:

    • Renal failure

      • Ensure renal function is okay before use since it requires proper/free filtration to increase urine output

    • Hypovolemia

    • Hypotension

    • Heart failure

    • Pulmonary edema

• Hypertonic saline

  • MOA:

    • NaCl concentrated solution

      • NaCl stays in lumen of blood stream drawing water towards it

    • Can increase BP since it does not cause significant diuresis like mannitol does

  • SE:

    • Hypernatremia risk

      • Depending on volume (increased volume = decrease Na concentration)

    • AKI

    • Central pontine myelinolysis (CPM) → damage to myelin sheath covering nerve cells

    • Volume overload/HF

When should you use mannitol over hypertonic saline and vice versa?

• Mannitol:

  • Increased ICP when adequate renal function is present

• Hypertonic saline:

  • Preferred when volume/BP support is needed

  • Concentrated bolus for impending herniation

What is the MOA, AE, monitoring, and reversal for Warfarin?

• MOA:

  • Inhibits vitamin K epoxide reductase (VKOR) → prevents regeneration of active vitamin K → decreases functional vitamin K-dependent factors II, VII, IX, X, and proteins C and S

• AE: Bleeding

• Monitoring: INR

• Reversal: 4-factor Prothrombin complex concentrate (PCC) (factors II, VII, IX, X + proteins C/S) + IV vitamin K

What is the MOA, AE, monitoring, and reversal for DOACs?

• MOA:

  • Directly inhibits factor Xa → ↓ conversion of prothrombin to thrombin → ↓ fibrin clot formation.

• AE: Bleeding

• Reversal: 4-factor Prothrombin complex concentrate (PCC) (factors II, VII, IX, X + proteins C/S)

What is the MOA, AE, monitoring, and reversal for Aspirin?

• MOA:

  • Inhibits COX → ↓ thromboxane A₂ (TXA₂). Since TXA₂ normally causes vasoconstriction and stimulates platelet aggregation, reducing TXA₂ inhibits platelet aggregation.

• AE:

  • Bleeding

  • GI ulcers

  • Renal toxicity

What is the MOA, AE, monitoring, and reversal for Clopidogrel and Ticlopidine?

• MOA:

  • Irreversible ADP receptor antagonists. They inhibit ADP-mediated platelet activation/aggregation. They are prodrugs requiring metabolic activation, including CYP2C19; therefore, loss of CYP2C19 function can reduce clopidogrel efficacy.

• AE: Clopidogrel has a better SE profile than Ticlopidine

  • Neutropenia

  • Thrombotic Thrombocytopenic Purpura (TTP)

  • Bleeding (low)

  • Ticlopidine - leukopenia is more frequent

What is the MOA, AE, and reversal for Direct thrombin inhibitors?

• MOA: dabigatran, argatroban, bivalirudin

  • Directly inhibit thrombin (factor IIa) → prevent conversion of fibrinogen → fibrin.

• AE: Bleeding

• Reversal agents:

  • Idarucizumab IV

What is the MOA, AE, monitoring, and reversal for Direct thrombin inhibitors?

• MOA: Dipyridamole and cilostazol

  • PDE inhibitors and vasodilators with antiplatelet effects.

• AE:

  • Bleeding

  • Headache

  • Diarrhea

What is the reversal for heparin/LMWH

Protamine (only partially reverses enoxaparin)

How do the sympathetic, parasympathetic, and somatic nervous systems differ in their control of pupil size?

• Sympathetic (ANS): Stimulates the dilator pupillae muscle → pupil dilation (mydriasis).

• Parasympathetic (ANS): Stimulates the sphincter pupillae muscle → pupil constriction (miosis).

• Somatic nervous system: Does not control pupil size.

  • Efferent fibers: Control voluntary skeletal muscle contraction.

  • Afferent fibers: Carry sensory information to the CNS.

Describe the process of an action potential

• Resting: -70mV

  • Voltage-gated Na and K channels are closed

• Stimulus → Threshold potential: -55mV

  • Excitatory and inhibitory inputs are summed at the axon hillock (decision-making location in the axon with a lot of Na channels)

  • Excitatory input depolarizes the membrane, making it less negative, while inhibitory input hyperpolarizes it.

  • If the net input depolarizes the membrane to −55 mV, the neuron reaches threshold and fires an action potential

  • At -55, voltage-gated Na channels open → further depolarization 

• Peak (+30mV) 

  • Na channels inactivate

  • K channels open → K moves out of the neuron, causing repolarization of the neuron

• Hyperpolarization

  • K channels stay open slightly longer than needed = more negative resting potential

• Return to resting potential

  • K channels close → membrane stabilized around =70mV

What is the difference between adaptive and maladaptive neural plasticity?

• Adaptive

  • Rewiring neuronal circuits can be useful in neuronal connections (learning and memory)

    • Repeated activity between neurons can strengthen their synaptic connection.

      • “neurons that fire together, wire together.”

    • Strengthening can involve:

      •  Insertion of additional AMPA receptors into the postsynaptic membrane 

      • Changes in AMPA receptor conductance 

      • Changes in the amount of neurotransmitter released 

      • Structural changes at the synapse (pre- and postganglionic closer together)

• Maladaptive

  • The same rewiring can also produce abnormal or harmful connections (depression, PTSD, addiction, anxiety, phantom limb pain, etc.)

What is the effect of CNS drugs on plasticity (acute vs chronic)?

• Acute: 

  • Alter receptors, ion channels, neurotransmitter synthesis/degradation, or neurotransmitter transport

• Chronic:

  • Longer-term remodeling helps explain why some CNS medications have a lag between their immediate molecular effects and their therapeutic effects

What are the main receptors involved in synaptic plasticity? What is the process involved?

• Primary receptors:

  • AMPA receptor

    • When activated, it opens and causes Na influx into the postsynaptic cleft

  • NMDA receptor

    • Normally, this channel is blocked by Mg

1) Repeated, high frequency of stimulus → glutamate release → activation of AMPA receptors

2) When activated, causes Na influx + postsynaptic depolarization

3) Postsynaptic depolarization relieves the block of Mg on NMDA receptors → influx of Ca into postsynaptic cleft

4) Calcium influx signals and promotes trafficking and insertion of additional AMPA receptors on the postsynaptic membrane

5) More AMPA receptors lead to:

• Changes in the amount of neurotransmitter released from presynaptic neuron

• Changes in distance of the pre- and postsynaptic clefts

• Changes in strength of AMPA conductance → increased depolarization + AP firing in post-synaptic cleft.

Describe the process of synaptic transmission, including fast vs. slow signaling and action potential generation.

• 1. Presynaptic neurotransmitter release:

  • AP reaches axon terminal → voltage-gated Ca²⁺ channels open → Ca²⁺ influx → vesicle fusion → neurotransmitter release into synaptic cleft.

• 2. Postsynaptic signaling:

  • Fast (LGIC): Neurotransmitter directly opens ion channels.

    • Excitatory (AMPA): Cation influx → depolarization → ↑ likelihood of AP.

    • Inhibitory (GABA-A): Cl⁻ influx → hyperpolarization → ↓ likelihood of AP.

  • Slow (GPCR): Neurotransmitter activates G-proteins → second messenger signaling.

• 3. Action potential generation:

  • Excitatory and inhibitory signals summate at the axon hillock.

  • If membrane potential reaches threshold (~−55 mV), voltage-gated Na⁺ channels open → rapid depolarization → AP fires.

What causes SSRI/SNRI discontinuation syndrome, what are its symptoms (+onset/duration), and how can it be prevented or managed?

• Cause: Abrupt discontinuation or missed doses, especially with short half-life antidepressants.

  • Risk (highest → lowest): Venlafaxine, paroxetine, fluvoxamine > duloxetine, sertraline, citalopram, escitalopram >>> fluoxetine.

• Symptoms (FINISH):

  • F – Flu-like symptoms (fatigue, chills, muscle aches)

  • I – Insomnia (vivid dreams, sleep disturbances)

  • N – Nausea (sometimes accompanied by vomiting or diarrhea)

  • I – Imbalance (dizziness, vertigo, lightheadedness)

  • S – Sensory disturbances ("brain zaps," burning, tingling, or electric-shock sensations)

  • H – Hyperarousal (anxiety, agitation, irritability → more sexually active??)

  • Other: Crying spells, suicidal ideation.

• Onset: 48–72 hours after discontinuation.

• Duration: Typically 3–7 days.

• Prevention/management:

  • Avoid missed doses and abrupt discontinuation.

  • Gradually taper over weeks to months (e.g., 50% dose reduction every 2–4 weeks).

  • Consider switching to fluoxetine (Prozac) before tapering due to its long half-life and active metabolite (norfluoxetine).

What causes serotonin syndrome, what are its symptoms, and how is it treated?

• Cause: Excessive serotonergic activity, often from combining serotonin-enhancing drugs.

  • Opioids: Meperidine, fentanyl, methadone, tramadol

  • Stimulants/psychedelics: MDMA, LSD

  • Other: SSRIs, SNRIs, MAOIs, and other serotonergic drugs

• Symptoms (triad):

  • Cognitive: Confusion, agitation, hallucinations, hypomania, coma

  • Autonomic: Diaphoresis, fever, HTN, tachycardia, shivering, nausea

  • Neuromuscular: Tremor, hyperreflexia, clonus, muscle twitching

• Treatment:

  1. Immediately discontinue serotonergic medications.

  2. Supportive care (IV fluids, cooling, monitoring).

  3. Benzodiazepines for agitation and muscle activity.

  4. Cyproheptadine (5-HT2A antagonist) for persistent or significant symptoms.

What causes MAOI-induced hypertensive crises, and which drug/food interactions can precipitate them?

• Cause: Excessive norepinephrine (NE) activity → increased α1-adrenergic stimulation → vasoconstriction → severe hypertension.

• Precipitating interactions:

  • Tyramine-rich foods: Fermented/aged foods contain tyramine, which is normally metabolized by intestinal MAO-A. MAO inhibition → ↑ tyramine absorption → ↑ NE release.

  • Sympathomimetics: Pseudoephedrine, phenylephrine, epinephrine → ↑ adrenergic stimulation.

  • Stimulants: Cocaine, methamphetamine → ↑ synaptic NE.

• Prevention: Avoid tyramine-rich foods and interacting sympathomimetic/stimulant drugs while taking MAOIs.

What is the biosynthesis and metabolism of serotonin?

• Biosynthesis:

  • Tryptophan (trp) --(Tryptophan hydroxylase and Aromatic amino acid decarboxylase)→  Serotonin (5HT) 

• Metabolism:

  • Serotonin (5HT) --(Monoamine oxidase and Aldehyde dehydrogenase)→ 5-Hydroxy indole acetic acid (HIAA)

What is the biosynthesis and metabolism of NE?

• Biosynthesis:

  • Tyrosine --(Tyrosine hydroxylase)→ L-dopa 

  • L-dopa --(Aromatic amino acid decarboxylase)→ Dopamine (DA)

  • Dopamine --(Dopamine B-hydroxylase)→ Norepinephrine

• Metabolism:

  • Dopamine AND Norepinephrine are metabolized by 

    • Monoamine oxidase (MAO)

    • Aldehyde dehydrogenase

    • Catechol-O-Methyl transferase (COMT)

What is the monoamine theory of depression, what is its major limitation, and what are the alternative theories?

• Monoamine theory: Depression results from deficient serotonin (5-HT) and/or norepinephrine (NE) in cortical and limbic brain regions.

  • Limitation: Antidepressants increase 5-HT/NE immediately, but mood improvement takes 1–2 weeks to begin and 4–6 weeks for fuller effects.

• Alternative theories:

  • 1) Neuroreceptor theory: Abnormalities in monoamine receptor number, sensitivity, or function contribute to depression.

  • 2) Neuroendocrine theory: Dysregulation of hormonal stress-response systems (e.g., HPA axis) contributes to depression.

  • 3) Network theory: Depression involves impaired neuronal circuitry and information processing.

    • Acute antidepressant effects alter synaptic transmission.

    • Chronic changes modify receptor levels, location, and sensitivity (lag phase).

    • Neural remodeling improves information processing and mood over time.

What is the diagnostic criteria for Major depressive disorder (MDD)?

• DSM5 - 5 of the following symptoms must be present >2 weeks (one must be from bolded)

  • Depressed mood

  • Loss of pleasure or interest (anhedonia)

  • Change in appetite

  • Change in sleep patterns

  • Loss of energy

  • Hopelessness, worthlessness, inappropriate guilt

  • Diminished ability to think or concentrate 

  • Psychomotor agitation or retardation

  • Recurrent thoughts of death or suicide

What are the subtypes, risk factors, and natural course of major depressive disorder (MDD)?

• Subtypes

  • Seasonal pattern (SAD)

  • Pregnancy/postpartum

  • Atypical

  • Severe/melancholic

  • Anergic/amotivational

  • Anxious/irritable

• Risk factors for depression

  • Women > men (typically because of menarche + after menopause) → comparable until then

  • Family history/genetics, medical conditions, medications, environmental stressors

• Natural course of depressive illness

  • Mean age of onset: ~40 years

  • Recurrence: high, >50%

  • Between episodes: about 80% have a full recovery

  • Episodes may show a seasonal pattern

What is the proposed pathophysiology of major depressive disorder (MDD)?

• Decrease neurotransmitters:

  • 5HT, NE, DA

• Increased inflammatory response due to increased cortisol levels (stress):

  • HPA axis dysfunction: increased CRF

  • Inflammatory cytokines: increased IL-1, IL-6, TNF

    • Leads to things like:

      • Change in sleep, appetite, energy

      • Depression, anhedonia, anxiety, concentration

What are the major risk factors for suicide, and how should suicide risk be assessed?

• Risk factors:

  • Older male, widowed, or living alone

  • Mood disorders (bipolar > unipolar depression)

  • Serious illness (self or loved one)

  • Job loss or loss of self-worth

  • Alcohol/substance abuse

  • History of impulsivity

• Suicide risk assessment:

  • Ideation: Current suicidal thoughts? When was the last occurrence?

  • Plan: Specific plan, intent, or preparation?

  • Means: Access to methods of suicide?

  • Capability: Ability to carry out the plan?

  • Impulsivity: History of impulsive behavior?

  • Substance use: Alcohol or drug use?

  • Safety: What would they do if suicidal thoughts returned or worsened?

What are the treatment options for MDD, and how does treatment selection differ by severity of diagnosis?

• 1) Psychotherapy

  • Cognitive Behavioral Therapy (CBT)

  • Dialectic Behavioral Therapy (DBT)

  • Interpersonal Psychotherapy (IPT)

    • Onset: 8-10 weeks

• 2) Pharmacotherapy - faster than psychotherapy, but not as long-term an impact

  • Selective Serotonin Reuptake Inhibitors (SSRI)

  • Serotonin Norepinephrine Reuptake Inhibitors (SNRI)

  • Norepinephrine Reuptake Inhibitors (NRI)

  • Others: mirtazapine, atypical antipsychotics, tricyclics (TCA), MAO inhibitors (MAOI), vortioxetine, ketamine

    • All antidepressants are created equal:

      • Onset: 1-2 weeks and 4-6 weeks for maximum improvement

• 3) Lifestyle modifications

  • Exercise

  • Mindfulness based stress reduction

  • Integrative medicines (St John's Wort, Omega-3 FA, methylfolate, SAMe)

  • Electroconvulsive therapy (ECT) - most effective

  • Repetitive transcranial magnetic stimulation (rTMS)

  • Deep brain stimulation

• When to use what:

  • Mild depression/Moderate depression: either psychotherapy OR pharmacotherapy

  • Severe depression: psychotherapy AND pharmacotherapy

Which antidepressants inhibit CYP2D6 and CYP3A4, and what are the clinically relevant drug interactions?

• CYP2D6 inhibition:

  • Strong: Fluoxetine, paroxetine, bupropion

  • Moderate: Duloxetine

  • Weak/minimal: Sertraline, citalopram, escitalopram

  • Substrates:

    • β-blockers, TCAs, opioids (codeine, tramadol, hydrocodone, oxycodone), Sulfonylureas, Metoclopramide

  • Clinical significance: Inhibition → ↑ concentrations of active parent drugs or ↓ activation of opioid prodrugs (especially codeine/tramadol) → reduced analgesia.

  • Alternatives: Morphine, hydromorphone, oxymorphone, fentanyl, buprenorphine, methadone.

• CYP3A4 inhibition (lecture ranking):

  • Norfluoxetine >> fluoxetine, paroxetine, sertraline, citalopram, escitalopram

  • Substrates:

    • CCBs, estrogens, corticosteroids, statins (atorvastatin, lovastatin, simvastatin), protease inhibitors, alprazolam, triazolam, buspirone, sildenafil, Z-drugs.

  • Clinical significance: Inhibition → ↑ substrate concentrations → increased adverse effects/toxicity.

What is the goal of MDD treatment? How should antidepressant therapy for MDD be adjusted based on response (no, partial response), monitored, and continued after remission (maintained)?

• Goal: Optimize monotherapy (dose + duration) before augmentation.

• Treatment response:

  • 1–2 weeks: Initial improvement

  • 4–6 weeks: Fuller therapeutic response

  • Minimal/no response: Switch to another SSRI or antidepressant class (SNRI, NDRI, mirtazapine).

  • Partial response: Consider augmentation with -

    • Bupropion, buspirone

    • Atypical antipsychotics

    • T3 (liothyronine), lithium

    • Other: Methylfolate, omega-3 fatty acids, DHEA

• Monitoring:

  • PHQ-9: Routinely assess symptom improvement

    • Response: ≥50% reduction in score

    • Remission (goal): Virtual absence of symptoms (PHQ-9 <5)

      • Anything above 10 is moderate below 9 = mild

  • Monitor adverse effects, safety, and DDIs.

• Maintenance:

  • Continue antidepressants for ≥6 months after remission.

  • Consider indefinite treatment for ≥3 depressive episodes.

  • Gradually taper SSRIs/SNRIs to prevent discontinuation syndrome (e.g., decrease dose by 50% every 2–4 weeks, individualized).

How is depression treated during pregnancy and lactation?

• Mild antepartum depression: Psychotherapy preferred.

  • Alternatives: UV light therapy, omega-3 fatty acids.

• Moderate–severe: Pharmacotherapy ± psychotherapy.

  • SSRIs preferred (sertraline): Low fetal exposure based on umbilical vein-to-maternal serum concentration.

  • Historical FDA categories: Most SSRIs/SNRIs/NDRIs category C; paroxetine category D.

  • ECT: Considered safe during pregnancy when clinically indicated.

• Lactation: Antidepressants are not specifically FDA-approved for lactation, but many are compatible with breastfeeding.

Which antidepressants are used or FDA-approved in pediatric patients?

• MDD:

  • Fluoxetine: FDA-approved for ages ≥8.

  • Escitalopram: FDA-approved for ages ≥12.

• OCD: Fluoxetine, sertraline, fluvoxamine, clomipramine.

• Bupropion: Off-label for pediatric MDD and ADHD.

What factors influence antidepressant selection in geriatric patients, and which medications are commonly considered?

• Selection factors: Medical comorbidities, polypharmacy, potential DDIs, and adverse effects.

• Common options:

  • SSRIs: Often first-line.

  • Bupropion: May be preferred for fatigue, low energy, or sexual dysfunction.

  • Mirtazapine: May be preferred for insomnia, poor appetite, or weight loss.

• Start at lower doses and titrate cautiously due to increased sensitivity to adverse effects.

Which antidepressant is preferred for patients with chronic or neuropathic pain?

SNRI (duloxetine, venlafaxine) due to increased 5-HT and NE signaling involved in pain modulation.

Which antidepressant is preferred for atypical depression (hypersomnia, hyperphagia, anergia)?

NDRI (bupropion) due to its activating effects on NE and DA.

Which antidepressants are preferred for patients with cognitive symptoms or inattention?

NDRI (bupropion) or vortioxetine (Trintellix).

How should SSRI-induced sexual dysfunction be managed?

• Augment: Add bupropion (NDRI).

• Switch: Taper SSRI and switch to bupropion, mirtazapine (NaSSA), or vortioxetine (Trintellix).

Which antidepressants are preferred based on residual depressive symptoms?

• Anxious/irritable: SSRI (5-HT)

• Anergic/amotivational: NDRI (NE/DA)

• Severe/melancholic: SNRI or TCA (5-HT + NE)

Which antidepressants are preferred or avoided in patients with cardiovascular disease?

• Preferred: SSRIs

• Avoid/caution: TCAs due to increased risk of cardiac events.

• Monitor: SSRI interactions involving CYP2D6 and CYP3A4.

Which antidepressants should be avoided in patients with hypertension and tachycardia?

SNRIs and NDRIs (bupropion) due to their potential to increase BP and HR.

What antidepressant considerations are important in patients with diabetes (weight, DDIs, neuropathic pain)?

• Avoid/caution: TCAs, mirtazapine, paroxetine (also maybe citalopram + escitalopram) due to weight gain.

• DDIs: Fluoxetine and fluvoxamine may inhibit sulfonylurea metabolism → hypoglycemia risk.

• Neuropathic pain: SNRIs may provide additional benefit.

Which antidepressants may benefit patients with breast cancer or menopausal symptoms?

SSRIs or SNRIs may reduce vasomotor symptoms (hot flashes).

Which antidepressants should be used cautiously in patients with peptic ulcer disease or concurrent NSAID use?

SSRIs and SNRIs due to increased GI bleeding risk, especially when combined with NSAIDs.

What antidepressants may be considered for patients experiencing weight gain with paroxetine?

Switch to another SSRI with less weight gain potential, such as fluoxetine or sertraline.

How do different brain regions and neurotransmitters interact to regulate sleep and wakefulness?

• Suprachiasmatic nucleus (SCN): Internal circadian clock → projects to dorsomedial hypothalamus (DMH).

• DMH projections:

  • Ventrolateral preoptic area (VLPO): Promotes sleep by releasing GABA and galanin to inhibit wake-promoting nuclei.

  • Lateral hypothalamic area (LHA) (orexin/hypocretin neurons): Promotes and stabilizes wakefulness.

    • Orexin neurons stimulate wake-promoting nuclei that release:

      • NE: Locus coeruleus

      • 5-HT: Raphe nuclei

      • Histamine: Tuberomammillary nucleus

      • ACh: Brainstem/basal forebrain nuclei

        • Orexin stabilizes sleep-awake switch, preventing sudden transitions between sleep and wakefulness.

    • These neuromodulators promote cortical arousal and wakefulness.

  • Paraventricular hypothalamus (PVH): Regulates corticosteroid release.

What is memory consolidation, and how does sleep before and after learning affect memory formation?

• Memory consolidation: The process of stabilizing newly learned information into long-term memory.

• Awake (encoding):

  • Sensory information is rapidly encoded in the hippocampus (rapid plasticity).

• Sleep (consolidation):

  • Recently encoded information is replayed.

  • Memories are transferred/integrated from the hippocampus into appropriate cortical networks (slower plasticity).

  • Strengthens long-term memory storage.

• Sleep before learning:

  • Prepares the brain to encode new information.

  • One night of sleep deprivation → ~40% reduction in new memory formation.

• Sleep after learning:

  • Promotes memory consolidation and long-term retention.

  • Improves insight, inference, and integration of learned information.

How do sleep patterns change with age, and how does aging affect memory consolidation?

• General trend: Aging → ↓ total sleep duration, ↓ deep sleep (NREM slow-wave sleep), ↑ sleep fragmentation.

• Children: More total sleep and deep sleep.

• Young adults: Less total sleep and deep sleep, especially later in the night.

• Elderly: Less total sleep, very little deep sleep, and more frequent awakenings.

• Impact on memory:

  • Aging → medial prefrontal cortex (mPFC) atrophy → disrupted NREM slow-wave activity (SWA).

  • ↓ SWA → impaired hippocampal-dependent memory consolidation → reduced long-term memory retention.

What are the characteristics of REM vs. NREM sleep, and what happens when each stage is disrupted?

• REM sleep:

  • Similar to waking state:

    • Increase of:

      • Neuronal activity

      • Metabolic rate

      • BP/HR 

  • There is loss of muscle tone (atonia) despite high brain activity

    • Disruption of REMS → loss of muscle tone (paralysis or REM sleep behavior disorder, depending on the dysfunction)

• NREM sleep:

  • Decrease of:

    • Neuronal activity

    • Metabolic rate

    • BP/HR 

  • Stage 1 (N1): Lightest sleep.

  • Stage 2 (N2): Light sleep.

    • Disruption → fragmented sleep and frequent awakenings.

  • Stages 3–4 (deep NREM): Slow-wave sleep (SWA).

    • Disruption → impaired memory consolidation, learning, and retention.

What are the four functions and purpose to why we sleep?

• 1) Conserve metabolic energy

  • During NREM decrease of metabolic processes = save energy

• 2) Restore our body and brain

  • Sleep provides time for physical and neural restoration 

  • Prolonged total sleep deprivation (studied in rats):

    • Failed to regulate core body temp

    • Developed infections

    • Eventually died after several weeks

• 3) Organize learned information → see above

• 4) Promote maturation of neurons and mental health

  • One observation consistent with a developmental role is that sleep duration is highest early in life and progressively decreases across the lifespan.

What is the structure of GABA-A receptors, where do drugs bind, and how do α-subunits determine their pharmacologic effects?

• Structure:

  • Ligand gated chloride channel with 5 subunits:2 alpha, 2 beta, plus 1 gamma, delta, epsilon, theta, or pi.

    • GABA binds to receptor and opens Cl-pore = hyperpolarizes the neuron decreasing the neuronal excitability and likelihood of an action potential → sedating + inhibitory effect

• Binding sites:

  • α/β interface: GABA, gaboxadol.

  • α/γ interface: Benzodiazepines (BZDs), Z-drugs → ↑ frequency of Cl⁻ channel opening.

  • Alcohol: Enhances GABA-A-mediated inhibition → sedation.

How do GABA-A receptor α-subunits determine pharmacologic effects and drug selectivity?

• α1 (~60%): Sedation, amnesia, anticonvulsant effects.

• α2 (15–20%): Anxiolysis, muscle relaxation.

• α3 (10–15%): Muscle relaxation (higher doses).

• α5 (less than 5%): Muscle relaxation.

• α4, α6 (less than 5% each): Insensitive to BZDs and Z-drugs.

Drug selectivity:

• BZDs: Bind α1, α2, α3, α5-containing receptors.

• Z-drugs: Preferentially bind α1-containing receptors → primarily hypnotic/sedative effects.

How is GABA synthesized and metabolized through the GABA shunt?

• Biosynthesis:

  • Glutamate → GABA + CO₂

  • Enzyme: Glutamate decarboxylase (GAD)

• Metabolism (GABA shunt):

  1. GABA transaminase (GABA-T): Transfers the amino group from GABA to α-ketoglutarate → succinic semialdehyde + glutamate.

  2. Succinic semialdehyde dehydrogenase (SSADH): Converts succinic semialdehyde → succinate → re-enters TCA cycle.

How are benzodiazepines metabolized, and which are preferred in elderly patients or those with liver impairment?

• Phase 1 (CYP3A4, CYP2C19):

  • Oxidative metabolism → may produce active metabolites.

  • Example: Diazepam

  • Reduced in elderly patients and liver impairment → ↑ accumulation/toxicity.

• Phase 2 (glucuronidation):

  • Produces inactive metabolites.

  • LOT: Lorazepam, Oxazepam, Temazepam.

  • Relatively preserved in aging and liver impairment.

Preferred: LOT benzodiazepines due to reduced risk of accumulation.

How do tolerance and dependence develop with benzodiazepines and Z-drugs?

• Tolerance: Requires higher or more frequent doses to achieve the same effect.

  • Neuroadaptation begins within 1–2 weeks.

  • Tolerance to sedation may develop within 2–4 weeks.

• Dependence: Brain adapts to drug presence and requires continued exposure to maintain balance.

• MOA:

  • Chronic GABA-A enhancement → compensatory neuronal adaptations to restore excitatory/inhibitory balance.

• Risk: Prolonged use increases the risk of tolerance and physical dependence.

What causes benzodiazepine/Z-drug withdrawal, what are its symptoms, and what increases withdrawal severity?

• Cause: Abrupt discontinuation after physical dependence → loss of GABAergic inhibition before neuronal readaptation.

• Risk factors:

  • Higher doses

  • Shorter half-life

  • Prolonged continuous use (>2 months)

• Symptoms:

  • Mild–moderate: Anxiety, insomnia, restlessness, sweating, ↑ HR/BP.

  • Severe: Seizures, hallucinations, delusions.

• Prevention: Gradual dose tapering rather than abrupt discontinuation.

What is the antidote for benzodiazepine/Z-drug overdose, and what are its mechanisms, considerations, and risks?

• Flumazenil (Anexate)

  • MOA: Competitive antagonist at the benzodiazepine binding site on GABA-A receptors.

    • Blocks benzodiazepine/Z-drug enhancement of GABA-mediated Cl⁻ conductance.

  • Half-life: ~30–60 minutes.

    • Repeat dosing may be necessary due to resedation.

  • Adverse effects: Agitation, anxiety, seizures (especially in dependent patients or mixed overdoses).

What are the primary neurotransmitters involved in anxiety, and what are their roles?

• GABA:

  • Primary inhibitory neurotransmitter → ↓ neuronal excitability and anxiety.

    • Dysregulation → increased anxiety.

• Serotonin (5-HT):

  • Modulates mood, anxiety, and emotional responses.

• Norepinephrine (NE):

  • Promotes arousal, vigilance, and sympathetic fight-or-flight responses.

What is insomnia, and what are its types, risk factors, and consequences?

Difficulty initiating or maintaining sleep associated with daytime impairment.

• Types:

  • Sleep-onset: Difficulty falling asleep.

  • Sleep-maintenance: Difficulty staying asleep or returning to sleep.

  • Primary: Not attributable to another condition.

  • Secondary: Associated with medical/psychiatric conditions, medications, or substances.

• Risk factors: Stress, poor sleep habits, medical conditions, caffeine, substance use/withdrawal, and medications (steroids, stimulants, decongestants, SABAs).

• Comorbidities: Depression, anxiety, chronic pain, other sleep disorders.

• Consequences: Fatigue, impaired concentration, mood disturbances, reduced quality of life.

What is the 3P model of insomnia?

• Predisposing factors: Baseline traits that increase vulnerability to insomnia.

• Precipitating factors: Events or conditions that trigger insomnia.

• Perpetuating factors: Behaviors or circumstances that maintain insomnia and contribute to its transition from acute to chronic.

What is the first-line treatment for chronic insomnia, and what are the components of it? Lifestyle changes?

• Cognitive behavioral therapy for insomnia (CBT-I).

  • ~70–80% effective; typically delivered over 6–8 weeks.

• Components:

  • Stimulus control: Associate bed with sleep; maintain consistent wake times.

  • Sleep restriction: Limit time in bed to approximate actual sleep time.

  • Cognitive restructuring: Address unhelpful beliefs, worry, and anxiety about sleep.

• Sleep hygiene: Avoid caffeine, alcohol, nicotine, long naps, and screens before bed; maintain a cool, dark bedroom and regular exercise.

  • Used alongside CBT-I, not as a standalone treatment.

  • Weight loss talk (see BMI + PMH)

What medications are used for chronic insomnia, and how are they selected based on sleep-onset versus sleep-maintenance symptoms?

Drug class	Clinical use	Key considerations
BZDs/Z-drugs	Sleep onset and/or maintenance	Enhance GABA-A; tolerance, dependence, CNS impairment
DORAs (orexin) Belsomra (suvorexant) DayVigo (lemborexant) Quviviq (daridorexant)	Sleep onset + maintenance	Block orexin; lower dependence risk, generally preserve sleep architecture
Ramelteon (melatonin synthetic)	Sleep onset	Melatonin receptor agonist; minimal dependence risk
Low-dose doxepin (TCA)	Sleep maintenance	H1 antagonism; low dependence risk

Consider pharmacotherapy alongside CBT-I when needed.

What other medications are mentioned for Insomnia but are not generally considered? Why?

• First-generation antihistamines:

  • Anticholinergic effects, next-day sedation.

  • Tolerance after extended use (1-2 weeks)

• TCAs

  • Tolerance after extended use (1-2 weeks)

• Trazodone:

  • Limited evidence for routine insomnia treatment; orthostatic hypotension.

• Antipsychotics (e.g., quetiapine):

  • Metabolic adverse effects, weight gain.

  • Generally avoid given many side effects

• Natural products:

  • Insufficient or inconsistent evidence.

• Gabapentinoids and other sedating medications:

  • Generally reserved for patients with another indication.