Neurology Test 2

PNS Efferents - Autonomic Nervous System

Describe the basic functional and structural organization of the autonomic nervous system.

Efferent division → Autonomic nervous system → Sympathetic & Parasympathetic

• Works on the internal environment

Preganglionic neuron: Synapses with the cell body of the postganglionic fiber in a ganglion outside the CNS

Postganglionic neuron: Sends axons that end on the effector organ

Effector organ: Organ affected by the NT (ex: Smooth muscle, cardiac muscle, intestine, etc.)

Differentiate sympathetic and parasympathetic anatomy, outflow, and neurotransmitters.

Parasympathetic:

• Most pre/postganglionic neurons pass uninterrupted, directly to the target organ. Specific innervation

Anatomy

Preganglionic neurons involved:

• Carry sensory & motor information (both directions)

Oculomotor nerve (III): Ciliary muscles, pupillary sphincter muscle of the eye (dilation/expansion of pupil)

Facial nerve (VII): Submandibular & sublingual salivary, lacrimal (tear duct) & nasal glands

Glossopharyngeal nerve (IX): Parotid glands

Vagus nerve (X): Carries 75% of preganglionic parasympathetic axons. Parasympathetic innervation to thoracic & abdominal region

Sacral spinal cord (S2-S4):

• Project via the pelvic nerves to pelvic ganglia located in the bladder, ureters, descending colon, rectum, and reproductive organs

Postganglionic neurons:

• In a ganglia near or with the walls of the effector organs

Sympathetic:

Two neuron chain: CNS → autonomic ganglion → effector organ

Dual innervation: Nearly all organs are impacted by both PsNS and SNS

Anatomy

Preganglionic neurons:

• Bilateral, in spinal segments T-1 to L-2

• Splachchnic nerves to celiac, hypogastric

• Ganglia is typically outside of the target

Postganglionic neurons:

Sympathetic chain ganglia:

• Innervates smooth muscle of blood vessels and piloerector muscles, sweat glands

• Innervate cardiac muscle, smooth muscle of bronchi and iris

• 8& of nerve fibers within spinal nerves

Prevertebral ganglia:

• Celiac ganglion: Ureter, stomach, adrenal, kidney

• Hypogastric plexus: Bladder

Adrenal Medulla

Key area for projection of epinephrine and norepinephrine

• Allows E and NE to stimulate structures of the body that are not innervated by direct sympathetic fibers

  • They can reach very distally because they are going through the blood

Chromaffin cells: Synthesis of epinephrine

Understand basic neurotransmission for the ANS and be able to differentiate neurotransmission in the parasympathetic versus sympathetic divisions.

Autonomic neurotransmission

Pregnaglionic fibers: ACh

Parasympathetic - Postganglionic fibers: ACh

Sympathetic - Postganglionic fibers: Most are adrenergic (NE/E), some are ACh

Adrenergic Receptors (GPCR)

Ligand: Norepinephrine or epinephrine

• Excitatory or inhibitory depending on the receptor and system

Activity termination:

1. Reuptake by the neuron that released it

2. Enzymatic inactivation

   1. COMMENT

   2. MAO

Define the autonomic nervous system's effects on specific effector organs. Differentiate parasympathetic versus sympathetic effects.

Understand the idea of an autonomic reflex and what functions utilize a reflex.

Autonomic reflexes allow the ANS to maintain visceral homeostasis

Reflex pathway

Receptor → Sensory neuron → Integrating center → Motor neuron → Effector → Response

Mass discharge (Adrenaline Rush)

• The sympathetic nervous system discharges simultaneously as a complete unit

Initiated by: Hypothalamus in response to fear, severe pain, or rage

What are CNS control centers for the ANS?

• Cerebrum/limbic system: Thoughts/emotions can influence ANS function via the hypothalamus

• Hypothalamus: ANS Integration Center

  • Nuclei monitor homeostatic things

  • Directly initiates autonomic responses through direct projections onto preganglionic neurons.

    • This is done to return to a homeostatic state or go into fight/flight mode

  • Regulates autonomic responses through projections to autonomic centers in the brain stem

• Brain stem: ANS reflex center

• Spinal cord: ANS reflex center

  • Urination, defecation, reproductive behaviors

Parasympathetic vs Sympathetic Summary

PNS Efferents: Motor Control

Define and differentiate the 3 types of movement

Voluntary (Cortex, cerebellum, basal ganglia)

• Cerebral cortex: Motor control

  1. Premotor cortex: Mental planning & “staging” of movement

     1. Anterior forms image → posterior translates

  2. Supplemental motor cortex: Integrates movement, “background movements”

  3. Primary motor cortex: Execution of movement

     1. Directing motor neurons to send a contraction message

     2. Primary motor cortex → motor neurons

  • Basal Ganglia

    1. Nuclei of the basal ganglia:

       1. Striatum: Caudate + putamen

       2. Globus pallidus

       3. Substantia nigra

       4. Subthalamic nucleus

  • Cerebellum

  • Red nucleus: Alternative tract to the spinal cord, allows for movement without the primary motor cortex.

    1. Accessory route

    2. Closely associated with cerebellar function

    3. Controls: distal motor groups, upper limbs (things more distal)

  • Reticular formation

  • Ponds

  • Thalamus

Involuntary (spinal cord, reflexes)

These motions happen without a real conscious awareness

1. Spinal cord

   1. The ventral horn is involved

Rhythmic motor patterns

Know the 4 major CNS regions involved in the integration of motor function

1. Cerebellum

2. Cerebral cortex

3. Basal ganglia

4. Thalamus

Differentiate the role of CNS regions involved in voluntary movement

Motor cortices: Where is the motor plan formed, translated, or executed?

• Planning: Prefrontal cortex

  • Translation: Premotor/supplemental cortex

  • Execution: Primary motor cortex → Spinal cord

Understand the basic anatomy and role of the cerebellum in motor control

• Cerebellum: Controls timing and coordination of movement (Comparator)

  1. Evaluate what you intend to do & what you do, if these don’t align → cerebellum adjusts

  2. Stimulate the cerebellum? : Nothing happens, but without it, there is a major impact

Differentiate the neuroanatomy and contribution of the Basal Ganglia to motor control.

Direct basal ganglia pathway

1. Input: Glutamatergic from the cortex

2. Result: Increase activity (enable movement)

3. Receptor involved: D1

Indirect basal ganglia pathway

1. Input: Dopamine from SNc

2. Result: Decrease activity (inhibit movement)

3. Receptor involved: D2

Define the corticospinal tract and differentiate from DCML, ALST tracts

Corticospinal tract: Direct pathway to the spinal cord

1. Controls: Speed and precision of fine motor control

2. Pathway: Cortex → spinal cord

3. Most fibers cross the medulla and synapse on interneurons in the spinal cord.

4. Cells: Betz cell (giant pyramidal cells)

   1. Responsible for direct connections

Red nucleus: Indirect pathway to the spinal cord

1. Cortex → red nucleus → reticular formation → spinal cord

Be able to identify symptoms of damage to the 3 motor brain regions

• Supplemental and premotor areas (hand skills): Motor apraxia

• Broca’s area: Base of premotor area

Cortical damage

Positive signs

1. Spasticity: Too much contraction

2. Exaggerated spinal reflexes

3. Babinski response

Negative signs

1. Hypotonia: Loss of muscle tone

2. Loss of sensation

3. Apraxia: Inability to carry out a skilled movement

4. Aphasia: Inability to produce words

Cerebellum damage

1. Ataxia: loss of coordination

2. Past pointing: Moving beyond the point of intention

3. Intention tremors: AS you're going to move, signals don’t align (ex: both extender and flexor contract)

4. Hypotonia: Loss of muscle tone

5. Failures of progression: Coordination error

Understand spinal cord anatomy for motor function

• Same as sensory system dermatomes

Myotomes

Cervical (C1-C8): Head neck, shoulders, parts of upper arms, and hands

Thoracic (T1-T12): Arms, hands, and trunk

Lumbar (L1-L5): Waist, thighs, legs, and part of feet

Sacral (S1-S5): Back of legs, buttocks, anus

Sacrococcygeal: Tailbone

White vs Grey matter

White: Tracts

Grey: Unmyelinated neurons

• Cell bodies of neurons (interneurons, lower motor neurons)

Types of Cells

Interneurons: Grey matter integration

Motor neurons

1. Alpha motor neurons (A alpha): Causing contraction

   1. Large

   2. Branches to innervate extrafusal muscle fibers

   3. Alpha motor neuron + extrafusal fibers = motor unit

2. Gamma motor neurons (A gamma): Helping sensitivity and sensory receptors

   1. Small & fewer than alpha

   2. Innervates intrafusal muscle fibers

   3. Controls muscle tone (for sensitivity)

Interconnections between motor neurons and interneurons are responsible for most of the integrative functions of the spinal cord.

Know muscle essentials for motor control.

1. Voluntary movement: Information flow

   1. Sensory cortex (detects)

   2. Sensory association cortex (integrate it)

   3. The prefrontal cortex (plan)

   4. Premotor/supplemental cortex (image/translate it)

   5. Primary motor cortex (execution center)

   6. Spinal cord (act)

Skeletal muscle basics

Tendon: Muscle-bone connection

Ligament: Bone-bone connection

Flexion: Contract a flexor muscle → closes joint angle (ex: biceps)

Extension: Contract an extensor muscle → opens a joint angle (ex: tricep)

Extrafusal muscle fibers: Outer muscle layer (what we think of when we think “muscle”)

Intrafusal muscle fibers: Inner muscle layer

• Does not contract

• Helps form receptors

• Controls sensitivity

Differentiate the muscle sensory receptors.

Structure and function (what each one senses)

Muscle spindle

• Detects stretch and speed of stretch

• Innervated by: Gamma motor neuron

  • Comes in & winds around the intrafusal muscle fibers

  • Intrafusal muscle fibers have no actin or myosin → it cannot contract

• Attached to extrafusal muscle fiber at each end

• Sensory receptor detecting stretch of the muscle & sends it to CNS

• Proprioception

Golgi Tendon organ

• Tension

Connections to the spinal cord and/or CNS

Muscle spindle

• Innervated by gamma motor neuron

  • Wraps around intrafusal muscle fibers (no contraction here)

• Attached to extrafusal muscle fiber

Golgi Tendon organ

• Encapsulated at the end of muscle fibers as they attach to tendon

• Synpase location: Interneuron

Role in reflexes

Muscle spindle

Monosynaptic stretch reflex: One synapse

Sensation: Muscle stretch

Golgi Tendon organ

Lengthening (relaxation) reflex that is protective

• Entirely inhibitory

• Equalizes contracting force

  • Some fibers have more tension than others

Have a general knowledge of the 3 reflexes circuits presented, and especially the role of each in movement.

Reflex Arc

1. Sensory neuron: Detects stimulus (muscle stretch)

2. Interneurons - (most often) can be excitatory or inhibitory

   1. Sometimes this bypasses

3. Motor neurons: Muscle contraction

Muscle Stretch Reflex

Components involved

Alpha motor neuron: Directs contraction

Sensory stimulus: Muscle spindle stretch

Synapse location: Directly on an alpha motor neuron

Mechanism

• Multiple circuits are involved

1. Stretch reflex circuit (monosynaptic)

   1. Working on “primary” muscle (ex: Quad)

   2. Splits in the spinal cord

      1. Continues circuit

      2. Synapses at reciprocal inhibition pathway

2. Reciprocal inhibition

   1. Working on the opposite muscle (ex: Hamstring)

Lateral inhibition circuit: Focuses the signal

Flexor withdrawal reflex: Pain reflex

Mechanism

1. Excitatory interneuron stimulates contraction

2. Inhibitory interneuron inhibits opposing muscle pair

3. Divergent interneuron sends info to the brain

   

   1. Crosses over & goes to the brain for pain recognition

Pain is synapsing on multiple interneurons

Crossed extensor reflex

Involves the compensation of the opposite limb to the flexor withdrawal reflex

• Ex: Step on something → lift foot → take a step back with the other foot

• Interneurons cross to the contralateral gray matter activate extensors and inhibit flexors

Delayed effect: Highlights the role of many interneurons

Skeletal Muscle Physiology

Differentiate skeletal muscle from cardiac and smooth

Skeletal muscle

Striation? Striated

Movement: Voluntary

Nucleus: Multiple nuclei in a single cell

Location: Attached to bones

Function: Movement of the body about the external environment

Cardiac muscle

Striation: Striated

Movement: Involuntary

Nucleus: Multiple nuclei in a single cell

Location: Wall of Heart

Function: Pumping blood out of the heart

Smooth muscle

Striation? Unstriated

Movement: Involuntary

Nucleus: Single nuclei per each cell

Location: Walls of hollow organs and tubes

Function: Movement of contents within hollow organs

Understand the key elements of the neuromuscular junction and how they drive muscle contraction

Neuromuscular junction: Where the terminal buttons of the one lower motor neuron synapse to the muscle fiber

• Motor unit

Neurotransmitter: ACh

What stops ACh?: Acetylcholinesterase

• Formation of the endplate potential

  • Always excitatory

• Initiation of an action potential

• Relationship to sarcolemma/transverse (T) tubules

Steps at a neuromuscular junction

1. AP comes down the axon and is propagated to the terminal

2. Action potential triggers the opening of voltage-gated Ca²⁺, Ca²⁺ flows in

3. Ca²⁺ triggers the release of ACh by exocytosis from a portion of the vesicles

4. ACh diffuses across and binds with nicotinic ACh receptors on the motor end plate of the muscle cell membrane

5. Binding of ACh to its receptor opens these nonspecific cation channels, leading to a relatively large movement of Na⁺ into the muscle cell and a small movement of K⁺ outward

6. The influx of Na⁺ results in a depolarization called an end-plate potential. Local current flow occurs between the depolarized end plate and the adjacent membrane

7. Local current flow opens voltage-gated Na⁺ channels in adjacent membrane

8. The resultant Na⁺ entry drives the potential to threshold, initiating an action potential, which is propagated through the muscle fiber

9. ACh is subsequently destroyed by acetylcholinesterase, an enzyme located on the motor end-plate membrane (blue dots), acetylcholinesterase terminates the muscle cell’s response

Know the muscle anatomy necessary for muscle contraction

Muscle → muscle fiber → myofibril → Dark A band & light I band

Sarcomere: The basic functional unit of muscle fiber (from Z line to Z line)

• Thick and thin filaments are coming together to cause the contraction of the muscle

Z line: thin filaments coming together

A band: thick filaments

I band: thin filaments

Titin filaments: Serves as scaffolding along with M-line proteins to stabilize the thick filaments as they attach to the Z disk

• Acts as an elastic spring to augment the muscle’s elasticity & helps the muscle recoil after a stretch

Thick filaments: Made up of myosin filaments

Thin filaments: Made up of actin filaments

• Tugs on the thick filaments when excited, which causes the contraction

Differentiate roles of myosin and actin (thick and thin filaments)

• Each thick filament is surrounded by 6 thin filaments

• Each thin filament is surrounded by 3 thick filaments

Myosin (thick filament)

Thick filaments are made up of numerous myosin molecules

Myosin heads:

1. Binds to active sites on the actin molecules to form cross-bridges

2. The hinge region can bend and straighten during contraction

3. ATPase enzymes break down ATP & release energy that is used to bend the hinge region of the myosin molecule during contraction.

Actin (thin filament)

Thin filaments are made up of numerous actin molecules held together by troponin and tropomyosin

Relaxed state

• No cross-bridge binding occurs

  • The active site is blocked

• The troponin-tropomyosin complex is blocking the active site

• Ca²⁺ is not present

Excited state

• Cross-bridge binding occurs

  • The active site is no longer blocked

• Ca²⁺ is being released (because the muscle fiber is excited)

• Ca²⁺ binds to the troponin-tropomyosin complex & exposes the active site

Contraction: Myosin (golf club) heads pull on the actin

Troponin

• There is one troponin bound to each tropomyosin

In the relaxed state:

• Troponin is blocking the active sites of the actin (which would bind to the myosin)

• Troponin is inactive

In the excited state:

• Troponin moves from blocking the active site of actin, thus myosin can bind

• Troponin is activated

  • Ca²⁺ binds to troponin, which pulls the complex aside & renders it active.

What is meant by sliding filament mechanism, cross bridge activity, and power stroke?

Sliding filament mechanism

Contraction is accomplished by thin filaments from the opposite sides of each sarcomere sliding closer together between the thick filaments.

• This shortens muscle length & causes tension.

Relaxed

H zone: Wide, wide banding power

I band: Wider

A band: Same width

Overall sarcomere: Wide

Contracted

H zone: Shorter

I band: Shorter

A band: Same width

Overall sarcomere: Shorter

Power stroke

Stroking motion pulls (bends) the thin filament toward the center of the sarcomere.

1. Active site on actin is exposed

2. Myosin head forms a cross-bridge with actin

3. Myosin head bends, and ADP and phosphate are released

4. A new molecule of ATP attaches to the myosin head, causing the cross-bridge to detach

5. ATP hydrolyzes to ADP + P, which returns the myosin to the “cocked” position

Cross-bridge activity

ATP Necessary

Presence of Ca²⁺, troponin changes shape

• All cross-bridge stroking is directed toward the center of the thick filament

• Simultaneous pulling inwards of all 6 thin filaments surrounding a thick filament is occurring

1. Binding: Myosin cross-bridge bins to the actin molecule

   1. Ca²⁺ must be present for this

2. Power stroke: Cross bridge bends, pulling thin myofilament inward

3. Detachment: Cross bridge detaches at the end of the power stroke and returns to the original conformation

4. Binding: Cross bridge binds to more distal actin molecule; cycle repeats

   1. Essentially is hoping down the line of actin molecules every cycle repeats

Understand excitation-contraction coupling and the role of Ca²⁺ and ATP in this process.

Calcium

When present: Pulls troponin-tropomyosin complex away from the active site on the actin (thus allowing it to bind to myosin)

When absent: Troponin-tropomyosin complex is blocking the actin active site (it cannot bind to myosin)

Where does the calcium come from?

Sarcoplasmic reticulum & T tubules

T tubules: Membranous, perpendicular extensions of the surface membrane that gid deep into the muscle fiber at the junctions between the A and I binds of the myofibrils

• The action potential travels down here quickly.

Sarcoplasmic reticulum: Fine, membranous network that runs longitudinally and surrounds each myofibril, with separate segments encircling each A band and I band.

Excitation-Contraction Coupling

Ca²⁺ is necessary for this to occur

1. AP at NMJ causes release of ACH → AP in the muscle fiber

2. AP moves across the surface membranes into the interior through T tubules. APs in the T tubules trigger the release of Ca²⁺ from the sarcoplasmic reticulum

3. Ca²⁺ binds to troponin on thin filaments

   1. This allows the actin/myosin to bind

4. Tropomyosin shifts, revealing myosin cross-bridge sites

5. Myosin cross-bridges attach

6. Power stroke (ATP used)

7. Cross bridge detaches

   1. Still more Ca²⁺? → Return to step 5 (do another power stroke!)

8. When APs stop, Ca²⁺ is taken back up by the sarcoplasmic reticulum. Contraction stops & thin filaments passively reset

Skeletal muscle pathophysiology & movement disorders

1. Pathophysiology: For each disorder differentiate based on: Definition, basic epidemiology, key symptoms, essential pathophysiology (basic mechanism), and any issues pertinent to pharmacy

Rhabdomyolysis

Idiopathic

Definition: Rare life-threatening muscle degenerative disease

Caused by: overexertion, trauma, toxins, dehydration, medications/drug interactions, prolonged bed rest

Epidemiology: Rare

High risk: Jobs that are outside with excessive heat/exertion, elderly, people taking statins

Statin risk factors: high dose, age, female, renal or hepatic insufficiency, diabetes, taking with other p450 inhibitors

Key symptoms: Myalgia, muscle weakness, dark urine, >11x creatine kinase in blood

Essential pathophysiology: Muscle cell disintegration → myoglobin release increases → kidney failure/death

Increased myoglobin = too much Ca²⁺ (BAD!)

Pertinent issues: Recent cases

Peripheral neuropathy

Symptomatic or idiopathic

Definition: Umbrella term for over 100 conditions that involve damage to the nerves of the PNS

Epidemiology

Key symptoms: No key symptoms

• Symptom severity, progression, and prognosis depend on the cause and type of nerve damage.

Predominantly motor: Muscle weakness/atrophy, cramps, twitching

Sensory: Loss of somatosensation (typically hands/feet)

Sensory-motor

Autonomic (excess sweating, heat intolerance, GI symptoms, BP)

Essential pathophysiology

Pertinent issues

• The most common cause is diabetes

Parkinson’s disease

Parkinsonian: Iatrogenic

• Can be trauma-induced

Parkinson’s disease: Idiopathic

Definition: Slow progressive degeneration of the nigrostriatal dopamine pathways

Epidemiology: 500,000+ affected

Risk factors:

• Age (onset at 60 years)

• Gender (male > female)

Key symptoms: Falls become likely

Motor signs: TRAP

Tremor

Rigidity

Akinesia (bradykinesia): slow movement

Posture reflex

• Festinating gait: gait with short steps

• Hypophonia: quiet speaking

• Dysarthria

• Dysphagia: Chewing issues

• Hypomima

Essential pathophysiology: Slow progressive degeneration of the nigrostriatal dopamine pathway

• Disease of the basal ganglia

Substantia nigra: Cell bodies of dopamine producers

Premotor phase

Duration: 5-10 years

Diagnosis? No

Symptoms (precursor):

• Hyposmia

• Constipation

• REM-sleep behavior

Dopamine: progressive degeneration

Motor symptoms: Minimally present (if present)

Non-motor symptoms: Minimally present, but more than motor

Symptomatic PD

Duration: Does not get cured once diagnosis occurs

Diagnosis: Yes

Symptoms (progression):

• Cognitive impairment

• Postural imbalance

• Dysarthria

Dopamine: Progressive degeneration

• Diagnosis typically occurs when 80% of the nigral DA levels are lost

Motor symptoms: Rapid increase in presence

Non-motor symptoms: Gradual increase

Pertinent issues

Apply knowledge of dopamine systems to understand the strengths and weaknesses of the DA theory of Parkinson’s disease

Parkinson’s disease likely affects more in the brain than just dopamine. Also, other diseases can affect dopamine receptors

Indirect vs direct paths in the basal ganglia

Direct pathway

Normal conditions:

1. Glutamatergic input from the cortex to the D1 receptor

   1. Increases activity

Parkinson’s disease:

1. Glutamatergic input from the cortex to the D1 receptor

   1. Constant activity

Indirect pathway

Normal conditions:

1. Dopamine input from SNc to D2 receptor

   1. Inhibits activity

Parkinson’s disease:

1. Loss of dopamine input

   1. Loss of activity inhibition

Normal conditions (summary):

1. Voluntary movement executed by the primary motor cortex

   1. Glu → spinal cord & brainstem

2. Nigrostriatal tract

   1. SNpc → striatum

      1. D₁ (GABA) → GPi/SNpr

      2. D₂ (GABA) → GPe (GABA) → STN (Glu) → GPi/SNpr

3. BG input to the cortex via the thalamus

   1. GPi/SNpr (GABA) → Thalamus (Glu) → Cortex

Parkinson’s disease (summary):

1. Voluntary movement executed by the primary motor cortex (to the spinal cord and brain stem)

2. Nigrostriatal tract (reduced activity!)

   1. No DA to Striatum (Works on D₁ and D₂)

      1. D₁: less active (GABA) → Increased GPi/SNpr activity (GABA can’t work on it to inhibit!)

      2. D₂ : Increased activity (GABA) → Decreased GPe (more GABA working on it) → Increaed STN (b/c less GABA working on it) → GPi/SNpr Increased (STN releases Glu)

3. BG input to the cortex via the thalamus

Parkinson’s: D1 (excitatory) remains the same, but D2 (inhibitory) is nonfunctional, so there is constant excitation → shakiness, stiffness, etc.

Parkinson’s treatment: Differentiate the mechanism of action of the primary treatment approaches by drug classes (DA replacement therapy, DA agonists, muscarinic antagonists)

DA replacement therapy: Increasing dopaminergic neurotransmission

Give precursor → crosses BBB → Converted to DA inside the brain

DA agonists: Increasing dopaminergic neurotransmission

Mimics DA

• D2 specific

Muscarinic antagonist: Anticholinergic (treating the tremor)

Appreciate why dopamine is a delicate balance in CNS function

• In Parkinsons, the balance between excitation and inhibition in the basal ganglia is lost

Tardive dyskinesia

Iatrogenic

Definition: Involuntary, repetitive excessive movements, especially around the mouth and jaw

Key symptoms: Involuntary, repetitive excessive movements

• Tends to be around the mouth & jaw very often

Essential pathophysiology: Prolonged dopamine receptor antagonism

Prolonged DA receptor antagonism → DA receptor function change

Pertinent issues: Causing tardive dyskinesia while treating other psychiatric conditions

Treating psychiatric conditions typically involves antipsychotics (typically block dopamine receptors), some anticholinergics, and SSRIs. If you antagonize the dopamine receptors for an extended period, tardive dyskinesia can result

• It can be reversed

Myasthenia gravis

Idiopathic & iatrogenic

Definition: Autoimmune disorder of neuromuscular transmission, that results in skeletal muscle weakness

• The small muscles around the face & eyes are affected greatly

Epidemiology: Rare (150-205/1mil)

Risk factors:

• Family history of autoimmune disease,

• Men > 60; women<40

• Genetics

Key symptoms: Fatigue, muscle weakness, ptosis, diplopia, dysphagia

• Ptosis: Eyelid drooping

Essential pathophysiology: Degeneration/impairment of neuromuscular junction

Antibodies bind nAChRs → impaired NMJ transmission

Pertinent issues

Treatment: anticholinesterases (increase ACh), immunosuppressants

Multiple sclerosis (MS)

Neither idiopathic nor iatrogenic

Definition: Conduction disorder caused by loss of myelin

Epidemiology: 2.3 million diagnosed worldwide

Diagnosis age: 15-45 years

Risk factors:

• Geography

• Age

• Sex (more women)

• Environment (urban): vitamin D deficiency, particularly viral infections, smoking, high sodium intake, circadian disruption

• Higher instance the further you are from the equator

Key symptoms

Primary: Direct consequence of conduction disturbances, reflecting where the damage occurred

• Paresthesias: numbness/tingling

• Ataxia: uncoordinated movement

• Weakness

• Spasticity

• Optic neuritis

Secondary: Complications from the primary symptoms

• UTIs

• Respiratory infections

• Poor nutrition

• Depression

Tertiary: Impact of the disease on life

• Disease

• Inability to work

• Social withdrawal

Essential pathophysiology: Inflammatory demyelinating disease of CNS white matter

• Loss of myelin

  • Oligodendrocyte loss

  • White matter plaques

  • Axonal loss

    • Schwann cells (PNS) are protected

  • Mononuclear cell infiltration

Pertinent issues: Diagnosis of exclusion

Relapse remitting (RRMS, 80% of cases): alternating of recovery and presence of symptoms

Primary progressive (PPMS, 15% of cases): No recovery period, just constant symptoms

ALS

Iatrogenic

Definition: Rapidly progressing and fractal motor neuron disease

Pathophysiology: Degeneration of upper & lower motor neurons

Muscular dystrophy

Idiopathic

Definition: Overarching disorder that includes hereditary, progressive muscle degeneration disorders (100+ muscle degenerative disorders)

Huntington's disease

Iatrogenic

Definition: Hereditary neurodegenerative disease that causes severe chorea and progressive dementia

Psychosis (Schizophrenia): Disorder of thought

Apply knowledge of neurotransmission: Glutamate, DA, 5HT3

Glutamate: Controls dopamine release

Dopamine: Major neurotransmitter that acts on multiple areas of the brain

Mesocortical: Covers all of the cortex & spreads outward

• Involves schizophrenia

Mesolimbic: Stays by the base of the brain

Nigrostriatal: Originating at the brain stem and dispersing in the middle of the brain (limbic system?)

• Involved with Parkinson’s disease

Serotonin (5HT3):

Understand the pathophysiology of Schizophrenia

Basic epidemiology/stats

Population: 1% (Male = Female)

Development: Neurodevelopmental

• Children who later develop schizophrenia have abnormal emotional reactions very early.

Onset: Early adulthood

Environmental risk factors

• Prenatal viral infection (2^nd trimester flu)

• Poor maternal and perinatal nutrition

• Perinatal hypoxia and other birth trauma

• Illicit drug use

• Psychological stress

• Advanced paternal age

Symptoms (positive vs negative vs cognitive)

Positive: Addition of a symptom

• Delusions (often paranoid): Strong beliefs that misrepresent reality

  • Thought-related

• Hallucinations (often auditory): Perceptual disturbances

  • Sensory perceptions

• Thought disorder

  • Grandiosity: The patient has a gift or is better than others

  • Wild trains of thought

  • Irrational conclusions

  • Rambling speech

• Abnormal, disorganized behavior and/or speech

• Catatonia: Added stiffness

Negative: Removal of something

• Socially withdrawn

• Flattened affect: Lack of emotional reaction or facial expression reactions

• Anhedonia: Inability to experience pleasure

• Avolition: Lack of motivation to start/complete tasks

Cognitive

• Attention: Difficult to focus on the primary task

• Memory

• Comprehension/Understanding: Lack of logic

Neuropathologies: Likely a heterogeneous collection of several poorly defined/understood diseases

• The frontal lobe is thought to be involved

  • Neurodegeneration?

  • Enlarged lateral ventricles

  • Slight reduction in the thickness of cortical gray matter

  • Hypofrontality: Loss of frontal lobe cortex functionality

• Loss of grey matter elsewhere in the brain: insular cortex, thalamus, striatum

Stages of pathology

Premorbid

• Cognitive: Present

Prodromal

• Cognitive: Present

• Negative: Present

• Positive: Slight presence

Diagnosis

• Cognitive: Present to point of disability

• Negative: Present to point of disability

• Positive: Spikes, psychotic break occurs

Progressive

• Cognitive: Present to point of disability

• Negative: Present to point of disability

• Positive: Up & down cycles of high and low presence

Residual

• Cognitive: Present, begins to decrease

• Negative: Present & persisting

• Positive: Treatment causes a decrease, but the presence remains

Dopamine vs glutamate vs serotonin hypotheses

Dopamine theory: Hyperactivity of the dopamine system

Follows the mesocortical tract

• D₂ receptor antagonists were used and relieved positive symptoms

• Stimulants (causing excess DA release) produce behaviors similar to a schizophrenic episode in humans

Dopamine receptors

D₁ & D₅: Gs (stimulatory)

• Increase cAMP

• Typically postsynaptic

• Located in:

  • Substantia nigra

  • Striatum

  • Frontal cortex

  • Hypothalamus

D₂, D₃ & D₄: Gi (inhibitory)

• Decrease cAMP

• Presynaptic & postsynaptic

• Located in:

  • Substantial nigra

  • Striatum

  • Prefrontal cortex

  • Limbic system

  • VTA

  • Pituitary gland

Limitations

• D2 receptor blockade occurs rapidly after antipsychotic dosing, but clinical response typically requires several weeks

  • D2 antagonist must be continually used to see the effect

• Other treatments (for other things) can cause psychotic symptoms

Serotonin theory: Serotonin hypofunction

• Agonists of serotonin receptors cause hallucinations

• Serotonin antagonists have been successful

Glutamate theory: Glutamate hypofunction

Glutamate controls DA release

• Postmortem changes in schizophrenics included:

  • Decreased glutamate in CSF

  • Decreased NMDA receptors

• NMDA-receptor antagonists produced positive and negative symptoms

• Rodent models of reduced NMDAR → decreased social interaction. Antipsychotics (D2 antagonist) reverse this

• Ionotropic (chart) & metabotropic glutamate receptors

Differentiate the mechanism of action of the primary treatment approaches or drug discovery approaches by drug classes. DA antagonists vs potential Glutamatergic approaches

D2 Antagonist: 1^st generation antipsychotics

• Block the D2 receptor binding site → Dopamine cannot bind to D2 receptors → DA signaling decreases → Symptoms relieved.

Appreciate why Dopamine is a delicate balance in CNS function

• EP movement disorders and tardive dyskinesia

  • If DA receptor antagonists are used for too long, then DA receptors change & this causes major issues.

Addiction

Understand what addiction is and general related terms

Addiction: Drug addiction is a chronic, relapsing disorder characterized by compulsive drug use, despite having harmful consequences

• Repeated drug use changes the brain in a way that impairs the body’s ability to control behavioral processes and interferes with one’s ability to resist drug cravings

Tolerance: Decrease in response after repeated exposure requires more product to reach the same initial feeling

• Pushes the curve to the right

Dependence

Psychological: Drug cravings and preoccupation with taking the drug

Physical: Required for conditions, such as cancer patients or terminally ill patients. They are not abusing the drug but may end up addicted.

Withdrawl: Removing the toxin and the body's response shifts the opposite direction to form a hyperresponse.

• Reveals that the person is dependent

Relapse: Going back to drugs after being sober for some time

Know the common misused substances and alcohol and their primary mechanism of action

Hallucinogens (Ketamine, LSD, PCP, MDMA “Ecstasy”

The mechanism of action is dependent on the agent

Ketamine: NMDA Receptor antagonist

LSD: D₂ agoinst/5HT_2A agonist

PCP: NMDA Receptor antagonist

MDMA “Ecstasy”: Serotonergic - agonist, reuptake inhibitor

Marijuana

Mechanism of action: CB1 receptor agonist

Synthetic cannabinoids

Mechanism of action: CB1 receptor agonist

Opiates

Mechanism of action: mu-opioid receptor agonist

• Different opioids have different levels of potency at different receptor subtypes.

Sedative-hypnotics

Mechanism of action: APL at GABA_A

Stimulants (Cocaine, methamphetamine, amphetamine, methylphenidate, nicotine)

Mechanism of action (amphetamine, cocaine, methamphetamine): Inhibits DAT/NET, VMAT₂

Methamphetamine: Also reverses DAT to toxic levels

Mechanism of action (nicotine): nAChR agonist

Alcohol

Appreciate which of the agents discussed today is our biggest problem - greatest harm, most overdoses, greatest use disorder.

Greatest harm to others: Alcohol

Greatest harm to self: Heroin

Most overdoses: Alcohol

Greatest use disorder: Alcohol

Highest rate of addiction: Heroine, nicotine, tobacco

What is the mesolimbic dopamine system and what differentiates it from the other dopamine systems?

Mesolimbic dopamine system: Activated by addictive drugs

• Dopaminergic projection from VTA to NAc (critical site for drug abuse)

Appreciate that all “addictive” drugs increase dopamine but they each have their mesolimbic reward system

• Dopamine increase is essential, but not proportional to the “addictive potential” of the drug

  • Amphetamine & cocaine have higher peaks than heroin, but not as addictive

Seizures

Differentiate seizures vs epilepsy

Seizure: Abnormal and excessive neuronal discharge (hyperactivation of neural activity) with or without a change in the level of consciousness

Epilepsy: Seizure disorder characterized by recurrent, unprovoked seizures (diagnosis = 2 unprovoked seizures > 24 hours apart)

• 70% idiopathic

• 30% symptomatic (secondary causes such as injury, tumor, infection, etc.)

Differentiate types of seizures

Focal onset: Aware/Impaired awareness

Psychomotor

May evolve into secondary generalized seizures

• Seizure focus → branches to thalamus → spreads throughout the brain

Simple focal (Retains consciousness)

• Affect small regions of brain

• Symptoms: Motor, somatosensory, autonomic, or psychiatric symptoms

• Duration: 15 secs - 3 min

Complex focal (loss of consciousness)

• Symptoms: May involve unconscious repetition of simple actions, gestures, or verbal utterances, or simply a blank stare

• Unawareness of the seizure, followed by no memory of the seizure

• May include an aura

• Duration: 15 secs - 3 min

Generalized onset: Impaired awareness

Brain region affected: Both hemispheres

Motor

Tonic-clonic (Grand mal): Typical seizure

• Duration: 30-60 secs

Myoclonic

• Duration: Seconds

Tonic

• Duration: Seconds

Atonic

• Duration: Seconds

Non-motor

Absence (Petit mal): Blip/short loss of

• Duration: 3-30 seconds

Know the pathophysiology of seizure.

Alterations in excitation or inhibition can lead to seizures

• Glutamate: Excitation

• GABA: Inhibition

Treatment: Anxiolytic, anti-convulsants, anesthetics, and alcohol enhance GABA receptor activity or block glutamate receptor activity

Basic epidemiology/stats

Prevalence: 4th most common neurological disorder

• 65 million worldwide with epilepsy

  • 3.4 million in the US with epilepsy

  • ⅓ of cases can’t be treated

Age: Very young & elderly is most common

• < 2 has a high occurrence of acute symptomatic seizures

• > 65 years has a higher occurrence of unprovoked idiopathic seizures

Symptoms (terms & definitions)

• Typically during the postictal phase (recovery period)

Sensory/thought: Blackout, confusion, deafness/sound issues, electric shock feelings, smell, spacing out, out of body experience, vision loss or blurring

Emotion: Fear, panic

Physical: Dizziness, nausea, tonic, clonic, myoclonic, atonic, etc.

Neuropathologies

Understand what EEGs are like in seizure vs normal waves, differentiate absent seizures vs others

Types of EEG Waves

Alpha

• 8-13 Hz

• Awake, but quiet

Beta

• 14-80 Hz

• Awake & attentive

• Asynchronous

Theta

• 4-7 Hz

• Sleep, emotional stress

• Some disorders

Delta

• <3.5 Hz, higher voltage (large peaks)

• Deep sleep, infancy

• Severe disorder

Absent seizure: Spike and dome

Grand mal: Out of control rapid spiking

Understand the 3 main pharmacotherapeutic approaches

Inactive voltage-gated Na⁺ channels - stop repetitive firing

• Goal: Decrease hyperactivity

Enhance GABAergic neurotransmission

• GABA is inhibitory

• Goal: Decrease hyperactivity

Limit T-type Ca²⁺ channel (absence seizure only)

Sleep Disorders

Understand brain systems regulating sleep

• Sleep is an active process, neurons are still firing

Systems regulating sleep

Arousal system: The reticular activating system in the brainstem regulated by the hypothalamus (hypothalamus and reticular activating system)

Hypothalamus: Promotes wakefulness when stimulated

Slow-wave sleep center: “Sleep on” neurons in the hypothalamus (hypothalamus)

• Sleep-promoting neurons activated → GABA released → Inactivates awake neurons

• Body awake = sleep neurons inactive

• Non REM sleep = sleep neurons very active

Paradoxical sleep center: REM sleep on neurons in the brainstem that switch to paradoxical sleep (REM) (brain stem)

• Controls transition from slow wave/deep sleep to REM

Molecules involved in the regulation of the sleep-wake cycle

Awake

Histamine

• Anti-histamine causes drowsiness

Orexin (hypocretin): Promotes awakeness, suppressed when sleeping

Noradrenaline: Wake-promoting

Acetylcholine: Wake-promoting

Sleep promoting

GABA: “Sleep on” neurons release

Cytokines: Sleep-promoting

Immune system communicator

Melatonin: Released when dark

Adenosine: Caffeine targets this

Studying sleep: EEG (records brain waves)

• Records small electrical fields generated by the synaptic currents in pyramidal cells

Sleep stages

Sleep cycle goes down non-rem (1-4) → REM sleep → up non-rem (4-1)

Non-REM or Slow-wave sleep

1. Beginning of the sleep cycle, light sleep (5-10 min)

   1. EEG waves: Theta waves

2. Bursts of rapid, rhythmic brain activity. Body temperature decreases and heart slows.

   1. EEG waves: Mixed activity (sleep spindles)

3. Deep, slow brain waves emerge. The transition between light and very deep sleep

   1. EEG waves: Progress into delta waves

4. Slow wave or delta sleep (deep sleep)

   1. EEG waves: Delta waves, slow waves

REM sleep (paradoxical sleep)

1. At the end of each sleep cycle (10-15 min)

• Dreaming occurs here

• EEG Waves: Similar to the awake state

Differentiate between types of sleep disorders.

Insomnia: A dissatisfaction with sleep quantity or quality with complaints of difficulty initiating sleep, maintaining sleep, or early morning awakening

Prevalence: 6-10% of US adults

• Older women

Risk factors: Temperamental, environmental, genetic, and physiological

Hypersomnolence disorder: Excessive quantity of sleep, deteriorated quality of wakefulness, and sleep inertia

Risk factors: Stress, alcohol use, viral infection, genetics

Narcolepsy: Irrepressible need to sleep, lapsing into sleep, or napping occurring within the same day (Autoimmune disease)

Prevalence: 0.02-0.04%

• Possible slight male preponderance

Onset: 15-25 years & 30-35 years; lifetime condition

Risk factors: Other familial sleep disorders; viral infections; head trauma; genetic; T cell genes (because it is autoimmune)

Breathing-related sleep disorders

Obstructive sleep apnea: Repeated episodes of upper airway obstruction during sleep that results in apneas or hypopneas

• Loss of O₂ when sleeping due to the tongue blocking the airway

Prevalence:

• J distribution (Increases with age)

• 1-2% in kids

• >20% in older adults

• 2:1 - 4:1 - male:female

  • Higher frequency in men

Risk factors: Obesity, sleep position, substance use, adenotonsillar hypertrophy (kids), genetic syndromes that reduce upper airway, genetics

Central sleep apnea: Repeated episodes of apneas or hypopneas during sleep

• The area of the brain that controls your breathing when sleeping (pons) does not function properly

Sleep-related hypoventilation: A rare condition of decreased respiration during sleep which results in insomnia and sleepiness

Circadian rhythm sleep-wake disorder: A persistent or recurrent pattern of sleep disruption that is primarily due to an alteration of the circadian system

Risk factors: mutation in the “clock genes”, melatonin mutations, blindness

Delayed sleep phase types: Individual who is delayed in falling asleep at night and waking up >2 hours (sleeps late)

Advanced sleep phase type: Individual who is premature in falling asleep at night and waking up > 2 hours (sleeps early)

Irregular sleep-wake type: Lack of discernible sleep-wake circadian rhythm (3 periods of shorter sleep through the day)

Non-24-hour sleep-wake type: Sleep-wake cycle is not aligned with the 24-hour day

Shift work type: Excessive sleepiness at work and impaired sleep at home

Parasomnias: Abnormal behavioral, experiential, or physiological events occurring in association with sleep, specific sleep stages, or sleep-wake transitions

Non-REM Sleep Arousal disorders: Incomplete awakening; “sleepwalking”

Nightmare disorders: Repeated occurrence of extended, extremely dysphoric, and well-remembered dreams

Restless leg syndrome: An urge to move the legs along with an uncomfortable sensation

Explain the clinical manifestations of sleep disorders

Insomnia: Sleep issues > 3 nights/week for > 3 months

Hypersomnolence disorder: Excessive quantity of sleep, deteriorated quality of wakefulness, and sleep inertia

Narcolepsy: Irrepressible need to sleep, lapsing into sleep, or napping occurring within the same day

Criteria:

1. Recurrent periods of an irrepressible need to sleep, lapsing into sleep, or napping occurring within the same day (3x/week for > 3 months)

2. Presence of >1 of the following:

   1. Episodes of cataplexy (loss of muscle tone)

   2. Orxein deficiency in cerebrospinal fluid

   3. Nocturnal REM sleep latencies <15 min

Pathophysiology: T cells may kill orexin neurons (wakeful neurons) → narcolepsy occurs

Circadian rhythm sleep-wake disorder: Alteration of the suprachiasmatic nucleus (which controls the circadian rhythm)

Identify the causes and consequences of select sleep disorders

Narcolepsy: Deficiency/destruction of orexin neurons

Orexin neurons: Maintain wakefulness

Obstructive sleep apnea: Physical changes in the body, having a floppy airway

Central sleep apnea: Changes in the brain

Sleep-related hypoventilation: PHOX2B gene & obesity

Circadian rhythm sleep-wake disorder: Alteration in the circadian system

Alzheimer’s disease and other dementias

Describe and differentiate types of neurocognitive disorders

Delirium: Acute condition that is characterized by disturbance of attention or awareness accompanied by a change in baseline cognition

DSM-V:

1. Disturbance in attention and awareness

2. Disturbance develops rapidly and tends to fluctuate throughout the day

3. Additional cognitive disturbances (e.g. disorientation, language, perception)

Exclusion criteria

1. A and C are not due to preexisting neurocognitive disorder

2. Evidence that disturbance is a direct physiological consequence of another condition (e.g. substance use, medication withdrawal, surgery, and infection)

Prevalence: 1-2% of the overall population, but much higher in the elderly (14% of 85+)

Onset: Rapid

Risk factors: Surgery, infection, hospitalization

• Things that activate the immune system

Duration: One week

Resolution: Best outcomes if treated rapidly; can progress to stupor, coma, death. Increases risk for long-term neurocognitive disorders in the future

Mild neurocognitive disorders: An acquired decline in one or more cognitive domains (noted by self, peer, clinical, or diagnostic test assessment)

DSM-V:

1. Evidence of modest cognitive decline in one or more cognitive domains

2. Cognitive deficits do not interfere with the capacity for independence

Exclusion criteria

1. Cognitive deficits do not interfere in the context of delirium

2. Cognitive deficits are not better explained by another mental disorder (e.g. schizophrenia, MDD)

Specify: With or without behavioral disturbances (e.g. psychotic symptoms, apathy, agitation; due to another condition)

Major neurocognitive disorders: An acquired decline in one or more cognitive domains (noted by self, peer, clinical, or diagnostic test assessment)

DSM-V:

1. Evidence of significant cognitive decline in one or more cognitive domain

2. Cognitive deficits interfere with the capacity for independence

Exclusion criteria

1. Cognitive deficits do not interfere in the context of delirium

2. Cognitive deficits are not better explained by another mental disorder (e.g. schizophrenia, MDD)

Specify: With or without behavioral disturbances (e.g. psychotic symptoms, apathy, agitation; due to another condition)

Dementia: Overarching condition that affects cognitive domains, mainly affecting learning and memory

Alzheimer’s Disease: 70% of dementia cases

Involves trouble creating new memories

Risk factors: Increased age, vascualr disease, genetics, head injury, lower education, sex, substance use, depression, sedentary lifestyle

Protective factors: Exercise, mediterranean diet, social engagement, mental activity, higher education

Vascular dementia: 17% of dementia cases

Involves trouble retrieving memories

Cause: Damage to subcortical fibers

• Reduced blood flow to the brain

Risk factors: Hypertension, Hypercholesterolemia, Insulin-resistant diabetes, tobacco use

Dementia with Lewy bodies (#3)

Parkinson’s disease (#4)

Causes of Dementia

Degenerative disease: Alzheimer's, Lewy body Disease

Endocrine: Thyroid, cortisol

Metabolic: Electrolyte imbalance

Exogenous agents: toxins, drugs

Neoplasia

Trauma: Brain injury

Infection

Affective psychiatric disorders: MDD, schizophrenia

Stroke

Identify changes in distinct neurocognitive domains and underlying neural circuitry

Learning and memory

Region:

Frontal lobe

Hippocampus

Thalamus: Medial diencephalon

Hypothalamus: New memory retrieval

• The strongest deficits occur here, it is very susceptible to disease

Most impacted: Hippocampus, episodic memory!!

• Short & long-term memory

Executive function

Region: Mainly frontal lobe

Functions: Planning, decision-making, working memory, self-behavior control, flexibility, multitasking

Complex attention: Focusing on a primary task

Regions:

Frontal lobe

Parietal lobe: Selective attention

Reticular activating system: Arousal

Social cognition: Recognizing own & others emotions

Regions:

Orbitofrontal cortex

Temporal lobe: Empathy control

Perceptual motor function

Language

Explain the clinical manifestations of Alzheimer’s disease

Development

Early onset: Genetic

Causative genes

1. B-Amyloid precursor protein (APP)

2. Presenilin 1

3. Presenilin 2

Late onset: Idiopathic/sporadic

Susceptibility genes

1. Apolipoprotein E

Symptoms

• Neurocognitive domains affected: (Learning memory → executive function → complex attention → social cognition)

• Declarative memory is affected (not non-declarative!)

• Apraxia: Impaired movements

Co-morbidities

• Agitation (50-70%)

• Anxiety (30-50%)

• Depression (25-50%)

• Disinhibition (20-35%)

• Delusions (15-50%)

• Hallucinations (10-25%)

• Aggression (25%)

• Sexual disinhibition (5-10%)

Discuss brain changes and genetic risks of Alzheimer’s disease: defining the role of APP, Aβ peptide, presenilins, and apolipoprotein E

Cholinergic hypothesis: Cholinergic neurons are negatively affected (in the nucleus basalis Meynert)

• Cholinergic neurons signal to cortex → attention & arousal

• Less cholinergic neurons = less attention/arousal = visible deficits

Excitotoxicity hypothesis (glutamate): Too much glutamate

Intraneuronal neurofibrillary tangles: Tangled clusters of tau proteins → no stabilization of microtubules → disintegration of microtubules

• Accounts for early symptoms of memory loss & issues with higher cortical function

Regions affected: Forebrain, hippocampus, entorhinal

Cause: Clumping of tau proteins

Result: Disintegrating microtubules

Extracellular neurotic plaques: Clusters of APP in the brain (it is sticky)

Amyloid material (APP): Dense core, the primary material in these plaques

• Sticky material that builds up and develops into a toxic oligomer

• Typically cleaved by a-secretase

  • When b-secretase & gamma-secretase are involved, this can be bad

Dystrophic neurites: Surround the amyloid core

Reactive astrocytes: Recruited when the plaques are detected

Microglia: Immune response in the brain

• Microglia & reactive astrocytes contribute to the problem because they increase inflammation.

Presenilin protein - gamma secretase

• Presenilin proteins regulate the secretase

• Presence of Presenilin 1/2 causes Alzheimer’s (raises risk greatly)

Presenilin 1 (Chromosome 14)

Presenilin 2 (Chromose 1)

Apolipoprotein E (Gene for late-onset Alzheimers): Regulates synthesis and secretion of microglia & astrocytes, lipid accumulation

Apo E2: Decreased risk for Alzheimer's

Apo E3: The most common gene possessed by people with Alzheimer's, but doesn’t necessarily increase risk.

Apo E4: Increases risk for Alzheimer's

Anxiety, Depression, and Bipolar Disorders

Describe and differentiate between types of anxiety, mood, and bipolar disorders.

Anxiety: Share features of excessive fear and anxiety and related behavioral disturbances

Fear of fear

Separation anxiety (1-2%, 5% kids)

Selective mutism (<1%): Failure to speak in certain situations, such as school or in crowds

Selective phobia (3-16%, culture/age): Fear of specific things, such as spiders

Social anxiety disorder (7% in the US, 1% in the world): Anxiety about interactions with others

Panic disorder (2-3%):

Agoraphobia (0.5-1%)

Generalized anxiety disorder (GAD): The most common

DSM-V Criteria

1. Excessive anxiety and worry, occurring more days than not for at least 6 months, about several events or activities.

2. The individual finds it difficult to control the worry

3. The anxiety and worry are associated with three (or more) symptoms, *only one required in children*

   1. Restlessness or feeling on edge

   2. Easily fatigued

   3. Difficulty concentrating or mind going blank

   4. Irritability

   5. Muscle tension

   6. Sleep disturbances

4. Anxiety, worry, or physical symptoms cause clinically significant distress or impairments in function

5. Exclusion criteria

   1. Disturbance is not caused by substance use or another medical condition

   2. Disturbance is not better explained by another mental disorder

Incidence and prevalence

Lifetime risk: 9% +

Median age of onset: 30 years

Comorbidity: Up to 50% with some conditions

Men: High comorbidity with depression and substance use disorder

Women: High comorbidity with depression

Depression

Major depressive disorder (MDD)

DSM-V Criteria

1. Must have at least one of these occurring daily for 2 or more weeks

   1. Depressed mood

   2. Loss of interest and pleasure (anhedonia)

2. Must have at least five of these occurring daily for 2 or more weeks

   1. Depressed mood

   2. Loss of interest and pleasure (anhedonia)

Increase or decrease:

1. Appetite/weight

2. Sleep

3. Activity/psychomotor

Decrease:

1. Energy

2. Concentration

Increase:

1. Guilt

2. Morbid death thoughts

c. Exclusion criteria: Depression is not due to psychosis, manic episodes, illness, medication/drug, or bereavement

Incidence and prevalence

Population: 5-7% of population

• 350 million people worldwide

Age: All ages

• Most suicides are in youth (15-29)

Genetics: Familial

• 21% rate across 1st degree family members

• 30-50% rate across identical twins

Candidate genes:

1. Serotonin-linked polymorphic region

2. Serotonin 1A receptor

3. Methylenetetrahydrofolate reductase

4. Dopamine D4 receptor

DNA Hypermethylation:

1. Brain-derived neurotrophic factor

2. Serotonin transporter

Alternative treatments

1. Electroconvulsive therapy

2. Ketamine: Involves glutamate

3. Transcranial magnetic stimulation: Stimulates neurons

4. Deep brain stimulation

Typical (melancholic)

Decrease:

1. Appetite/weight

2. Sleep

Increase:

1. Activity/psychomotor

Atypical (most common form)

Decrease

1. Activity/psychomotor

Increase

1. Appetite/weight

2. Sleep

Psychotic: Depression characterized by psychotic symptoms

Anxious depression

Postpartum depression

Seasonal affective disorder

Bipolar

A disorder characterized by periods of mania alternating with periods of depression

DSM-V Criteria

1. Must have for at least 1 week, or hospitalization may occur before the one-week mark

   1. Abnormally and persistent elevated or irritable mood with increased energy/activity

2. Must have 3 or more symptoms (4 or more if “a” is irritable mood)

Increase

1. Grandiosity

2. Talkative

3. Racing thoughts

4. Distractibility

5. Goal-directed activity

6. Negative consequences

Decrease

1. Sleep

c. Cause marked impairment in social or occupational function or hospitalization occurs

d. Exclusion criteria: Mood shifts are not due to medications/drugs or another medical condition

Incidence & Prevalence

Population: 1-2% of population

• 25% of the population with anxiety & depression

Genetic: 85% familial

• 12% rate across 1st degree family members

Candidate genes:

• Glutamate neurotransmission

• Neurogenesis/brain development

• Serotonin transporter

• Catechol-methyl-transferase

• Monoamine oxidase

• Tryptophan hydroxylase

Treatment

• Lithium, antipsychotics, and certain anticonvulsants can treat manie

Explain the clinical manifestations of the distinct disorders

Anxiety

Symptoms

• Inability to be still and calm

• A feeling of panic, fear, uneasiness

• Vigilance: Hyperarousal and awareness of surroundings

• Difficulty sleeping

• Feelings of panic

• Tension/muscle tension

• Sweating

• Dry mouth

• Shortness of breath

• Dizziness

• Palpitations

Depression

Symptoms

A: Must have at least one of these occurring daily for 2 or more weeks

1. Depressed mood

2. Loss of interest and pleasure (anhedonia)

B: Must have at least five of these occurring daily for 2 or more weeks

1. Depressed mood

2. Loss of interest and pleasure (anhedonia)

Increase or decrease:

1. Appetite/weight

2. Sleep

3. Activity/psychomotor

Decrease:

1. Energy

2. Concentration

Increase:

1. Guilt

2. Morbid death thoughts

Relationships with other illnesses

Secondary to other diseases

1. Hypothyroidism

2. Neurodegenerative diseases

3. Inflammatory conditions (trauma, cancer, diabetes)

Complicates treatment of medical conditions

1. Severe trauma

2. Cancer

3. Diabetes

4. Cardiovascular disease

Typical (melancholic)

Decrease:

1. Appetite/weight

2. Sleep

Increase:

1. Activity/psychomotor

Atypical (most common form)

Decrease

1. Activity/psychomotor

Increase

1. Appetite/weight

2. Sleep

Psychotic: Psychotic symptoms

Bipolar

Type 1

Manic episode: Required for diagnosis

• 1+ week duration

• Impairs functioning

• Severe mania

Depressive episode: Not required for diagnosis

• Longer duration

• Severe depressive episode

Type 2

Manic episode: Required for diagnosis

• 4+ consecutive days

• Hypomania (not as severe)

Depressive episode: Required for diagnosis

• Longer duration

• Severe depressive episode

Name key brain structures involved in fear conditioning, anxiety disorders, and mood disorders.

Fear conditioning: Useful for studying fear and anxiety

Amygdala: Fear center in the brain

• Increase in activity

Hippocampus: Learn fearful association

• No change in activity

Insular cortex: Similar to the amygdala, provides emotional context

• Increase in activity

• Processes emotions

Anxiety

Amygdala: Fear center in the brain

• Increase in activity

Hippocampus: Learn fearful association

• No change in activity

• Less prevalent once anxiety is established, but the hippocampus forms the fearful association.

Insular cortex: Similar to the amygdala, provides emotional context

• Increase in activity

• Processes emotions

Depression

Hippocampus: Decrease in size

Amygdala: Increase or decrease in reactivity

Frontal cortex: Decrease in connectivity to the amygdala

Typical (melancholic)

Increase in the HPA Axis (Negative feedback loop that controls cortisol release): There is a lack of cortisol rhythm in the body.

Atypical (most common)

Increase in hypersensitivity

• Sensitive to criticism and feedback

Amine hypothesis

Raphe nuclei: Source of serotonin

Locus coeruleus: Source of norepinephrine

Long-term effects of antidepressants

• Increased adrenergic or serotonergic receptor density or sensitivity

• Increased G protein coupling and cyclic nucleotide signaling

• Induction of neurotrophic factors

• Increased neurogenesis in the hippocampus

Bipolar

Hippocampus: Increase in activity

Frontal cortex: Decrease in activity

Amygalada: Increase or decrease in reactivity

Explain changes in brain function that are associated with anxiety, mood, and bipolar disorders.

Anxiety

Serotonin decrease

Treatment: Increase serotonin through SSRIs and other antidepressants

• Common treatment

GABA_A: Key in brain excitability

Treatment: Increase GABA_A activation through the use of benzodiazepines

• Less common treatment because benzos are addictive

• Very short-term

Depression

Depression may be caused by a multitude of factors in different patients

• STAR*D Trial: Some patients responded to certain things, while others didn’t

Amine hypothesis: Depression is related to a deficiency of monoamines in the brain

Amine neurotransmitters (such as serotonin, dopamine, etc.) are related to improved mood

• Patients were treated with iproniazid (MAO inhibitor) and they displayed inappropriate levels of happiness, and when they were treated with reserpine (depletes catecholamines) they displayed symptoms similar to that of depression

• Dopamine, serotonin, and norepinephrine are primary contributors to MDD

Cytokine hypothesis: Increased cytokines are a key factor in the development of depression

Cytokines: Proteins released when there is inflammation in the body, common during illness and injury

• Symptoms of depression are very similar to symptoms the body experiences when sick

Bipolar

Hippocampus: Increase in activity

Frontal cortex: Decrease in activity

Amygalada: Increase or decrease in reactivity