Patho Exam 3

Tab 1

PNS Efferents: Autonomic Nervous System (Lecture 29)

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

• Internal environment → sensory neurons “interoreceptors” → CNS → motor neurons

  • 2 motor neurons in series

    1. 1st neuron cell body is in spinal cord (preganalionic)

       1. Synapses with cell body of the postganglionic fiber in a ganglion outside the CNS

    2. 2nd neuron cell body is in autonomic ganglion (postganglionic) innervates effector (e.g. tissue, organ)

       1. Sends axons that end on the effector organ

  • Involuntary control

  • Broken down into parasympathetic and sympathetic

Differentiate sympathetic versus parasympathetic anatomy, outflow and neurotransmitters

• Parasympathetic

  1. Rest and digest

     1. Body- maintenance activities such as digestion

  2. Cranial sacral

  3. Outflow

     1. Preganglionic parasympathetic neurons

        1. Cranial nerve III, VII, IX, X

Oculomotor nerve (III) - ciliary muscles, pupillary sphincter of eye

Facial Nerve (VII) - submandibular, sublingual salivary, lacrimal, nasal gland

Glossopharyngeal Nerve (IX) -parotid gland

Vagus Nerve (X) - thoracic & abdominal region

primary parasympathetic nerve

• Sacral spinal cord (S2-S4)

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

• Postganglionic neurons

  1. Short

  2. In a ganglia near or within the walls of the effector organ

  1. SLUDD (Salivation, lacrimation, urination, digestion, defecation)

  2. 3 decreases:

     1. heart rate

     2. airway diameter

     3. pupil diameter

  1. Sympathetic

     1. Fight or flight

        1. Responses that prepare the body for strenuous physical activity

     2. Thoracolumbar

     3. Output

        1. Preganglionic neurons

           1. bilateral , in spinal segments T-1 to L-2

           2. Splanchnic nerves to celiac, hypogastric

        2. Postganglionic neurons

           1. Sympathetic chain ganglia:

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

Innervates cardiac muscle, smooth muscle of bronchi and iris

• Prevertebral ganglia

Celiac ganglion

Hypogastric plexus

• Adrenal medulla

Releases epinephrine & norepinephrine

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

Chromaffin cells synthesize epinephrine

• Mass discharge → symp, can discharge simultaneously as complete unit

  • Increased heart rate and contractility, bronchi relaxation, sweat gland secretion, inhibits secretion and motility in GI tract, sphincter contraction, bladder (relax detrusor muscle, contract internal sphincter)

    1. Sweat gland receptor is mAch (cholingeric)

All other receptors are adrengeric

[Make a small chart comparing parasympathetic and sympathetic, Slide 23]

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

• All preganglionic fibers = acetylcholine

  • Postganglionic fibers of para = acetylcholine

  • Postganglionic of symp = most are adrenergic; few are ACh

  • Symp. reaction → long lasting b/c transmitter substance is not directly broken down but diffuse away

    1. Alpha

       1. a1: excitatory

       2. a2: inhibitory

    2. Beta

       1. B1: excitatory

       2. B2: inhibitory

       3. B3: only found in brown adipose tissue

  • Activity terminated in 1 or 2 way:

    1. Reuptake by neuron that released it

    2. Enzymatically inactivated:

       1. catechol-O-methyltransferase (COMT)

       2. Monoamine oxidase (MAO)

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

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

• ANS maintains visceral homeostasis through autonomic reflexes

  • Reflex arc

    1. Receptor

    2. Sensory neuron

    3. Integrating center

    4. Motor neurons

    5. Effector

  • Body functions that utilize a reflex:

    1. Blood pressure

    2. Salivation

    3. Gastric secretions

    4. Defecation

    5. Gallbladder emptying

    6. Pancreatic secretions

    7. Micturition (urination)

    8. Sweating

    9. Blood glucose concentrations

What are CNS control centers for the ANS?

• Brain stem - ANS reflex center

  • Hypothalamus

    1. Nucelic monitor, BP, body temp, feeding, digestion, etc.

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

  • Spinal cord - ANS reflex center - urination, defecation, reproductive behaviors

  • Cerebrum / limbic system - thoughts/ emotions can influence ANS function via hypothalamus

PNS Efferents: Motor Control (Lectures 30-31)

Define and differentiate the 3 types of movement

• Voluntary

  • Involuntary - movement happening without conscious awareness

  • Rhythmic motor patterns

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

• Cerebral cortex

  • Basal ganglia

  • Cerebellum - timing and coordination

  • Brain stem

  • Smaller roles:

    1. Red Nucleus - alternative tract to spinal cord

       1. “Accessory route”

       2. Rough topographical map

       3. Closely associated with cerebellar function

       4. Control of distal motor groups, upper limbs

    2. Reticular formation

    3. Pons

    4. Thalamus

Differentiate the roles of CNS regions involved in voluntary movement:

• Motor cortices - where is the motor plan formed, translated or executed?

  1. Sensation → movement

     1. Sensory cortex : detect it

     2. Sensory association cortex : integrate it

     3. Prefrontal cortex : think about it/plan

     4. Premotor/ Supplement Cortex : image/ translate it

     5. Primary motor cortex : tells SC to do it

     6. Spinal cord: do it!!

        1. Contract muscle & move!

  • Understand the basic anatomy and role of the cerebellum to motor control

    1. Timing & coordination of movement

    2. Monitoring & making adjustments when movement is happening

    3. Spinocerebellum - comparator function

    4. Cerebrocerebellum - planning & programming of movement

    5. Vestibulocerebellum - body equilibrium & eye movement

  • Differentiate the neuroanatomy and contributions of the Basal Ganglia to motor control, (to be presented in detail with Parkinson’s Disease)

    1. 5 nuclei: Caudate, putamen, globus pallidus, substantia nigra, subthalamic nucleus

    2. Direct: enables movement

       1. Glutamatergic input from cortex → D1 receptor → increase activity (movement)

       2. Glutamate

    3. Indirect: inhibits movement

       1. Dopaminergic input from SNc → D2 receptor → decrease activity (movement)

       2. Goes through all nuclei nuclei and then to the motor cortex

       3. GABA

  • Define the corticospinal tract and differentiate between from DCML, ALST tracts

    1. Also called “Pyramidal tract” or “upper motor neurons”

       

    2. Controls speeds and precision of fine motor

    3. Fibers cross → medulla

    4. Synapse → interneuron of spinal cord

    5. Betz cell → giant pyramidal cells

       1. Responsible for direct connects

       2. Very fast

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

• Symptoms of Cortical Damage

  1. Positive signs: spasticity, exaggerated spinal reflexes, Babinski response (toe does not raise)

  2. Negative signs: hypotonia, loss of sensation (damage to sensory cortex), apraxia, aphasia (speech production)

  • Damage to cerebellum

    1. Ataxia

    2. Past pointing - moving beyond point of intent

    3. Intention tremors - going to make movement, then get tremor

    4. Hypotonia

    5. “Failures of progression” - another error in coordination

Understand the spinal cord anatomy for motor function

• Ventral Horn = Motor

  • Spinal segment = myotomes

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

    2. Thoracic (T1-T12): arms, hands, and trunk

    3. Lumbar (L1-L5): waist, thighs, legs, and part of feet

    4. Sacral (S1-S5): back of legs, buttocks, anus

    5. Sacrococcygeal

  • White vs grey matter

    1. White = tracts

       1. Heavily myelinated

    2. Grey = unmyelinated neurons

       1. Cell bodies of neurons (interneurons, motor neurons)

  • 3 types of cells

    1. Interneurons

    2. Motor neurons

       1. Alpha motor neurons (A𝜶) - causing contraction

          1. Large

          2. Branches to innervate extrafusal muscle fibers

          3. Excites contraction of skeletal muscle fibers

       2. Gamma motor neurons (A𝛾)- help sensitivity, controls tone of sensory receptors

          1. Smaller and half as many

          2. Innervates intrafusal muscle fibers

          3. Controls muscle tone

Know muscle essentials for motor control

Differentiate the muscle sensory receptors

• Structure and function (what each one senses)

  1. Muscle spindles = sensory receptors (proprioception)

     1. Central position has no actin or myosin ( so no contraction) and acts as the sensory receptor

     2. Afferent is A𝜶 - fastest in body

  2. Golgi tendon = sensory receptor (proprioception)

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

     2. Detects muscle tension

        1. Via A𝜶 fibers = fastest

     3. Synapse on interneuron

  • Connections to the spinal cord and/ or CNS
    Role in reflexes

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

• Stretch reflex (monosynaptic)

  1. 1 synapse

  2. Sensory receptor (muscle spindles) synapses directly on motor neuron

  3. Relaxed muscle; spindle fiber sensitive to stretch of muscle → contracted muscle with no spindle coactivation → contracted muscle with spindle coactivation

     

  • Flexor withdrawal reflex

    1. Thermal pain receptor in finger

    2. Afferent pathway

    3. Integrating center (spinal cord)

    4. Efferent pathways

    5. Effectors

    6. Ascending pathway to brain

Excitatory interneuron stimulates motor neuron to contract biceps

Inhibitory interneuron inhibit opposing muscle pair, the triceps

Divergent interneuron sends info to the brain

• Crossed extension reflex

  1. Compensation of the opposite limb to the flexor withdrawal reflex

  2. Interneurons cross to the contralateral gray matter and activate extensors and inhibit flexors (by reciprocal inhibition)

  3. Delayed effect - which highlights the role of many interneurons

  • Golgi tendon reflex

    1. Golgi tendon organs detect tension applied to tendon

    2. Sensory neurons conduct action potentials to the spinal cord

    3. Sensory neurons synapse with inhibitory interneurons that synapse with alpha motor neurons

    4. Inhibition of the alpha motor neurons causes muscle relaxation, relieving the tension applied to the tendon.

       1. The muscle that relaxes is attached to the tendon to which tension is applied

    5. Entirely inhibitory

       

    6. Function:

       1. Lengthening reaction = protective

       2. Equalizes contractile force

Skeletal Muscle Physiology (Lecture 32)

Differentiate skeletal muscle from cardiac and smooth

• Skeletal- striated muscle, voluntary

  1. Bundles of long, thich, cylindrical, striated, contractile, multinucleated cells that extend the length of the muscle

  2. Location : attached to the bones

  3. Function : movement of body in relation to external environment

  • Cardiac - striated muscle, involuntary

    1. Interlinked network of short, slender, cylindrical, striated, branched, contractile cells connected cell to cell by intercalated discs

    2. Location: wall of heart

    3. Function: pumping of blood out of heart

  • Smooth - striated muscle, involuntary

    1. Loose network of short, slender, spindle- shaped, unstriated, contractile cells

    2. Arranged in sheets

    3. Location: walls of hollow organs and tubes e.g. stomach and blood vessels

    4. Function: movement of contents within hollow organs

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

• Neuromuscular junction - the junction between the lower motor neuron & muscle fibers

  1. Motor unit

  2. Neurotransmitter = acetylcholine (AcH)

  3. Acetylcholinesterase

     1. Hydrolyzes AcH & prevents it from having continuous synapses

  4. Formation of the endplate potential

     1. Always excitatory (compare to a synapse in the brain)

  5. Initiation of an action potential

  6. Relationship to sarcolemma / Transverse (T) tubules

Know muscle anatomy necessary for muscle contraction

• Slide 8

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

• Myosin heads

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

  2. Hinge region can bend and straighten during contraction

  3. Are ATPase enzymes: activity that breaks down adenosine triphosphate (ATP), releasing energy

     1. Part of the energy is used to bend the hinge region of the myosin molecule during contraction

  • Actin

    1. Thin filaments

       1. Relaxed

          1. No cross-bridge binding because cross -bridge binding site on actin is physically covered by troponin- tropomyosin complex

       2. Excited

          1. Muscle fiber is excited = Ca2+ release

          2. Released Ca2+ binds with troponin, pulling troponin - tropomyosin complex aside to expose cross-bridge binding site

          3. Cross-bridge binding occurs

    2. Thick filaments

       1. Think golf club

       2. Contain a myosin head and tail

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

• Sliding filament mechanism

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

  • Cross bridge activity

    1. Contraction = cycles of cross- bridge binding and bending pull thin filaments inward

       1. Binding: myosin cross bridge binds to actin molecule

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

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

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

    2. Single cross- bridge cycle

    3. All cross- bridge stroking directed toward center of thick filament

    4. Simultaneous pulling inward of all 6 thin filaments surrounding a thick filament

  • Power stroke

    1. Stroking motion pulls the thin filament toward the center of the sarcomere

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

• Ca2+ comes from surface membrane of muscle fiber

  • Excitation- contraction coupling

    1. AP at NMJ causes release of ACh, triggers AP in muscle fiber

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

    3. Ca2+ binds to troponin on thin filaments

    4. Tropomyosin shifts, reveals myosin cross bridges sites

    5. Myosin cross bridges attach

    6. Power stroke (ATP used)

    7. Cross bridge detaches

       1. If Ca2+ is still present, the cross-bridge cycle returns to step 5 for another power stroke

    8. When APs stops, Ca2+ taken back up by sarcoplasmic reticulum. Contraction stops. Thin filaments passively reset

  • ATP powers the cross bridge cycling

Skeletal Muscle Pathophysiology & Movement Disorders (Lectures 33, 34)

Additional Points for Parkinson’ Disease:

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

• Indirect vs direct paths in the basal ganglia

  1. Direct (enables movement):

     1. D1 receptors (G-excitatory)

     2. Increases activity, increases movement

  2. Indirect (inhibits movement):

     1. D2 receptors (G-inhibitory)

     2. Inhibits movement, decrease movement

  3. For parkinson’s disease, too much movement coming out of cortex

     1. Loss of inhibition (D2 receptors)

        1. Leads to increase D1 receptors, so increase movement

  • Differentiate the mechanisms of action of the primary treatment approaches by drug classes (DA replacement therapy, DA agonists, Muscarinic antagonists)

    1. DA replacement therapy

       1. L-Dopa

       2. Give precursor of dopamine, goes to brain & get converted to dopamine

    2. DA agonists

       1. Acts as dopamine

    3. Muscarinic antagonists

Psychosis (Lecture 35)

Apply knowledge of neurotransmission: Glutamate, DA, 5HT

• Glutamate

  1. Controls dopamine release

  • DA

    1. All positive symptoms correlate with high dopaminergic signaling

    2. D2 agonists

    3. A lot of side effects and does not treat negative symptoms

    4. Historic treatment

  • 5HT (serotonin)

    1. Works well with without adverse reactions

Understand the pathophysiology of Schizophrenia:

• Basic epidemiology/ stats

  1. ~1% of the population

  2. Equivalent across males and females

  3. Onset in early adulthood (16-25)

  • Symptoms (positive vs negative vs cognitive)

    1. Positive (gaining, adding)

       1. Delusions - strong beliefs that misrepresent reality

       2. Hallucinations - perceptual disturbances (hearing or seeing)

       3. Thought disorders

          1. Delusions of grandeur - have a ‘gift’

          2. Wild trains of thoughts - thoughts implanted in head by someone else

          3. Irrational conclusions

          4. Rambling speech

       4. Abnormal, disorganized behavior and/ or speech

       5. Catatonia

    2. Negative (taken away or lost)

       1. Socially withdrawn

       2. Flattened affect - absence of an outward emotional reaction to things

       3. Anhedonia - inability to pleasure or joy

       4. Avolition - debilitating lack of motivation

    3. Cognitive

       1. Attention - inability to disengage from stimulus in environment

       2. Memory

       3. Comprehension / understanding

  • Neuropathologies

    1. Frontal lobe

    2. Enlarged lateral ventricles

    3. Slight reduction in thickness of cortical gray matter

    4. Hypofrontality

    5. Loss of gray matter elsewhere: insular cortex, thalamus, striatum

  • Dopamine vs Glutamate vs Serotonin Hypotheses

    1. Dopamine

       1. Indirect evidence of overactive DA system

       2. Stimulants produce a behaviors similar to a schizophrenic episode in humans

          1. Can mimic in animals

       3. D2 receptor antagonists - on positive symptoms

       4. Mesocortical - how widespread is around the cortex

          1. Negative and cognitive symptoms

       5. L-Dopa increased synthesis and release of dopamine

          1. Could lead to hallucinations

       6. Treating symptoms, not cause

    2. Glutamate

       1. Controls dopamine release

       2. Decreased glutamate in CSF and NMDA receptors

       3. Metabotropic glutamate receptors can be modified for drug targets

          1. Ionotropic glutamate receptors are not a good drug target because of excitatory toxicity and cell death that can occur from excess glutamate

    3. Serotonin

       1. Success of 5HT2A serotonin antagonists

          1. Atypical antipsychotic (high 5HT2A)

GQ type antagonisting serotonin receptor

Do not have the adverse response of extrapyramidal or movement disorders (do not have the risk of tardive dyskinesia)

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

• DA antagonists

  1. D2 antagonist is 1st generation antipsychotics

  2. Limitation of D2 antagonist, ADRs: EP movement disorder, tardive dyskinesia

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

  • Glutamatergic

    1. Decreased glutamate in CSF and NMDA receptors

    2. NMDAR hypofunction though to reduce activity of mesocortical DA neurons but increase activity of mesolimbic DA neurons

    3. NMDA- receptors produce both positive and negative symptoms

    4. Limitations: drug discovery is tricky

       1. Excess glutamate is toxic!

Appreciate why Dopamine is a delicate balance in CNS function

Addiction (Lecture 36)

Understand what addiction is and general related terms

• A chronic, relapsing disorder characterized by compulsive drug use, despite harmful or negative consequences

  • Not a diagnosis, substance abuse is the diagnosis

  • Tolerance - decreased in response after repetitive use or exposure

    1. Shifts dose response curve to the right

  • Dependence - more that you use the drug, body & brain change

    1. Psychological - drives the dependence

       1. craving , preoccupations with the drug

    2. Physical - occurs with the chronic use of any substance

       1. Does not mean you have an addiction

    3. Withdrawal - psychological dependence

       1. Remove drug, and now see that shift

       2. Reveals that an individual is dependent

  • Relapse - return to drug seeking and taking

Know the common misused substance and alcohol and their primary mechanism of action (see notes of slide #13 for exactly what you need to know

• Hallucinogens – a variety of mechanisms of action

  1. Dependent upon the agent

  • Cannabinoids – CB1 receptor agonist

  • Opiates - µ (mu) opioid receptor agonist

  • Sedative Hypnotics – APL at GABAa (potentiates GABA’s actions at the GABAa receptor)

  • Stimulants – inhibit the monoamine transporters but methamphetamine also reverses the DAT (toxic!)

    1. Inhibits dopamine transporters and norepinephrine transporters

  • Nicotine – agonist at nicotinic acetylcholine receptors

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

• Alcohol

  1. CNS depressant

  2. Promiscuous pharmacology (acts on every system)

  3. Greatest use disorder

  4. Greatest harm to self and others

  • Most overdoses - synthetic opioids (fentanyl)

What is the mesolimbic dopamine system and differentiate it from the other dopamine systems

Appreciate that all “addictive” drugs increase dopamine but they each do it uniquely in the mesolimbic reward system

• Activate the mesolimbic dopamine system

Seizures (Lecture 37)

Differentiate seizures vs. epilepsy

• Seizure - abnormal and excessive neuronal discharge with or without a change in the level of consciousness

  • Epilepsy - a seizure disorder

    1. Recurrent, unprovoked seizures (diagnosis = 2 unprovoked >24h apart)

Differentiate types of seizures

• Focal seizures

  1. Focused on a particular area of the brain

     1. Affect small region of the brain

  2. Symptoms could be motor, somatosensory, autonomic, or psychic symptoms

  3. Complex focal

     1. May involve unconscious repetition of simple actions, gestures

  • Generalized seizure

    1. Affect whole brain (both hemispheres), loss of consciousness

    2. Generalized tonic-clonic (Grand mal) - stiffening of the body, and repeated jerks

    3. Myoclonic - seizures and twitches of the upper body

    4. Tonic - loss of normal muscle tone

    5. Atonic -

    6. Absence (petit mal)- blip loss of consciousness

       1. Blank out for a second

Know the pathophysiology of seizure:

Basic epidemiology/ stats

• 4th most common neurological disorder

  • Causes:

    1. Idiopathic (do not the cause)

       1. Stroke, severe traumatic brain injury,

    2. Symptomatic (secondary to some other cause)

       1. Alcohol withdrawal, dehydration, hypoglycemia, adverse drug reactions

Symptoms (terms & definitions)

• Sensory/ thought:

  • Emotion:

  • Physical:

Neuropathologies

Understand what EEGs are like in seizure vs normal waves, esp differentiate absence vs. others

Understand the 3 main pharmacotherapeutic approaches

• Trying to dampen heighten activity of APs

  • Inactive voltage gated Na+ channels - stop repetitive firing

  • Enhance GABAergic neurotransmission

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

Sleep Disorders (Lecture 38)

Understand brain systems regulating sleep

• Sleep: readily reversible state of reduced responsiveness to, and interaction with, the environment

  1. Is an active process - neurons still fire

  • Electroencephalogram (EEG) - measures generalized cortical activity

    1. Noninvasive, painless

    2. Diagnose neurological conditions such as epilepsy, sleep disorders

    3. Electrodes placed on scalp

    4. Each EEG electrode records small electrical fields generated by synaptic currents in pyramidal cells

       

    5. Large EEG signals when have synchronous activity occurring within neurons

    6. Rhythms:

       1. Beta - awake, greater than 14 Hz

       2. Alpha - quiet, waking state, lower frequency (8-13 Hz)

       3. Theta - some sleep states

       4. Delta- deep sleep

  • Two main types of sleep:

    1. Non- REM or slow- wave sleep

       1. Stage 1- beginning of the sleep cycle, light sleep lasting 5-10min

       2. Stage 2- bursts of rapid, rhythmic brain activity

          1. Get sleep spindles

       3. Stage 3- deep, slow brain waves begin to emerge

       4. Stage 4- slow wave or delta sleep

    2. REM Sleep or “paradoxical sleep”

       1. 10 to 15 min period at the end of each “sleep cycle”

       2. Looks most like awake waves

       3. Dreaming occurs here

  • Arousal system - reticular activating system in the brainstem regulated by hypothalamus

    1. Promotes wakefulness

    2. Brainstem integrates information

  • Slow - wave sleep center - sleep on neurons in the hypothalamus

    1. Sleep promoting neurons

    2. Release GABA to inhibit wake promoting neurons

  • Paradoxical sleep center - REM- sleep on neurons in the brainstem that switch to paradoxical sleep

    1. Transition from slow- wave sleep to REM - sleep

  • Major neurotransmitters:

    1. Histamine is involved in promoting wakefulness

       1. Slow firing with fatigue or during rest

       2. Cease activty when NREM and REM sleep occurs

    2. Orexin (hypocretin)

       1. essential neuropeptide for sleep/wake and energy balance

       2. Two kinds: orexin A and orexin B

          1. exclusively synthesized in the lateral hypothalamus from prepro-orexin.

       3. Orexin neurons are active during wakefulness and suppressed during REM sleep.

       4. Also known as hypocretin and has been extensively studied for regulating appetite as well.

       5. In order to sleep, orexin neurons MUST be inhibited.

    3. GABA

       1. Primary inhibitory NT of CNS

       2. Sleep-on neurons in the slow wave sleep center are though to inhibit the arousal promoting neurons by releasing GABA

  • Other modulators:

    1. Noradrenaline - major NT of sympathetic nervous system

       1. Mobilizes the brain and body for action

       2. Release is lowest during sleep

    2. Cytokines - chemical signal for the immune system

    3. Melatonin - released from the pineal glad and is regulated by light/ dark cycle (light inhibits melatonin)

    4. Adenosine - generated while awake by metabolically active neurons and glial cells

       1. Inhibits arousal centers

       2. Administration induce sleep and blockade of adenosine receptors promotes wakefulness

          1. Caffeine inhibits adenosine

Differentiate between types of sleep disorder

• Insomnia - a dissatisfaction with sleep quantity or quality with complains of difficult initiating sleep, maintaining sleep, or early morning awakening

  1. Occurs for 3 nights/ week for at least 3 months

  • Hypersomnolence disorder - excess quantity of sleep, deteriorated quality of wakefulness, ans sleep inertia

    1. Difficulty waking or trouble staying awake

  • Narcolepsy - irrepressible need to sleep, lapsing into sleep, or napping occurring within the same day

    1. Diagnostic criteria:

       1. Recurrent periods of an irrepressible need to sleep AND

       2. Must occur with either:

          1. episodes of cataplexy (bilateral loss of muscle tone), OR

          2. Hypocretin deficiency (measured in CSF), OR

          3. Sleep polysomnography showing REM sleep latencies < 15 min

    2. Pathophysiology:

       1. Orexin - wake promoting neuropeptide in the lateral hypothalamus

       2. Neurons project too much of the CNS

       3. Injection of orexin A - promotes wake

       4. Loss of oxerin MAY be sufficient to explain narcolepsy BUT some features like fragmented sleep and hypersomnia not fully explained

       5. Autoreactive T cells may kill orexin inducing narcolepsy

  • Obstructive sleep apnea - repeated episodes of upper (pharyngeal) airway obstruction during sleep that leads to airway being blocked

    1. Changes in body (floppy airway)

  • Central sleep apnea - Repeated episodes of apneas or hypopneas during sleep, caused by changes in brain

    1. Changes in brain

    2. More common in males, stroke is a big risk factor

    3. In kids often caused by tonsillar tissue, in adults due to excess weight and obesity causes soft tissue of the airway to collapse

  • Sleep - related hypoventilation- 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

    1. Paired hypothalamic nuclei called suprachiasmatic nucleus are “primary” circadian pacemaker in humans that regulates 24h rhythms

    2. Subtypes:

       1. Delayed sleep phase type

       2. Advanced sleep phase type

       3. Irregular sleep - wake type

       4. Non - 24h sleep-wake type

       5. Shift work type

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

    1. Examples:

       1. non-REM sleep arousal disorders - incomplete awakening; “sleep - walking”

       2. Repeated occurence of extended, extremely

Explain the clinical manifestations of sleep disorders

Identify causes and consequences of select sleep disorders

• Insomnia -

  1. Causes:

  2. Consequences:

     1. interpersonal , social, occupations problems may develop, increased sleepiness, trouble concentrating, irritability

Dementia (Lecture 39)

Describe and differentiate types of neurocognitive disorders

• Delirium - disturbance of attention or aware accompanied by a change in baseline cognition

  1. Disturbance in attention and awareness

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

  3. Additional cognitive disturbances

  4. Not due to a pre existing neurocognitive disorder

  5. Evidence that disturbance is direct physiological consequence of another condition

Conditions: substance abuse (alcohol, cannabis, opioid, etc), medication (add or withdrawal), surgery, and infection

• Mild neurocognitive disorders - an acquired decline in one or more cognitive domain (noted by self, peer, clinician, or diagnostic test assessment)

  1. Evidence of modest cognitive decline in on or more cognitive domain

  2. Do not interfere with capacity for independence

  3. Do not interfere in the context of delirium

  4. Are not better better explained by another mental disorder

  • Major neurocognitive disorders - n acquired decline in one or more cognitive domain (noted by self, peer, clinician, or diagnostic test assessment)

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

    2. Cognitive deficits interfere with capacity for independence

    3. Cognitive deficits do not interfere in the context for delirium

    4. Cognitive deficits are not better explained by another mental disorder

Identify changes in distinct neurocognitive domains and underlying neural cavity

• Learning and memory

  • Executive function

  • Complex attention

  • Social cognition

  • Perceptual - motor function

  • Language

Explain the clinical manifestations of Alzheimer’s disease

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

Mood Disorders (Lecture 40)

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

Explain the clinical manifestations of these distinct disorders

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

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