Review

3. IDENTIFY THE FOLLOWING STRUCTURES: CORNEA,
SCLERA, PUPIL, IRIS, CILIARY BODY, LENS, RETINA,
OPTIC NERVE, VITREOUS CAVITY.

4. CORNEAL LAYERS
 Corneal Layers: Make up the major refractive surface in the eye
 1 - Epithelium on a basement membrane, site of free nerve endings
contributing to ciliary (blink) reflex
 2 - Bowman layer: acellular, forms a barrier against malignant cells
 3 - Corneal stroma: avascular and alymphatic and precise alignment of
collagen allows for transparency
 4 - Descemet membrane: thickens with age and is the area of copper deposit
in Wilson’s disease (the Keyser - Fleischer rings)
 5 - Endothelium - derived from neural crest cells, its basement membrane is
the Descemet membrane

5. CILIARY BODY
 Ciliary body: composed of ciliary muscle and ciliary processes. Functions are
accommodation of the lens (by the muscle) and the production of aqueous
humor (by the processes)
 The ciliary bodies contract to change the convexity of the eye, altering the focal
distance of the eye, also known as accommodation. This process allows us to
see at various distances.

6. LENS
 Lens: biconvex structure within the eye whose job is to refract and focus light
 The lens sits behind the iris. The lens is unique in that it doesn’t have any
innervation or vascularization. It gets its nourishment entirely from nutrients
floating in the aqueous fluid. The lens also has the highest protein
concentration of any tissue in the body (65% water, 35% protein).
 The lens has three layers in a configuration similar to a peanut M&M. The outer
layer is called the capsule. The capsule is thin with a consistency of saran wrap
and holds the rest of the lens in place. The middle layer is called the cortex,
while the central layer is the hard nucleus.

7. IRIS
 The colored part of the eye is called the iris. It controls light levels inside the
eye similar to the aperture on a camera. The round opening in the center of the
iris is called the pupil. The iris is embedded with tiny muscles that dilate (widen)
and constrict (narrow) the pupil size.
 The sphincter muscle lies around the very edge of the pupil. In bright light, the
sphincter contracts, causing the pupil to constrict. The dilator muscle runs
radially through the iris, like spokes on a wheel. This muscle dilates the eye in
dim lighting.
 The iris is flat and divides the front of the eye (anterior chamber) from the back
of the eye (posterior chamber). Its color comes from microscopic pigment cells
called melanin..

8. RETINAL LAYERS
 The retina is approximately 0.5 mm thick and lines the back of the eye. The
optic nerve contains the ganglion cell axons running to the brain and,
additionally, incoming blood vessels that open into the retina to vascularize the
retinal layers and neurons.
 A radial section of a portion of the retina reveals that the ganglion cells lie
innermost in the retina closest to the lens and front of the eye, and the
photosensors (the rods and cones) lie outermost in the retina against the
pigment epithelium and choroid. Light must, therefore, travel through the
thickness of the retina before striking and activating the rods and cones

9. CHOROID
 The choroid is a bed of blood vessels that lie right under the retina. The choroid
supplies nutrition to the outer one-third of the retina which includes the rod and
cone photoreceptors. Retinal detachments can separate the retina from the
nutritious choroid, which is disastrous for the photoreceptors as they quickly die
without this nourishment.

10. SCLERA
 The outer wall of the eye is called the sclera. The sclera is white, fibrous,
composed of collagen, and is actually continuous with the clear cornea
anteriorly.
 In fact, you can think of the cornea as an extension of the sclera as they look
similar under the microscope. The cornea is clear, however, because it is
relatively dehydrated.
 At the back of the eye, the sclera forms the optic sheath encircling the optic
nerve.

11. BE ABLE TO RECOGNIZE THE CLASSIC “COLLAR-BUTTON”
CONFIGURATION OFTEN SEEN IN UVEAL
MELANOMAS.

12. KNOW AT LEAST TWO KEY PATHOLOGICAL
FEATURES OF UVEAL MELANOMA THAT
INFLUENCE CLINICAL OUTCOME.
 1. Size - in this case we’re talking about the lateral extent of tumor, not depth
 2. Cell type - tumor can have epithelioid and spindle cells, the more epithelioid
the worse the prognosis
 3. Proliferative index - the faster it grows, the worse prognosis
 4. Scleral extension - poor prognostic factor, can metastasize (liver most likely
site)

13. GIVEN A CLINICAL PHOTOGRAPH, BE ABLE TO
RECOGNIZE LEUKOCORIA AND ITS
SIGNIFICANCE.
 can be a sign of many possible
diseases (congenital cataract,
Coats disease, ciliary body
melanoma), but the big one for us
is retinoblastoma

14. KNOW A KEY DIFFERENCE BETWEEN UVEAL
MELANOMA AND RETINOBLASTOMA IN TERMS
OF OPTIC NERVE INVOLVEMENT.
 Retinoblastoma - degree to which there is optic nerve involvement is a
significant factor, if not one of the most important, in determining prognosis
 Uveal melanoma - usually does not involve optic nerve, and involvement of
optic nerve has no impact on prognosis and usually is simply due to tumor size
or proximity

15. GIVEN A MICROSCOPIC IMAGE, BE ABLE TO
IDENTIFY AT LEAST TWO HISTOLOGICAL
FINDINGS IN GLAUCOMA.
 Optic nerve cupping
 Retinal atrophy

16. DEFINE GLAUCOMA AND DESCRIBE THE
DIFFERENCE BETWEEN ANGLE-CLOSURE AND
OPEN-ANGLE GLAUCOMA.
 Glaucoma is a disease where the optic nerve dies and is associated with high
intraocular pressure. Glaucoma is one of the leading causes of preventable
blindness in the U.S., and patients with acute glaucoma can develop irreversible
vision loss within a few hours.
 Open-angle glaucoma is the most common type in our country. It occurs from
decreased aqueous drainage caused by an unidentified dysfunction or microscopic
clogging of the trabecular meshwork. This leads to chronically elevated eye
pressure, and over many years, gradual vision loss.
 This differs from closed-angle glaucoma, also called “acute glaucoma,” which occurs
when the angle between the cornea and iris closes abruptly. With this closure,
aqueous fluid can’t access the drainage pathway entirely, causing ocular pressure to
increase rapidly. This is an ophthalmological emergency and patients can lose all
vision in their eye within hours.

17. IDENTIFY PATIENTS MOST AT RISK FOR OPEN-ANGLE
GLAUCOMA AND NAME THREE RISK
FACTORS.
 Age (Old = over 40 y.o.) = #1 risk factor
 Family history
 Race (More common in African Americans)
 High eye pressure (increased IOP)
 Large vertical nerve cupping
 Thin-corneas

18. NAME THE CLINICAL SYMPTOMS OF GLAUCOMA
& PERTINENT POSITIVES ON EXAMINATION.
 Open Angle Glaucoma exam findings: Elevated eye pressure, optic disk
changes, Repeatable Vision Loss (gradual)
 Closed Angle Glaucoma: Patients present with an extremely red and painful
eye, often complaining of nausea and vomiting. On exam, pupils are sluggish
and mid-dilated. Pressures in the affected eye can be very high, often 60 mm
Hg or higher. The eye will feel rock hard, and you can actually palpate the
difference between the eyes with your fingers. Patients often describe seeing
halos around lights. This occurs because the cornea swells as water is pushed
under high pressure through the endothelium into the corneal stroma.

19. NAME THREE GLAUCOMA TREATMENT OPTIONS
 Medical Therapy
 Topical Beta Blockers
 Carbonic Anhydrase Inhibitors
 Alpha Agonists
 Prostaglandin analogues
 Surgical Therapy
 Trabeculectomy-- alternate drainage pathway is surgically created
 Small hole is cut through superior limbus so aqueous can drain under
conjunctiva
 Plastic Tube-shunt can be inserted into the anterior chamber that drains to a
plate fixed under the conjunctiva further behind the eye.
 Laser therapy
 Argon Laser Trabeculoplasty (ALT)
 Burn portions of trabecular meshwork  scarring opens up meshwork leading
to increased outflow

20. IDENTIFY A GLAUCOMATOUS OPTIC NERVE
Optic cupping

21. DEFINE CATARACT
 A cataract is opacification of the lens
 Nuclear sclerotic plaques are the most common type of cataract and many
consider them to be a normal maturation of the lens. Over time, the lens
becomes larger and brunescent (yellow or brown) especially in the denser
central nucleus
 The posterior subcapsular cataract forms on the back of the lens, on the inner
surface of the posterior capsule bag. These cataracts tend to occur in patients
on steroids, with diabetes, and those with history of ocular inflammation. The
opacity looks like breadcrumbs or sand sprinkled onto the back of the lens.
 Lens opacities in children are of concern because they can mask deadly
disease (remember the differential for leukocoria from the pediatric chapter) but
also because they are highly amblyogenic.

22. NAME TWO SYMPTOMS OF CATARACT
 Slow painless progressive loss of vision
 Glare
 Occasional diplopia

23. PROVIDE THE INDICATIONS FOR CATARACT
EXTRACTION
 1. Decrease in visual acuity due to lens opacity causing limitation of function in
daily activities
 2. 20/50 is a guideline for surgery
 3. BUT, it Depends on your patient and their particular needs (e.g. pilot)
 5. Underlying retinal disease

25. DEFINE DIABETIC RETINOPATHY AND STATE THE
TWO MAIN CATEGORIES.
 This is retinal bleeding, edema, ischemia, and ultimately neovascularization caused by
diabetic damage to the retinal blood vessels
 Nonproliferative Diabetic Retinopathy (NPDR)
 95% of retinopathy
 early stages with slow progression
 Fundus Exam:
 Vessel Microaneurysms
 Hemorrhages
 Dot-blot: small, round; located deep in retina
 Flame: spread; superficial ganglion nerve layer; HTN-related
 Cotton-Wool Spots: superficial retinal nerve ischemia/infarction
 Proliferative Diabetic Retinopathy (PDR)
 prolonged diabetic damage to retinal vessels leads to occlusion to large areas
 ischemia promotes VEGF to induce neovascularization
 50% of pt with proliferative retinopathy will go blind if untreated

26. PATHOPHYSIOLOGY
 Diabetics have high systemic BGL which creates an ideal environment for a
glycosylation rxn to occur. This reaction damages the collagen/protein within
the capillary walls leading to wall thickening and breakdown.
 Larger areas can get ischemic → promote VEGF to induce neovascularization*
 friable & prone to leak
 grow in the wrong place (surface of retina or off of retina into vitreous or iris)
 Neovascularization of Iris (NVI):
 VEGF penetrates anterior chamber/iris → vessels over trabecular meshwork →
sudden neovascular glaucoma
 Vessels adhere to lattice framework proteins of vitreous → when vitreous
moves/contracts → vessels pull on retina → retinal detachment
 Vessels can regress/scar down → traction onto retina beneath

27. LIST THE SYMPTOMS OF DIABETIC MACULAR
EDEMA. LIST THE SYMPTOMS OF
PROLIFERATIVE DIABETIC RETINOPATHY.
 Macular Edema: microaneurysm/capillary leakage of fluid causing macular
thickening and swelling
 macula appears mildly elevated w/ hard exudates (yellow lipid residues from
previous retinal swellings)
 Most common cause of blindness in diabetics
 Occurs in about 10% of diabetics
 Sx:
 blurred vision
 distorted images
 missing areas of vision
 change in visual contrast

28. RX FOR DIABETIC RETINOPATHY
 Medical: BGL control (lower A1C)
 Surgical Treatment
 Vitrectomy
 Remove strands creating traction on retina
 Argon Laser
 Burns/seals off leaking vessels
 Pan-Retinal Photocoagulation (PRP) gets 1000s of spots in retinal periphery →
destroy ischemic retina → decreasing VEGF production
 SE: peripheral vision loss, decreased night vision (peripheral rods)

29. MACULAR EDEMA RX
 Macular Edema Treatment
 DR treatments +
 Intravitreal anti-VEGF
 Ranibizumab - Anti VEGF
 Lucentis
 Intravitreal Steroids → reduce macular thickness (again only a transient
response)
 Triamcinolone

30. LIST THE CONSEQUENCES OF UNTREATED
PROLIFERATIVE DIABETIC RETINOPATHY.
 Proliferative retinopathy tends to advance rapidly via VEGF induced
neovascularization.
 If left untreated, 50% of patients with proliferative diabetic retinopathy will go
blind within five years.

32. NAME THE SYMPTOMS OF A RETINAL
DETATCHMENT
 Patients tend to see flashing lights (Photopsias) in their peripheral vision
 Often present when detachment first occurs
 Produced when mechanical disturbance (i.e. retinal detachment) stimulates
photoreceptors
 Patients tend to see floaters
 Floaters are dark specks obscuring vision
 Floaters are created by objects (blood cells or pigment) floating in the vitreous
fluid that cast shadows on the retina
 Patients can see a “dark curtain” that obscures their peripheral vision
 A particularly ominous symptom indicating progression of the retina across the
visual field
 More rare
 Note: the combination of flashing lights and floaters should be considered a retinal
detachment until proven otherwise

34. NAME THE SYMPTOMS OF A RETINAL TEAR
 Retinal Tear:
 Can occur via trauma, surgery, or extend from preexisting retinal holes
 Requisite for a rhegmatogenous retinal detachment to occur
 Patients liable to experience flashing lights, floaters, and occasional “dark
curtain” described above

35. DEFINE AGE RELATED MACULAR
DEGENERATION (ARMD).
 Age Related Macular Degeneration (ARMD):
 Leading cause of blindness in the elderly
 Extracellular breakdown deposits called “drusen” form deep in Bruch’s membrane
 Bruch’s membrane is the thin layer separating the Retinal Pigmented Epithelium
(RPE)/Retina from the underlying choroidal blood supply
 Blockage by drusen prevents:
 Nutrition from passing from the choroidal blood supply to the retina
 Photoreceptor waste products from draining down into the choroidal bed
 Over time, this causes deterioration of the macula and death of the retinal pigment
epithelium and photoreceptor cells, resulting in a blurry or spotty loss of central vision
 Exam:
 Localized retinal atrophy and pigmentary changes in the macula
 Findings correlate with poor central vision
 Visual loss tends to occur slowly

36. LIST THE TWO TYPES OF ARMD.
 “Dry” ARMD
 Characterized by yellow drusen deposits
 This is the most common type (85-90%)
 Neovascular “wet” ARMD (shown below)
 A break in Bruchs membrane enables vessels to grow up out of the deep
choroidal circulation directly up into the retina (making the treatment difficult).
 These neovascular growths are often weak and prone to hemorrhage and/or
edema, which can rapidly destroy vision.

38. STATE WHO IS AT RISK FOR ARMD. DESCRIBE
THE SYMPTOMS OF ARMD.
 Risk Factors for ARMD:
 Increased Age
 Caucasian
 Family history of ARMD
 Smoking
 Symptoms:
 Deterioration of central vision
 Vision loss occurs slowly over several years
 Tends to occur bilaterally
 Diminished or changed color perception

39. NAME TWO AVAILABLE TREATMENT OPTIONS
FOR ARMD.
 PDT (photodynamic therapy)
 A photoreactive chemical (verteporfin--reacts to a specific wavelength of
light) is injected and allowed to reach the retinal blood vessels, at which
point light with wavelength specific for verteporfin is directed at the fovea to
induce coagulation in the nearby blood vessels, thus preventing further
hemorrhage/edema in wet ARMD
 Injection of anti-VEGF drugs
 Anti-neovascular drugs stop angiogenesis, decrease vessel wall leakage, and
can help with other causes of macular edema.
 e.g. Avastin, lucentis; injected directly into the vitreous humor on a monthly
basis

41. CONJUNCTIVITIS

42. ENDOPTHALAMITIS

43. ORBITAL CELLULITIS

44. CORNEAL ULCER: KERATITIS

45. GIVE THE STEPS OF YOUR EVALUATION AND
TREATMENT OF CHEMICAL EXPOSURE IN THE
EMERGENCY DEPARTMENT SETTING.
 1. Immediate irrigation (with topical anesthetic, at least 30 min or until pH
neutral)
 Morgan lens helps
 2. Examine surrounding area for foreign bodies, document visual acuity,
measure IOP, slit lamp examination
 3. ID substance
 4. Check cornea
 Red - inflamed from acid exposure, better outcome
 White - from bleach or other basic substance, loss of blood vessels in
conjunctiva, bad

46. NAME THREE IMPORTANT STEPS IN YOUR
APPROACH TO A PATIENT WITH SUSPECTED
PENETRATING OCULAR INJURY IN THE ED.
 1. Asses injury/take history
 -protruding foreign bodies should be left in place
 -check for Seidel sign (fluorescein streaming in tear drop pattern away from
puncture site. This assesses for leakage of the anterior chamber into the cornea)
 -illuminate with a penlight
 -uvea prolapsing into or through wound diagnostic
 -be cautious about using medicinal eyedrops
 -visual acuity
 CT if foreign body suspected
 2. Shield eye!
 3. Give antiemetics to prevent increases in ICP
 Antiemetics to prevent “expulsion of tissues through the wound” during vomiting
 NPO in case surgery is needed
 Prophylactic antibiotics (cefazolin and gentamicin)

47. TREATMENT OF ACUTE ANGLE GLAUCOMA
 Treatment in ER: (reduce intraocular pressure via meds/position change)
 supine position
 Diamox (aka acetazolamide→ carbonic anhydrase inhibitor, a p.o. drug to reduce
ciliary body aqueous production)
 Beta blocker eye drops (timolol-- also decreases aqueous humor production).
 Alpha agonists - decrease aqueous humor production
 Cholinergic agonists - (pilocarpine drops) also help to deepen the anterior
chamber by pupillary miosis and ciliary muscle contraction (opens angle)
 Call the on-call ophtho resident.
 Treatment in eye clinic: (actually drain some aqueous humor out of the eye)
 Emergency iridotomy/iridectomy
 Laser peripheral iridoplasty (shrink the iris margin near the limbus so that it
contracts away from the cornea thus deepening the chamber)
 Lower IOP

48. NAME AT LEAST TWO EMERGENT CONDITIONS
THAT CAUSE PAINLESS RAPID VISUAL LOSS.
 #1:Branch Artery Occlusion
 To treat--> LOWER PRESSURE
 Topical IOP lower medicines
 Breath into paper bag to increase CO2 and cause vasodilation
 Paracentesis
 Very bad prognosis- only 90min window for re-perfusion and save sight
 Also
 Retinal detachment
 Vein occlusion
 Hemorrhage
 Cataract
 Giant cell arteritis
 Papilledema
 Optic neuritis

49. DEFINE GIANT CELL ARTERITIS. STATE THE
POTENTIAL VISUAL CONSEQUENCES OF THIS
CONDITION.
 GCA (Giant cell arteritis) aka temporal arteritis: a vasculitis within the medium
and small-sized arteries around the head.
 The vasculitis can lead to a sudden occlusion of the blood supply to the eye
leading to sudden and permanent vision loss.
 Think in older people >70 yo; also affects women more than men (3.7:1) the
disease essentially never occurs in individuals younger than 50

51. IDENTIFY THE DIFFERENCES BETWEEN
CLINICAL PSYCHOLOGY, PSYCHIATRY, AND
CLINICAL NEUROPSYCHOLOGY.
 Clinical psychology
 Treat mental distress and dysfunction, primarily through psychotherapy and
counseling
 Career assessment, group therapy, relationship counseling
 Psychiatry
 Physicians who specialize in the treatment of mental illness
 Prescribe medications, order and interpret laboratory tests
 Clinical neuropsychology
 The study and function of the brain as it relates to psychological processes
and behavior

52. IDENTIFY INFORMATION THAT YOU CAN HOPE
TO OBTAIN FROM NEUROPSYCHOLOGICAL
TESTING.
 Characterize cognitive, emotional behavioral deficits and strengths
 Relate deficits to functional neuroanatomy
 Provide diagnostic considerations
 Offer etiology for neuropsychological deficits
 Offer predictive information with respect to the outcome of a suspected or
known condition
 Provide information re: the level of supervision needed, and for planning for
future care
 Document improvement or decline in function, assist in evaluating treatment
effectiveness, monitor for what type or intensity of intervention may be needed

53. DESCRIBE THE PURPOSE AND USE OF
NORMATIVE DATA IN NEUROPSYCHOLOGICAL
TESTING.
 Normative Comparison Standards:
 Species-specific standards reflect species wide capacities. The patient’s
attributes are compared against those of their entire species. For example, the
deep tendon reflex of the patient is compared against the normal reflex of well-functioning
adults.
 Population averages: determined by the performance of a large sample of
individuals on a particular cognitive or behavioral test. The sample of
individuals comes from a known population whose distribution of scores is
assumed to approximate a normal or bell-shaped curve.
 Individual Comparison Standards: reflect the individual patient’s level of
ability before the onset of known or suspected disease. Used to measure how
the patient’s current level of functioning differs from their premorbid level of
functioning.

54. DIFFERENTIATE BETWEEN PERSONALITY TESTS
AND NEUROCOGNITIVE TESTS
 Neurocognitive functions are defined as cognitive functions closely linked to
particular areas, neural pathways, or cortical networks in the brain. Neurocognitive
tests gauge:
 Intellectual
 Academic
 Attention/ concentration
 Learning / memory
 Language
 Abstract reasoning
 Complex problem solving
 Processing speed
 Motor/ sensory
 A personality test, on the other hand, is designed to reveal aspects of an individual’s
character or psychological makeup.

55. DIFFERENTIATE BETWEEN SYMPTOM
CHECKLISTS AND OBJECTIVE PERSONALITY
MEASURES AND THE BENEFITS OF EACH
 Symptom checklists: Tests that inventory straightforward symptoms of a
psychological disorder. These tests are short and may be completed in 5 – 10
minutes. They also have minimal requirements concerning the patient’s
reading ability and cognitive function.
 Objective Personality Measures:
 Are longer and more complex than symptom checklists. They usually include
validity scales to reflect the extent to which patients answer test questions
accurately and to the best of their abilities. For example, the MMPI-2 has built
in validity scales than can detect when patients have provided inconsistent,
exaggerated, or downplayed responses. The PAI is another objective
personality measure with similar validity scales. These tests tend to take longer
to administer (40 – 50 minutes) and require a grade 4 – 8 reading level.

56. IDENTIFY COMPONENTS OF TEST VALIDITY.
 Face Validity: Face validity is the extent to which the measurement method
appears “on its face” to measure the construct of interest.
 Content Validity: Content validity is the extent to which the measurement
method covers the entire range of relevant behaviors, thoughts, and feelings
that define the construct being measured
 Criterion Validity: Criterion validity is the extent to which people’s scores are
correlated with other variables or criteria that reflect the same construct.
 Discriminant Validity: Discriminant validity is the extent to which people’s scores
are not correlated with other variables that reflect distinct constructs

61. EXPLAIN TWO DIFFERENT PERSPECTIVES ON
THE MEANING OF THE TERM "TRANSLATIONAL
RESEARCH".
 T1: transfer of new understandings of disease mechanisms gained in the lab into the
development of new methods for diagnosis
 requires master of molecular biology, genetics, other basic sciences; trained scientists
working in labs with cutting-edge technology; supportive infrastructure w/in the institution
 struggles more with biological & technological mysteries, trial recruitment, regulatory
concerns
 garners much more attention & funding than T2
 T2: translation of results from clinical studies into clinical practice and decision making
 requires mastery of implementation science - fielding/evaluating interventions in real-world
settings, disciplines that inform design of those interventions (clinical epidemiology
& evidence synthesis, communication theory, behavioral science, public policy, finance,
organizational theory, system redesign, informatics, mixed methods/qualitative research)
 struggles more with human behavior & organizational inertia, infrastructure & resource
constraints, messiness of proving effectiveness of “moving targets” under conditions that
can’t be controlled fully
 as vital as T1, but still defining itself as a field

62. DISTINGUISH BETWEEN THE GOALS AND
METHODS OF BASIC SCIENTIFIC (PRECLINICAL)
RESEARCH AND CLINICAL RESEARCH.
 Preclinical research starts in the lab, trying to identify possible methods of
intervention and improvement on existing methods
 Promising targets found in the lab are then tested on animals to determine
safety and efficacy
 Preclinical research is focused on finding new ways to improve health and
treatment, then determining if any of those seem safe enough to test in humans
 Clinical research is focused on determining if the therapy works, any side
effects, the appropriate dosage, and if it works better than the existing
treatment, use RCTs

63. EXPLAIN HOW PRECLINICAL, CLINICAL AND
TRANSLATIONAL RESEARCH CAN BE
EXPLAINED TO PATIENTS.
 Preclinical: research in the lab that seeks to develop breakthroughs in drug
therapy or human interventions
 Clinical: research that tests the new drug discoveries made in the lab on
humans to determine their efficacy, risks, and side effects
 Translational: “bench-to-bedside”, applying results from preclinical & clinical
research to real-world, hospital settings so that patients can have access to the
newest therapies. also bedside to bench- taking clinical observations or
problems and applying them to lab research

64. EXPLAIN THE STANDARD TRAJECTORY OF
STEPS IN CLINICAL RESEARCH.
 Researcher submits Investigational New Drug (IND) application to FDA in the
form of written protocol delineating purpose, criteria for participants, schedule
of tests/procedures/etc., length of study, outcomes/measurement of outcomes,
statistical analysis, and anticipated risks/benefits.
 Must be approved by IRB and obtain informed consent from participants
 Begin RCTs (randomization, control group, blinding/masking, statistical
evidence)

65. COMPARE AND CONTRAST THE DIFFERENT
PHASES OF CLINICAL TRIALS.

67. LIST THE CONSEQUENCES OF UNTREATED
POSTOPERATIVE PAIN FOR THE PATIENT AND
THE HEALTH CARE SYSTEM.
 Improper initial Tx → ↑ CNS/PNS sensitization → ↑analgesic use, restricted activity,
↓ quality of life, ↑healthcare utilization
 unnecessary patient discomfort
 patient dissatisfaction
 longer hospital stays
 undue medical expense
 over-utilization of the stressed health care system
 poor clinical outcomes
 Pathophysiologically
 Cardiovascular: tachycardia, hypertension
 Pulmonary: hypoxia, hypercarbia (too much Co2 in the blood), decreased cough,
vital capacity and FRC, atelectasis, V/Q abnormalities
 Gastrointestinal: nausea, vomiting, ileus, intolerance to oral intake

68. LIST SEVERAL INFLAMMATORY MEDIATORS
THAT CAUSE PAIN AT THE SITE OF INJURY
 Bradykinin [sensitize AND stimulate receptors]
 Free H+ (low pH)
 Serotonin
 Histamine
 Substance P
 Prostaglandins [only sensitize peripheral receptors]
 Thromboxanes
 Leukotrienes
 Adenosine
 ATP
 Protein kinase C (PKC)
 Nerve growth factor (NGF)
 Cytokines
 Excitatory amino acids
 Capsaicin (TRPV1)

69. NAME FOUR PHYSIOLOGICAL CONSEQUENCES
OF PERIPHERAL SENSITIZATION TO PAIN.
 Decreased threshold for activity (ouch easier)
 Shorter response latency (ouch faster)
 Spontaneous activity (ouch without stimulus)
 Exaggerated response to a given stimulus (ouch excessively)

70. DISTINGUISH BETWEEN A-DELTA AND C-POLYMODAL
FIBERS
A-delta C-polymodal
Stimuli Mechanical/thermal Mechanical, thermal,
chemical
Myelination/Speed Yes/fast No/slow
Pain localization Sharp, localized pain Aching, throbbing, diffuse
pain
Fatiguability Fatigue with use Do not fatigue
Response involved Withdrawal response Reflex muscle spasm

71. DESCRIBE THE ROLE OF A-ALPHA AND A-BETA
FIBERS IN MEDIATING HIGH INTENSITY ACUTE
PAIN AND LOW INTENSITY CHRONIC PAIN.
 A-alpha & A-beta fibers normally do not transmit pain information to the dorsal
horn, but can be induced to carry pain if it is high-intensity acute pain or low
intensity chronic pain. If the stimulation is continuous it can cause release of
chemicals into dorsal horn and sensitization of CNS.

72. DESCRIBE THE CHEMICAL CONSEQUENCES OF
CONTINUED NOXIOUS STIMULATION FOR THE
DORSAL HORN OF THE SPINAL CORD.
 When noxious stimulation is continuous → cytokines, prostanoids, excitatory
amino acids (EAAs), peptides like substance P and CGRP (calcitonin gene
related peptide) are released in the dorsal horn of the spinal cord → so
sensitization of the response in the CNS occurs (central sensitization or wind-up)
 This sensitization happens through G-protein coupled receptors & ligand-gated
ion channels (Na+ channel, voltage-dependent Ca2+ channels)
 Glutamate, neuropeptides, and the expression of immediate early genes and
neurotrophic factors (i.e. nerve growth factor) are key

73. EXPLAIN HOW THE DESCENDING MODULATION
SYSTEM ALTERS PAIN PERCEPTION.
 Descending circuits from the brain synapse on afferent fibers in the dorsal horn.
These fibers can provide excitatory or inhibitory inputs onto afferent pain fibers
(dial up or dial down pain).
 The descending circuit alters pain perception via attention, expectation, placebo
effects, and hypnotic manipulation.
 NE, 5-HT, glutamate, NMDA-R, GABA, and opioids are all thought to be
important in descending modulation of pain

74. GATE CONTROL THEORY
 Collaterals of the large sensory fibers carrying cutaneous sensory input activate
inhibitory interneurons  inhibit (modulate) pain transmission information
carried by the pain fibers.
 Non-noxious input suppresses pain, or sensory input “closes the gate” to
noxious input.
 The gate theory predicts that at the spinal cord level, non-noxious stimulation
will produce presynaptic inhibition on dorsal root nociceptor fibers that synapse
on nociceptors spinal neurons (T), and this presynaptic inhibition will block
incoming noxious information from reaching the CNS

75. DISTINGUISH BETWEEN CLINICAL PAIN AND
PHYSIOLOGICAL PAIN

76. LIST THREE REGIONS OF THE SPINAL CORD
AND PNS THAT ARE TARGETS FOR ANALGESICS.
NAME TWO MECHANISMS THROUGH WHICH
LOCAL ANESTHETICS BLOCK PAIN.
 Spinal Cord
 Dorsal root ganglion
 Site of pain
• Presynaptic block of release of NT
• Postsynaptic hyperpolarization

77. DESCRIBE THE MECHANISM BY WHICH
PATIENT-CONTROLLED ANALGESICS ARE
THOUGHT TO BE EFFECTIVE. DESCRIBE THE
MECHANISM BY WHICH PRE-EMPTIVE
ANALGESIA IS THOUGHT TO BE EFFECTIVE.
 Patient Controlled Analgesia: Based on the idea that small, frequent doses of IV
opioids will have a more consistent and enduring effect on post-op pain than
large, single doses prescribed by the physician; avoids the pt oscillating
between intense pain and a drug-induced stupor
 Pre-emptive Analgesia: Prevents sensitization and long-term chronic effects
from maladaption of the pain neurons leading to neuropathic pain

78. LIST THE GOALS OF ACUTE PAIN MANAGEMENT
 Optimize pain control for the individual patient
 Maximize safety
 Minimize side effects
 Reduce/eliminate complications of recovery
 Maximize return of function and rehabilitation
 Address ease of use of the pain management program for the staff and the
patient

79. DESCRIBE THE DIFFICULTIES OF MANAGING
CHRONIC PAIN CONDITIONS. LIST THREE GOALS
OF CHRONIC PAIN MANAGEMENT.
 Chronic pain lingers, which leads to:
 Failed expectations for tx leading to cure
 Frustration among MDs and pts
 Changes in attitudes about regaining health, changed behavior, altered
lifestyle
 Neuroplastic alterations to the CNS/PNS: changes in patterns of RNA
expression
 Goals:
 Decrease the frequency and/or intensity of the pain over time
 Increase the pt’s ability to function
 Help pt cope with residual pain and pain-related issues

80. LIST 5 PHYSIOLOGICAL MECHANISMS
UNDERLYING NEUROPATHIC PAIN.
 CNS sensitization:
 A plastic response to the release of cytokines, prostanoids, excitatory AAs, peptides
(substance P, CGRP) etc released in dorsal horn
 Excitatory Aas: Excreted at the terminus of neuron in response to opening of Ca2+ gates
 Primary EAAs: glutamate, aspartate
 Mediate transmission of pain through each level, from primary afferents to thalamus
 Sensitization (induction) of primary afferents:
 Fibers that don't normally conduct pain become induced to transmit noxious information
 Adrenergic sensitivity:
 Elaboration of adrenergic receptors in damaged tissue results in transmission of pain as
a part of sympathetic.
 Sprouting of primary afferents from damaged neurons:
 More areas of nociceptive activity
 Disinhibition:
 Loss of descending modulatory control over unpleasant stimuli
 Glial activation:
 Increased production of inflammatory mediators, perpetuating pain response

81. NAME 3 COMPLICATIONS OF PAIN
MANAGEMENT
 Drug Addiction
 Delirium
 Constipation

82. IDENTIFY THE THREE FAMILIES OF
ENDOGENOUS OPIOID PEPTIDES.
 Endorphins
 Enkephalins
 Dynorphins

83. NAME THE RECEPTORS ACTIVATED BY
ENDOGENOUS OPIOID AGONISTS.
 There are three receptor types for endogenous opioids. All of the opioid
receptors are G Protein Coupled Receptors (GPCRs)
 μ (MOR)
 δ (DOR)
 κ (KOR)
 μ (MOR) is the target of most opiates either natural or synthetic.
 Activating μ (MOR) leads to
 (1) opening of potassium channels (causing hyperpolarization)
 (2) closing of the calcium channels (inhibiting the release of neurotransmitter
 (3) inhibition of cAMP

84. NAME AREAS WITH A HIGH DENSITY OF OPIOID
RECEPTORS
 Widespread with high density of opioid receptors in:
 prefrontal cortex
 hippocampus
 periaqueductal gray
 spinal cord dorsal horn

85. WHICH CLASS OF RECEPTORS IS THE
PRINCIPAL TARGET OF OPIOID ANALGESICS
 μ receptor

86. EXPLAIN THE EFFECTS OF MU-OPIOID
RECEPTOR AGONISTS ON SYNAPTIC
TRANSMISSION.
 Normally an inhibitory GABA-ergic neuron dampens the excitatory impulses
from the PAG to the Dorsal horn of the spinal cord
 These excitatory impulses can block or modulate pain by release of serotonin
and norepinephrine from neurons originating in the nuclei raphe magnus at the
dorsal root ganglion
 Mu- opioid agonists block calcium channels and open K+ channels to
hyperpolarize the inhibitory GABA neuron in the PAG and increase excitatory
signals from the PAG to induce analgesia

88. IDENTIFY STRONG, MODERATE AND MIXED
OPIOID ANALGESICS.
 Strong
 Morphine
 Methadone
 Fentanyl
 Sufentanil
 Remifentanil
 Moderate
 Codeine
 Hydrocodone
 Oxycodone
 Mixed Action
 Pentazocine
 Nalbuphine
 Buprenorphine
 Butorphanol

89. DESCRIBE THE KEY PHYSIOLOGICAL EFFECTS
OF MORPHINE AND RANK-ORDER THEIR
IMPORTANCE
 Miosis (useful for diagnosing overdose)
 Respiratory depression
 Analgesia
 Truncal rigidity
 Sedation
 Cough suppression
 Euphoria
 Nausea & vomiting
 Temperature

90. LIST SOME MEDICAL/CLINICAL SETTINGS
WHERE MORPHINE IS USED/OR IS
APPROPRIATE.
 Post-operative pain control
 Hospice pain control
 Emergency room/ambulance for MIs
 Highly painful conditions (burns, kidney stones, trauma)
 Diarrhea
 Shivering
 Best at relieving severe, constant pain

91. DESCRIBE THE SPASMOGENIC ACTIVITY OF
OPIOID AGONISTS AND ITS THERAPEUTIC
IMPLICATION.
 Intrathecal doses > 20 mg/day increases the development of tolerance and
serious toxicity including myoclonic spasms. Intrathecal dosage is usually
1/10th the epidural dosage.
 Morphine and opiate agonists increase the tone of the biliary tract causing
spasms (especially in the sphincter of Oddi) increasing biliary tract pressure.
Morphine should be used cautiously in patients with biliary tract disease or
undergoing biliary tract surgery

92. SIDE EFFECTS
 Respiratory Depression
 Decreases respiratory rate, affects respiratory centers
 Decreased gut motility
 Inhibits output of myenteric plexus
 Constipation results, used therapeutically for diarrhea
 DON’T USE W/ ANTIMUSCARINICS
 Difficulty with urination
 Inhibits voiding reflex
 Orthostatic hypotension
 Depressant of medullary vasomotor center

94. IDENTIFY MOR PARTIAL AGONISTS
 Pentazocine
 Buphrenorphine
 Can be used to wean patients off of Opioids

95. IDENTIFY OPIATE WITHDRAWAL SYMPTOMS
 dysphoria
 anxiety
 restlessness
 insomnia
 high BP
 tachycardia
 diarrhea

96. EXPLAIN WHAT NALOXONE, NALTREXONE AND
NALMEFENE ARE, WHEN THEY ARE USED AND
THEIR ROUTE OF ADMINISTRATION
 Naloxone: MOR antagonist used for opiate overdose - Short T½ if given orally,
most effective in repeated, small IV doses - Bad oral bioavailability
 Naltrexone: MOR antagonist used for opiate addiction. Long T ½ - Can take
orally
 Nalmefene: More ‘universal’ opioid antagonist (blocks MORs, KORs, and
DORs), Long T ½ - Can take orally - primarily used for alcohol dependence

97. NALOXONE
 Administration in:
 Opiate free individual: probably no effect
 Taking opiates, nonabuser: actions of current opiate will be diminished and they
will feel pain again
 Taking opiates, abuser/dependent: will go through immediate withdrawal which
can be very severe and painful

98. BUPHRENORPHINE
 Administration in:
 Opiate free person: may induce some analgesia
 Taking opiates, nonabuser: May mitigate or exacerbate
 Taking opiates, abuser/dependent: Effective treatment because you can start
weaning them off the drug
 Not taking opiates, past abuser/dependent: High probability of relapse

100. 5 COMPONENTS OF THE BASAL GANGLIA
 Caudate
 Putamen
 Globus Pallidus
 Subthalamic nucleus
 Substantia Nigra

101. BASAL GANGLIA

102. STRIATUM AND LENTIFORM NUCLEUS
 Striatum: Caudate + Putamen
 Lentiform nucleus: Putamen + Globus Pallidus
 Nucleus accumbens: Part of ventral striatum

103. SUBSTANTIA NIGRA PARS COMPACTA VS.
SUBSTANTIA NIGRA PARS RETICULATA
 Substantia nigra pars compacta = More dorsal, darkly pigmented, dopaminergic
neurons. Sends inhibitory D2 and excitatory D1 input to the striatum.
Degeneration of these neurons important mechanism in Parkinson’s disease
 Substantia nigra pars reticulata = Ventral portion of SN; Inhibitory GABA
neurons to VL of thalamus for head and neck.

104. INPUT TO BASAL GANGLIA
 Excitatory Glutamate Cortical Input
 Excitatory and Inhibitory input from Substantia Nigra Pars Compacta
 Excitatory Acetylcholine Interneurons

105. OUTPUT FROM BASAL GANGLIA
 Motor control: (These pathways are inhibitory and use GABA)
 Substantia nigra pars reticulata convey info for the head and neck
 Internal segment of globus pallidus convey motor control for the rest of the
body
 Main output pathways are to ventral lateral (VL) and ventral anterior nuclei of
the thalamus via thalamic fasciculus.
 Thalamic fasciculus carry outputs from the basal ganglia to the anterior portion
of VL and cerebellar outputs to the the posterior VL (Caudal parts of VL receive
inputs from Cerebellum)

108. INDIRECT AND DIRECT PATHWAYS OF THE
BASAL GANGLIA

109. PARKINSON’S PATHOPHYSIOLOGY
 1. Dopamine neurons in the substantia nigra pars compacta degenerate.
 2. Dopamine appears to have excitatory effects on striatal neurons of the direct
pathway but inhibitory effects on striatal neurons of the indirect pathway.
 3. Therefore, dopamine normally has a net excitatory effect on the thalamus.
 4. Loss of dopamine will result in net inhibition of the thalamus.
 5. Paucity of movement seen in Parkinson’s disease.
 Drugs that bolster dopaminergic transmission can improve the symptoms of
Parkinson’s disease.

110. EFFECT OF ANTICHOLINERGIC DRUGS FOR
PARKINSON’S DISEASE
 The striatum contains large acetylcholinergic interneurons.
 These may form direct excitatory synapses on the indirect pathway.
 With low dopamine, anticholinergic interneurons exacerbate inhibition.
 Removal of cholinergic excitation of the indirect pathway produces a net
decrease in inhibition of the thalamus  therapeutic
 Benztropine and Trihexyphenidyl
 Can cause memory loss
 Addresses sx, but not dopaminergic degeneration

111. HEMIBALLISMUS
 Unilateral wild flinging movements of the extremities contralateral to a lesion in
the basal ganglia. The lesion in hemiballismus often involves the subthalamic
nucleus.
 Damage to the subthalamic nucleus decreases excitation of the internal
segment of the globus pallidus, resulting in less inhibition of the thalamus,
causing a hyperkinetic movement disorder

112. HUNTINGTON’S DISEASE
 In Huntington’s disease, striatal neurons in the caudate and putamen
degenerate.
 There is histological evidence that, at least initially, the enkephalin-containing
striatal neurons of the indirect pathway are more severely affected.
 Cause loss of inhibition from external globus pallidus, allowing it to inhibit the
subthalamic nucleus.
 Inhibition of the subthalamic nucleus is similar to a lesion of the subthalamic
nucleus and may account for the hyperkinetic movement disorder seen in
Huntington’s disease.
 In more advanced stages of Huntington’s disease, both the direct and the
indirect pathways degenerate, and a rigid hypokinetic parkinsonian state
results.

113. LEAD PIPE RIGIDITY, COGWHEEL RIGIDITY,
PARATONIA, DYSTONIA, ATHETOSIS, CHOREA,
BENIGN RESTING TREMOR.
 Lead Pipe Rigidity: Uniform stiffness and inflexibility throughout passive
movement
 Cog Wheel Rigidity: Tension in a muscle that gives way in little jerks
 Paratonia: Hypertonia with an involuntary resistance during passive movement.
 Dystonia: Abnormal, distorted positions of limbs, trunk, or face
 Athetosis: Twisting movements of the limbs, face, & trunk
 Chorea: Nearly continuous involuntary movements that have a fluid, jerky
quality
 Benign Resting Tremor: Most prominent when the limbs are relaxed
 Important feature of Parkinson’s disease (“Parkinsonian tremor”)

114. NAME THREE FUNCTIONS, OTHER THAN MOTOR
FUNCTION, THAT ARE REGULATED BY PARALLEL
BASAL GANGLIA PATHWAYS.
 Eye Movement
 Cognitive Function
 Emotional Function/motivational drives

115. SIGNS, SYMPTOMS AND TIME COURSE OF
PARKINSON’S DISEASE
 Unilateral “pill rolling” tremor, masked facies, bradykinesia, hypophonic voice,
hurried/muttered speech, micrographia, postural instability, Parkinsonian gait
 Initially: slowing, difficulty initiating movement, resting tremor
 ONSET AGE 40-70
 CLASSIC TRIAD appears later: resting tremor, bradykinesia, cogwheel rigidity
 Insidious progression over 5-15 years
 Unilateral  bilateral
 Festinating (shuffling) gait, Retropulsion, En bloc turning

116. PHARMA FOR PARKINSON’S
 Anticholinergics: Benztropine, Trihexyphenidyl
 Amantidine: increases DA release
 MAOI: Selegeline, Rasagiline
 DA agonists: Apomorphine, Pramipexole, Ropinirole
 Levadopa – Give with Carbidopa and COMT inhibitors

117. MICROSCOPIC AND MACROSCOPIC FINDINGS
 Gross:
 Pallor of the substantia nigra and locus ceruleus
 Microscopic Histopathology:
 Loss of pigmented, catecholaminergic neurons in the substantia nigra/locus
ceruleus  associated w/ gliosis
 Lewy Bodies: single or multiple, cytoplasmic, eosinophilic (pink), round to
elongated inclusions that often have a dense core surrounded by a pale halo
 Composed of fine filaments of alpha-synuclein

118. LEVADOPA PHARMACOLOGY
 Levodopa is converted to DA by DOPA decarboxylase in peripheral circulation and
CNS
 Activation of dopamine receptors in the CNS  improves sx of Parkinson’s
 Activation of dopamine receptors in periphery  cardiac arrhythmias
 Carbidopa is inhibits DOPA decarboxylase and is VERY polar, so it doesn’t cross the
BBB
 Prevents peripheral effects of Levodopa
 Also increases the amount of levodopa available to enter brain (no peripheral
conversion)
 COMT inhibitors: entacapone, tolcapone
 High dose of L-DOPA/carbidopa  accumulation of 3-O-methyl DOPA (a metabolite
COMT metabolizes L-DOPA)
 3-O-methyl DOPA has a really long half life ~20 hrs (remember L-DOPAs is ~90
mins) AND it competes with L-DOPA for entry into brain!
 Reduction of 3-O-methyl DOPA  bioavailability of L-DOPA

119. DESCRIBE THE MECHANISMS BY WHICH
TETRABENAZINE AND HALDOL ARE EFFECTIVE
IN TREATING CHOREA.
 Haldol (haloperidol) = typical D2 receptor antagonist
 Chorea results from functional over activity in dopaminergic nigrostriatal
pathways
 Haldol is a nigrostriatal D2 receptor antagonist --> suppresses the over
activity
 Risperidone/olanzapine favored because of reduced side-effect profile
 Tetrabenzine (Xenazine)
 Selective antagonist of VMAT-2 = ATP-driven transporter that loads
dopamine into vesicles in dopaminergic pre-synaptic terminals
 Reduction in presynaptic dopaminergic transmission by decreasing the
amount of dopamine that can be released
 Side effects = drug induced Parkinsonism and depression

120. TREATMENT OF DYSTONIAS
 Botox injections can be helpful in relieving pain and muscle contraction in focal
dystonias, but are not curative and are commonly repeated at intervals of 3-6
months.
 Severe generalized dystonia and refractory torticollis have been successfully
treated with neuroleptics, tetrabenazine or DBS surgery.

121. DESCRIBE HOW SEROTONIN RECEPTOR HELPS
TO MINIMIZE EXTRAPYRAMIDAL SIDE EFFECTS
BY SECOND GENERATION (“ATYPICAL”)
ANTIPSYCHOTIC AGENTS.
 Serotonin → ↓ dopamine from nigrostriatal → ↑ ACh → ↑ extrapyramidal
symptoms
 Blocking serotonin → ↑ dopamine from nigrostriatal → ↓ ACh → ↓
(counteracts) extrapyramidal symptoms from D2 antagonist

122. RIGHT HEMIPARETIC GAIT, GOOD BALANCE, NO
ATAXIA
 Left Hemisphere stroke/lesion

123. ARCHED BACK, WADDLING, MYOPATHIC GAIT
 Muscular dystrophy

124. SHUFFLING GAIT, ARM SWING, EN BLOC TURN
 Parkinson’s

125. WIDE-BASED, IRREGULAR, STIFF LEGGED,
UNSTEADY GAIT WITH POOR BALANCE AS HE
GOES TO MAKE A TURN
 Ataxic gait

126. LIST THE CLINICAL TRIAD OF SYMPTOMS IN
HUNTINGTON’S DISEASE. STATE THE TYPICAL
AGE OF ONSET OF THE DISEASE AND THE
TYPICAL DURATION OF THE DISEASE.
 Clinical triad: Motor, cognitive, and behavioral deficits (mood problems)
 Typical age of onset: 40's and 50's (for adult-onset disease, which represents
about 95% of the patients)
 Typical duration of disease: average survival AFTER diagnosis is 15-20 years.
There is no treatment that delays disease progression.

127. DEFINE THE FOLLOWING TERMS AS THEY
RELATE TO GENETIC DISORDERS: TRUE
DOMINANCE, ANTICIPATION.
 True dominance - in which the clinical presentation of a patient with 1 mutant
copy of the gene is similar to the clinical presentation of a patient with 2 mutant
copies (heterozygote = homozygote)
 Clinically, there is no "dosage effect" seen
 This is probably unique to Huntington's disease
 Anticipation - the age of onset decreases and the severity increases from
generation to generation.
 Especially seen if the disease is inherited from the father

128. MOTOR DEFICITS OF HUNTINGTONS
 Chorea
 Athetosis
 Ballismus
 Myoclonus
 Dystonia
 Akinesia
 Dysarthria
 Loss of manual dexterity
 Dysphagia
 Slowing and interruption of saccades

129. BEHAVIORAL DISORDERS OF HUNTINGTONS
 Depression - suicide is one of the leading causes of death in these patients
 Apathy
 Obsessive-compulsive disorders
 Less often: Irritability, impulsivity, anxiety
 Much less often : "Schizophrenia-like disorders" and mania

130. IDENTIFY TWO BRAIN REGIONS (ONE CORTICAL,
ONE SUBCORTICAL) THAT DEGENERATE IN
HUNTINGTON’S DISEASE.
 Subcortical: Striatum
 Degeneration of the caudate nucleus and putamen.
 Medium spiny neurons (GABAergic) are preferentially affected
 Cortical: Degeneration of layer 6 of the cerebral cortex
 There is accompanying loss of white matter
 Shrinkage of brain volume and consequent expansion of ventricles

131. EXPLAIN THE ABNORMALITY IN
POLYGLUTAMINE EXPANSION REPEATS THAT
UNDERLIES HUNTINGTON’S DISEASE.
 The HD gene contains a CAG triplet repeat which translates to a “stretch” of
polyglutamine.
 Normal alleles contain 9-34 CAG repeats
 If the gene has 40 or more CAG repeats, the patient WILL have Huntington's.
 There is an inverse correlation between age of onset of disease and CAG
repeat length  The longer the triplet repeat (and polyglutamine stretch), the
earlier the onset of disease.
 The huntingtin protein forms aggregates (precipitates) when the gene CAG
repeat length is above ~ 36. In vitro: >36 repeats and the protein is insoluble, <
36 repeats and the protein is soluble.

132. NNIS
 NNIs in HD are composed of htt aggregates.
 The appearance of these aggregates correlates with the appearance of the
motor phenotype in HD mouse model.

133. POTENTIAL MECHANISMS
 Excitotoxicity hypothesis - some metabolic defect makes striatal neurons extra sensitive to
excitatory signaling via NMDA receptor and they die by excitotoxicity.
 Sequestration hypothesis - The insoluble mutant huntingtin sequesters other important
proteins like transcription factors in the aggregate, causing cell death.
 Proteolytic cleavage hypothesis - The mutant huntingtin causes cell stress and activates
caspases, and the chopped-up mutant protein mediates apoptosis.
 Proteosome dysfunction - Mutant huntingtin aggregates somehow block proteosome
function, which leads to cell death via reduced protein turnover.
 Cell-specific expansion of CAG triplet repeat - the mutant gene already has lots of repeats,
and maybe cells in the striatum specifically undergo MORE triplet expansion, which causes
cell death.
 Loss of trophic support for striatal neurons - huntingtin needed to get cortical neurons to
express the trophic factor BDNF for the striatum. Mutant huntingtin interferes with this and
there's a lack of trophic (growth) support for the striatum from the cortex.

135. MAJOR DEPRESSIVE DISORDER
 Five (or more) of the following symptoms over a 2-week period; at least one of
the symptoms is either (1) depressed mood or (2) anhedonia
 (1) Depressed mood (Note: In children and adolescents, can be irritable
mood)
 (2) Anhedonia
 (3) Significant weight loss or weight gain or decrease or increase in appetite
 (4) Insomnia or hypersomnia
 (5) Psychomotor agitation or retardation
 (6) Fatigue or loss of energy
 (7) Worthlessness or guilt
 (8) Decreased concentration or indecisiveness
 (9) Suicidal ideation
 B. Not due to Bipolar Mixed Episode
 C. Clinically significant impairment
 D. Not due to substance use or general medical condition
 E. DSM-IV: Symptoms not due to bereavement (eliminated in DSM-5)

136. DYSTHYMIC DISORDER
 Depressed mood for most of the day, for more days than not, for at least 2
years (can be irritable mood and at least 1 year in children/adolescents)
 Two (or more) of the following:
 Poor appetite or overeating.
 Insomnia or hypersomnia.
 Low energy or fatigue.
 Low self-esteem.
 Poor concentration or difficulty making decisions.
 Feelings of hopelessness.
 Criteria for a major depressive disorder may be intermittently (or continuously)
present during these 2 years (“double depression”)
 Never a manic episode or a hypomanic episode

137. BIPOLAR I
 One or more manic or mixed episodes
 Manic episode:
 A distinct period of abnormally and persistently elevated, expansive, or irritable mood,
lasting at least 1 week (or any duration if hospitalization is necessary).
 B. Three (or more) of the following symptoms have persisted (four if the mood is only
irritable): DIGFAST
 1)inflated self-esteem or grandiosity
 2) decreased need for sleep
 3) more talkative or pressured speech
 4)flight of ideas or racing thoughts
 5)distractibility
 6)increase in goal-directed activity or psychomotor agitation
 7)excessive involvement in pleasurable activities with potential for painful
consequences
 D. Symptoms cause marked impairment or necessitate hospitalization to prevent harm
to self or others, or there are psychotic features
 E. Not due to substance or general medical condition

138. MIXED EPISODE
 A. The criteria are met both for a Manic Episode and for a Major Depressive
Episode (except for duration) nearly every day during at least a 1-week period.
 B. The mood disturbance is sufficiently severe to cause marked impairment in
occupational functioning or in usual social activities or relationships with others,
or to necessitate hospitalization to prevent harm to self or others, or there are
psychotic features.
 C. Not due to a substance or general medical condition

139. BIPOLAR II
 One or more Major Depressive Episodes and at least one hypomanic episode
 Hypomanic episode:
 A distinct period of abnormally and persistently elevated, expansive, or irritable mood
 B. Three (or more) of the following symptoms have persisted (four if the mood is only
irritable): DIGFAST
 (1) inflated self-esteem or grandiosity
 (2) decreased need for sleep
 (3) more talkative or pressured speech
 (4) flight of ideas or racing thoughts
 (5) distractibility
 (6) increase in goal-directed activity or psychomotor agitation
 (7) excessive involvement in pleasurable activities with potential for painful
consequences
 C. Unequivocal change in functioning that is uncharacteristic of the person when not
symptomatic.
 D. Disturbance in mood and the change in functioning are observable by others.
 E. Not severe enough to cause marked impairment in social or occupational functioning,
or to necessitate hospitalization, and there are no psychotic features [i.e. not full-blown
mania].
 F. Not due to a substance or general medical condition

140. CYCLOTHYMIC DISORDER
 At least 2 years of hypomanic and dysthymic symptoms

141. ADJUSTMENT DISORDER
 Development of emotional or behavioral symptoms in response to an
identifiable stressor(s) occurring within 3 months of the onset of the stressor.
 B. Symptoms are behaviorally or clinically significant, as evidenced by:
 (1) Marked distress in excess of what would have been expected from
exposure to the stressor, or
 (2) Significant impairment in social or occupational (academic) functioning
 C. Doesn’t meet criteria for another Axis I disorder, and isn’t just an
exacerbation of another Axis I disorder due to stress
 D. Not bereavement
 E. Once the stressor or consequences terminated, symptoms don’t persist
beyond 6 months

142. DESCRIBE HOW MDD MAY PRESENT DIFFERENTLY
IN CHILDREN, TEENAGERS, ADULTS, AND THE
ELDERLY.
 Children/Adolescents:
 Somatic complaints, irritability, social withdrawal, poor grades
 Less likely to have sleep disturbance, weight loss, delusion, less likely to say, “I feel sad”
 Commonly co-occurs with other psychiatric conditions. Comorbid conditions are present in 80% to 95% of
depressed youths
 The average length of a depressive episode in children and adolescents is about 9 months
 In younger patients, consider the possibility of bipolar disorder because MDD tends to have a later onset.
 Adults
 Haggard appearance, hunched shoulders, drooping facial expression, psychomotor retardation, “old”
appearance
 Decreased physical and social activity, decreased function in social roles
 Average onset is in late 20s, 2x as common in women
 50% of cases begin after age 40. Even so, be careful to rule out medical conditions in older adults first
 Average patient will have recurring episodes, an average of 5-6 over 20 years
 Elderly
 Anxiety and somatic complaints, weight loss, and anhedonia
 Less likely to feel guilt or have lowered self attitude, more likely to have psychotic symptoms
 Can be “subsyndromal” and therefore might not meet full criteria for depression
 Outside of nursing homes, MDD is less common than in the general population: 1-2%
 Within nursing homes, it is more common: 12%

143. DESCRIBE THE RISK OF EXPERIENCING A
RECURRENCE IN A PATIENT WHO HAS HAD 1, 2,
OR 3 PRIOR EPISODES OF MAJOR DEPRESSION
 After 1 episode of MDD: 50% likelihood of recurrence without treatment
 After 2 episodes: 70%
 After 3 episodes: 90%
 Patients who suffer “multiple” episodes should stay on maintenance treatment
indefinitely, either in the form of medication or psychotherapy.
 The average patient with MDD will have 5-6 episodes over 20 years

144. DISTINGUISH BETWEEN POST-PARTUM “BABY
BLUES” AND POST-PARTUM MAJOR
DEPRESSIVE DISORDER.
 Postpartum “baby blues”
 Crying, irritability, mood swings
 Onset: 3-10 days postpartum
 Resolves in ~1 week
 Related to hormonal changes, stress, sleep deprivation
 True Postpartum Major Depressive Disorder
 Meets full criteria for major depressive episode (SIG E CAPS)
 Greatest risk is first 2 weeks postpartum but can be up to several months out
 Women with PPD are more likely to have future PPD
 Also hormonally related but you would not just treat with hormonal therapy,
need antidepressants!

145. HOW CAN MAJOR DEPRESSIVE DISORDER CAN
BE APPROACHED FROM A DIMENSIONAL
MODEL OR FROM A DISEASE MODEL?
 Dimensional model -- depressive personality spectrum
 Disease model -- depression is an abnormal state due to imbalance of brain
chemistry

146. BIOLOGICAL FACTORS OF DEPRESSION
 Monoamine neurotransmitter deficiency (low serotonin, norepinephrine)
 Dysfunctional regulation of serotonin and norepinephrine receptors (5-HT2A
serotonin receptor and β-adrenergic norepinephrine receptor)
 Loss of hippocampal volume
 Excessive glucocorticoid activity
 Endocrine abnormalities
 Circadian rhythm abnormalities
 Reduced activity in the dorsolateral prefrontal cortex
 Increased activity in the ventral prefrontal cortex
 Life events that produce high levels of stress have biological effects on
neurochemistry and neuroanatomy may influence:
 Production of neurotransmitters and surface receptors
 Number and complexity of dendritic branches
 Strength or weakness of synaptic connections formed between neurons and
neighboring neurons.
 Neuronal plasticity: the neurotrophic and “pruning” activity

147. DESCRIBE THE MONOAMINE MODEL OF
DEPRESSION AND ITS LIMITATIONS.
 Drugs can cause and cure depression.
 Monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs)
treat depression
 Reserpine (an antihypertensive drug) causes depression in about 15% of
patients.
 Because MAOIs and TCAs increase brain levels of norepinephrine (NE) and
serotonin (5-HT) and reserpine depletes these biogenic amines, the hypothesis
posits that “clinical depression is the result of a monoamine deficiency.”
However, this observation does not prove an underlying monoamine imbalance
is the etiology of depression. Instead, antidepressants may establish
downstream effects from the monoamine receptors that improve patients’
moods.

148. IN PATIENTS WHO HAVE MAJOR DEPRESSIVE
DISORDER, DESCRIBE THE TREATMENT
RESPONSE TO ANTIDEPRESSANT THERAPY.
 60% of patients clinically respond to antidepressant medicines that raise
monoamine levels, and the clinical response is delayed compared to the timing
of the pharmacologic action of the drugs.
 One explanation that falls under the umbrella of the monoamine model of
depression and focuses on the presynaptic and postsynaptic receptors is the
neuroreceptor hypothesis of depression.
 Beta-adrenergic norepinephrine receptors and 5-HT2A receptors are
downregulated several weeks after treatment with most antidepressants.
This chronology better correlates with the clinical time course seen during
drug administration.

149. DESCRIBE THE PREVALENCE OF POST-STROKE
DEPRESSION AND STATE WHICH STROKE
LOCATIONS ARE MOST COMMONLY
ASSOCIATED WITH POST-STROKE DEPRESSION.
 Depression occurs in 30-50% of stroke patients.
 The most commonly implicated stroke locations are the left frontal region and
left basal ganglia.

150. DESCRIBE THE PREVALENCE OF SUICIDALITY IN
CHILDREN AND ADOLESCENTS TREATED WITH
ANTIDEPRESSANTS VERSUS PLACEBO IN
CLINICAL ANTIDEPRESSANT TRIALS.
 Antidepressants (9 different drugs including SSRIs): 4%
 Placebo: 2%

151. DIFFERENCES BETWEEN THE PSYCHODYNAMIC
MODEL AND THE COGNITIVE-BEHAVIORAL
MODEL OF MOOD DISORDER
 Based on “function” rather than form
 Psychodynamic model:
 Internal, but unconscious conflict
 Disturbance of interpersonal relations early in life
 Impairs subsequent relationships and leads to depression
 Symptom of the problem not the problem itself
 Cognitive-behavioral model
 Automatic thoughts accompany depressed mood states, unnoticed but not
truly unconscious. Emphasis on thoughts rather than relationships
 Automatic thoughts which contain cognitive distortions that reflect
maladaptive cognitive schemas
 Depression is a result of these maladaptations

152. MAO Inhibitors
Irreversible Inhibitors of MAO A and B:
Phenelzine (Nardil)
Tranylcypromine (Parnate)
Reversible Inhibitors of MAO A (RIMAs):
Moclobemide
Tricyclic Antidepressants
Tertiary Amine Tricyclics:
Imipramine (Tofranil)
Amitriptyline (Elavil)
Doxepin (Sinequan)
Trimipramine (Surmontil)
Clomipramine (Anafranil)
Secondary Amine Tricyclics:
Desipramine (Norpramin)
Nortriptyline (Pamelor)
Protriptyline (Vivactil)
Maprotiline (Ludiomil)
Selective Serotonin Reuptake Inhibitors
(SSRIs):
Fluoxetine (Prozac)
Sertraline (Zoloft)
Paroxetine (Paxil)
Fluvoxamine (Luvox)
Citalopram (Celexa)
Escitalopram (Lexapro)
Selective Norepinephrine Reuptake Inhibitor (NRI):
Atomoxiten (Strattera) [approved for ADHD]
Reboxetine (Vestra) [not approved in U.S.]
Dopamine-Norepinephrine Reuptake Inhibitor (DNRI):
Bupropion (Wellbutrin)
Serotonin-Norepinephrine Reuptake Inhibitor (SNRI):
Venlafaxine (Effexor)
Duloxetine (Cymbalta)
Serotonin (5-HT2) antagonist/reuptake inhibitors
Trazodone (Desyrel)
Nefazodone (Serzone)
Serotonin (5-HT2 and 5-HT3) and alpha-2 antagonist
Mirtazepine (Remeron)
Serotonin (5HT1A) partial agonist
Buspirone (BuSpar)
Monoamine Releasing Agents (“Stimulants”)
Dextroamphetamine (Dexedrine)
Methylphenidate (Ritalin, Concerta, Metadate)
Pemoline (Cylert)
Amphetamine Mixture (Adderall)

153. MAO INHIBITORS
 Effective for:
 Dysthymic Disorder
 “Atypical” Depression
 Most common use would be for medication-refractory depression
 Side Effects
 Insomnia, daytime somnolence, orthostatic hypotension, anorgasmia, weight gain,
myoclonus, and pedal edema
 “Cheese” or Tyramine Reaction
 Dietary tyramine is a potent releaser of NE, which in turn is a pressor. In the
presence of an MAO inhibitor, the tyramine isn’t degraded, nor is the excessive NE
that is released, leading to the hypertensive response.
 Serotonin Syndrome
 Overactivation of central 5-HT receptors
 Milder cases: abdominal pain, diarrhea, sweating, fever, tachycardia, hypertension,
delirium, myoclonus, irritability, hostility, and mood change.
 Severe cases: hyperpyrexia, cardiovascular shock, or death

154. WAYS TO OVERCOME TYRAMINE REACTION
 Selective MAO-B inhibition
 Transdermal Ensam
 Selegeline
 Reversible MAOIs
 Moclobemide

155. MAOIS
 Phenelzine (Nardil)
 Tranylcypromine (Parnate)
 Moclobemide

156. TRYCYCLIC ANTIDEPRESSANTS
 “Dirty drugs”
 Block reuptake of serotonin and norepinephrine at the synaptic cleft
 Action at several receptors: H1, Ach, alpha1, alpha2, 5HT2, 5HT3
 All the side effects
 Helps with chronic pain (also Duloxetine)
 Serum levels can be useful: sigmoid curve
 Tertiary amine agents act more on 5HT (especially clomipramine)
 Secondary amine agents act more on NE
 Inexpensive; also useful for chronic pain and migraine
 Overdose can be lethal!

157. TCAS
 Tertiary Amine Tricyclics:
 Imipramine (Tofranil)
 Amitriptyline (Elavil)
 Doxepin (Sinequan)
 Trimipramine (Surmontil)
 Clomipramine (Anafranil)
 Secondary Amine Tricyclics:
 Desipramine (Norpramin)
 Nortriptyline (Pamelor)
 Protriptyline (Vivactil)
 Maprotiline (Ludiomil)

158. SSRIS
 Block reuptake of serotonin selectively, with little effect on other
neurotransmitters or receptors
 Allows for a greatly improved side-effect profile
 Lower rate of discontinuation of medication by patients
 Little cardiotoxicity and safe in overdose
 Side effects
 anxiety, nervousness, or restlessness (and even subtle akathisia), insomnia
(fitful sleep, along with REM sleep), fatigue or sedation (despite insomnia),
GI distress (nausea, cramps or diarrhea), headache, weight loss (usually only a
few pounds), and dizziness or lightheadness
 Decreased libido, anorgasmia, impotence up to 70%
 Hypofrontality/apathy
 SSRI discontinuation syndrome

159. SSRIS
 Fluoxetine (Prozac)
 Sertraline (Zoloft)
 Paroxetine (Paxil)
 Fluvoxamine (Luvox)
 Citalopram (Celexa)
 Escitalopram (Lexapro)

160. SEROTONIN-NOREPI REUPTAKE INHIBITORS
 SNRIs block reuptake of serotonin and norepinephrine
 Not cardiotoxic and safe in overdose
 Venlafaxine - highest response rate for antidepressants
 Duloxetine has more balanced action between 5HT and  fewer sexual side
effects, helps with chronic pain
 Resembles TCA therapeutic effects without all its nasty side effects
 Side effects
 anxiety, nervousness, restlessness, insomnia, fatigue and/or sedation (yes,
despite the possibility for insomnia), headache, weight loss,
dizziness/lightheadedness (resembles SSRI side effects)
 decreased libido, anorgasmia, impotence
 10% of people experience increase in diastolic BP of ~8 mmHg

161. SNRIS
 Venlafaxine (Effexor)
 Duloxetine (Cymbalta)

162. BUPROPRION, WELLBUTRIN
 Dopamine-norepinephrine reuptake inhibitor
 Doesn’t interact at any of the usual receptors that cause side effects in TCAs
and MAOIs, a major advantage
 Weakly inhibits norepinephrine reuptake and to a lesser extent dopamine
reuptake
 Can have a mild stimulant effect in depressed patients
 Can be prescribed for ADHD
 Also used for nicotine addiction
 Side effects
 Similar to SSRIs
 Less sexual side effects
 Potential for SEIZURES at high doses

163. SEROTONIN (5-HT2) ANTAGONIST/REUPTAKE
INHIBITORS
 Trazodone (Desyrel)
 Only a weak 5HT reuptake inhibitor, but is a direct 5-HT2 antagonist
 Also acts at alpha-1 receptor
 Sedation, orthostatic hypotension, RARE PRIAPISM
 Often used as a hypnotic
 Nefazodone (Serzone)
 Modified to reduce alpha1 effects
 Associated with rare cases of hepatic failure

164. MERTAZAPINE, REMERON
 5HT2 antagonist but also blocks the 5HT3 receptor and increases NE and 5HT
release by blocking presynaptic -2 autoreceptor
 Decreased sexual side-effects and no interference with sleep architecture Low
anticholinergic and anti- -1 adrenergic receptors, leading to an improved side-effect
profile.
 Antihistamine activity and so is sedating and causes significant weight gain
 Safe in overdose, not cardiotoxic

165. DESCRIBE THE RISKS AND BENEFITS OF
LITHIUM CARBONATE
 Mood stabilizer: effective for about 70-80% of patients with Bipolar Disorder
 Latency period of from 5-10 days for lithium to take effect.
 Many acute episodes don’t respond as well to lithium.
 Dysphoric manic states, mixed states, rapid cycling poor response (Carbamazepine/Valproic Acid)
 Side-Effects: Dose Related
 Tremor
 Renal: Polyuria, Diabetes Insipidus, renal injury (rare)
 Gastrointestinal, Hypothyroidism, Weight Gain
 Cardiac: effect on ECG resembles hypokalemia
 Benign Leukocytosis
 Overdose/Intoxication
 Moderate to severe intoxication (2.0-2.5 mEq/L): impaired consciousness which progresses to
delirium, stupor and finally coma. Nausea and vomiting persistent. Ataxia now accompanied by
muscle fasciculation and myoclonus. Patients may have syncope or seizures
 Severe intoxication (>2.5 mEq/L) leads to seizures, renal failure, and death.
 Side-Effects: Idiosyncratic (not dose-related)
 Facial Rash Resembling Acne, Alopecia, Aggravation of Psoriasis

166. WHAT ORGAN SHOULD BE CLOSELY
MONITORED WITH LITHIUM
 Renal function

167. POWER COMBO
 SNRI + Mertazapine

168. CARBAMAZEPINE
 Good alternative for manic patients that are lithium nonresponders
 As effective as Li for euphoric manic states
 More effective than Li for mixed states, dysphoric manic states, and rapid cycling
 Less effective than Li (and other antidepressants) for depression
 Dose-related side effects
 GI effects (N&V, cramps, diarrhea)
 CNS effects (confusion, drowsiness, ataxia, hyperreflexia/clonus, tremor)
 Risk of neurotoxicity when used in combination with Li and/or antipsychotic drugs
 Cardiac toxicity possible (less likely than with TCAs)
 Fatal in overdose
 Idiosyncratic side effects:
 Bone Marrow: Transient leukopenia (10%), Aplastic anemia or angranulocytosis
 Skin: Transient pruritic rash (10%), Exfoliative dermatitis, Erythema multiforme, Stevens-
Johnson syndrome
 Liver: Mild increases in LFTs or signs of cholestasis (10%)
 Hyponatremia (10-30%)

169. VALPROIC ACID
 Valproic Acid & carbamazepine equal in terms of efficacy for dysphoric mania, mixed
states, and rapid cycling
 More effective than Li for euphoric manic states.
 Less effective than Li (and other antidepressants) for treatment of depression
 Complicated pharmacokinetics if given with carbamazepine: Combined neurotoxicity
 Side effects:
 Sedation, nausea, vomiting, and diarrhea
 Fine tremor
 Weight gain
 Elevated liver enzymes & bone marrow suppression (especially
thrombocytopenia)
 Rare, idiosyncratic:
 Fatal hepatotoxicity, hemorrhagic pancreatitis, agranulocytosis

170. LAMOTRIGINE
 The first approved maintenance treatment for Bipolar Disorder since lithium
 Has been proven effective in extending stability by delaying mood episodes
(including depression, mania, hypomania, and mixed episodes) in bipolar I
disorder (particularly in treating depression)
 Not for acute mania either – compare to lithium.
 Side-effects
 Most are benign and transient: headache, somnolence, GI upset
 However, of greater concern is risk of serious rash, including Stevens-Johnson
rash

171. WHAT TREATMENT CAN YOU USE FOR
PREGNANT WOMEN WITH BIPOLAR DISORDER
 Electroconvulsive therapy

173. NAME THE CORTICAL LOBE THAT MEDIATES THE
CONSCIOUS FEELINGS THAT ACCOMPANY THE
EXPRESSION OF EMOTIONS.
 Cortical lobe: The cingulate cortex and frontal lobes mediate conscious feelings
associated with the physical sensations.

174. NAME THE SUBCORTICAL REGIONS OF THE CNS
THAT MEDIATE THE PHYSICAL SENSATIONS
THAT ACCOMPANY THE EXPRESSION OF
EMOTIONS
 Subcortical regions: The brainstem, hypothalamus, and amygdala mediate
physical sensations via autonomic, endocrine, and somatic motor systems.

175. NAME THE REGION OF THE BRAIN THAT
COORDINATES THE SOMATIC AND VISCERAL
MOTOR RESPONSE IN EMOTIONAL BEHAVIOR.
 The hypothalamus is an important coordinator (effector) of somatic and visceral
motor response in emotional behavior.

176. LIST THE MAJOR INPUTS TO AND OUTPUTS
FROM THE RETICULAR FORMATION RELATED TO
EXPRESSION OF EMOTION
 Inputs to the reticular formation: hypothalamus, additional structures in the
forebrain (components of the limbic system).
 Outputs from the reticular formation: widespread somatic motor and autonomic
responses (e.g. the fight or flight response to a fear-arousing stimulus involves
both sympathetic and somatic motor activity)

179. DISTINGUISH BETWEEN A DUCHENNE SMILE
AND A PYRAMIDAL SMILE
 The Duchenne smile is a spontaneous smile (emotional) that is characterized
by an involuntary contraction of the orbicularis oculi.
 The Duchenne smile originates in the prefrontal cortex (accessory motor
areas within the cingulate gyrus) and the ventral basal ganglia.
 These regions project via extrapyramidal pathways through the reticular
formation to brainstem motor nuclei.
 A smile elicited by volition (pyramidal smile), in contrast, looks contrived and
originates in the motor cortex and project through pyramidal pathways.

181. NAME TWO GYRI THAT COMPRISE THE LIMBIC
LOBE
 Cingulate gyrus
 Parahippocampal gyrus

182. DISTINGUISH BETWEEN THE BEHAVIORAL
MANIFESTATIONS OF LESIONS TO THE
AMYGDALA AND OVEREXCITATION OF THE
AMYGDALA.
 Amygdala lesions:
 person becomes docile,
tame
 Amygdala overexcitation:
 person becomes fearful,
apprehensive

183. STATE THE BEHAVIORAL CONSEQUENCES OF
BILATERAL DEGENERATION OF THE
AMYGDALOID BODIES IN CHILDHOOD
 Urbach-Wiethe disease: calcium deposits --> amygdala degeneration (can
occur in child or adulthood)
 If bilateral lesions occur in childhood --> kids have inability to correctly
interpret facial expressions – association of emotion with expression.
 Can’t discriminate subtle differences in facial expression, but CAN recognize
faces (which shows that ability is localized elsewhere in the brain)
 No fear.

184. DISTINGUISH BETWEEN THE AMYGDALA AND
THE HYPOTHALAMUS IN TERMS OF THE TYPE
OF SENSORY INFORMATION EACH RECEIVES.
 Amygdala receives BOTH...
 processed sensory information (visual, somatic sensory, visceral sensory,
auditory)
 direct unprocessed sensory input from thalamus (somatic sensory), olfactory
bulb, brainstem (visceral sensory).
 Hypothalamus receives mostly…
 - indirect UNprocessed visceral sensory input from amygdala and cortex

185. STATE THE PHYSIOLOGICAL FUNCTION OF THE
AMYGDALA IN GENERAL TERMS.
 The amygdala is involved in learned emotional responses/fear
 Located in the rostral part of the parahippocampal gyrus
 3 layers of neurons
 Associative learning (likely via LTP)
 Involved in creating association between neutral sensory stimuli and stimuli
with reinforcement value (good or bad) -- note that the amygdala controls
whether this association is important, NOT associating specific stimuli with
specific good or bad results

186. STRIA TERMINALIS
 Main connection
between amygdala
and hypothalamus.

187. NAME THE TRANSMITTER USED BY NEURONS IN
THE BASAL NUCLEUS OF MEYNERT. NAME THE
COMMON DISORDER IN WHICH THESE
NEURONS ARE LOST.
 Acetylcholine
 Alzheimer’s
 The ventral striatum encompasses the nucleus accumbens, parts of the
olfactory tubercle, and ventral medial portions of the caudate-putaman, while
the ventral pallidum includes the substantia innominata. Located in the
substantia innominata is the basal nucleus of Meynert, consisting of large
cholinergic neurons. This nucleus receives cortical input from the limbic region,
and projects to the entire cerebral cortex. In Alzheimer’s disease, the
cholinergic neurons within the basal nucleus of Meynert are lost.

188. NAME THE COMPONENT OF THE LIMBIC
SYSTEM THOUGHT TO BE INVOLVED IN REWARD
PATHWAYS STIMULATED BY DRUGS OF ABUSE
 Drugs increase the levels of dopamine released by neurons in the ventral
tegmental area. These dopaminergic neurons project to the nucleus
accumbens in the ventral striaum, the dorsal striatum, and the frontal cortex–all
brain regions that are involved in motivation
 Bed nucleus of the stria terminalis

189. LIST THE 4 MAJOR PATHWAYS COMPRISED OF
THE DOPAMINERGIC NEURONS OF THE BRAIN.
 Mesocortical pathway:
 VTA  prefrontal cortex
 Decrease in activity  negative symptoms of schizophrenia (social withdrawal, low emotion, low
motivation)
 Mesolimbic pathway
 VTA  Limbic system
 Increase in activity --> positive symp of schizophrenia (psychosis)
 Normal: mesocortical pathway  inhibit mesolimbic pathway
 Schizophrenia: decreased mesocortical activity  decreased inhibition (increased activity) of
mesolimbic pathway
 Nigrostriatal
 Substantia nigra  striatum
 Implicated in Parkinson’s
 Tuberoinfundibular pathway
 Hypothalamus  Pituitary gland
 Relates to release of Prolactin

191. DESCRIBE THE BRAIN’S FEAR CIRCUIT, AND THE
LINKAGE BETWEEN THE FEAR CIRCUIT, THE
PLEASURE CIRCUIT, AND THE MEMORY CIRCUIT.
 The fear circuit centered on the amygdala leads to avoidance behaviors
 The pleasure circuit centered on the nucleus accumbens leads to approach behaviors
 Sensory input from cortex and thalamus to Amygdala
 Modulation by prefrontal cortex and hippocampus
 Logical, cognitive processing
 Memory association
 Projects to
 Striatum: Motor
 PAG: analgesia
 Locus Ceruleus : NE
 Raphe nucleus: 5-HT
 VTA: DA
 Sympathetic and stress axis activation

192. DESCRIBE HOW 5-HT, NE AND GABA PLAY
DIFFERENT ROLES IN MEDIATING ANXIETY AT
THE SYNAPTIC LEVEL.
 Serotonin: monoamine neurotransmitter released from the Raphe Nucleus
throughout the brain and can affect NE and DA neurotransmission. Also there is
a strong link between depression and anxiety.
 Norepinephrine: monoamine released from Locus Ceruleus throughout the
nervous system. Plays large role in peripheral symptoms anxiety like arousal-
 Presynaptic alpha-2 autoreceptors: receptor for Clonidine agonism
 Post-synaptic alpha-1 receptors
 Post-synaptic beta-receptors
 GABA: fast inhibitory effect on a variety of systems through the brain. Very
important in acute anxiety treatment (Benzodiazepines – GABA-A)

193. 5-HT AND NE IN ANXIETY
 NE seems to play a larger role in the peripheral side effects of Anxiety
(increased blood pressure, sweating, tremors, arousal, etc.), while 5-HT plays a
larger role in the cognitive effects (apprehension, worry, etc.)

194. NE TARGETING DRUGS
 Beta-Blockers
 Act on the postsynaptic beta-adrenergic receptors to block noradrenergic input.
 Useful for blocking the peripheral signs of arousal (sweating, tremors, etc.).
 Used to treat essential tremor - the postural tremor often seen with aging or as a side
effect of drugs (Lithium).
 NOT useful for treating the cognitive symptoms of anxiety.
 Clonidine
 Presynaptic NE alpha-2 agonist – stimulates the autoreceptors of noradrenergic neurons
in the LC, lowering NE release.
 Is used to treat autonomic arousal in opiate and alcohol withdrawal
 Used as adjunctive therapy in ADHD
 Not 1st line in anxiety
 Prazosin
 Post-synaptic NE alpha-1 antagonist
 Used for treating nightmares and hyperarousal in PTSD

195. 5-HT TARGETING DRUGS
 SSRI’s
 -selective serotonin reuptake inhibitors
 Highly effective at controlling the cognitive effects of anxiety disorders
 Affect other transmitter systems (decrease NE release from locus ceruleus and
decrease dopamine release in the striatum)
 First-line treatment of anxiety disorders (along with Benzodiazepines)

196. SYMPTOMS OF ANXIETY
 Normal anxiety physical and emotional symptoms
 Increased blood pressure, heart rate, respiratory rate, skin conductance,
muscle tension
 Increased plasma levels of epinephrine, norepinephrine, growth hormone,
cortisol, and prolactin

197. LIST 4 CIRCUMSTANCES WHEREBY THE
“STRESS THERMOSTAT CAN BECOME
MALADAPTIVE AND A SOURCE OF IMPAIRMENT.
 Individual is faced with more extreme circumstances
 Chronic stress, acute trauma, bereavement
 Affected by medical illness or neurological condition that affects levels of
glucocorticoids, monoamines or other neurotransmitters or direct injury to brain
 Ingesting substances that stimulate reward centers
 Rendered more vulnerable to developing impaired affective or cognitive
regulation due to genetic factors

198. BENZODIAZEPINES
 Bind GABA-A receptor (along with GABA) and allosterically enhance the effects
of GABA. The effect is to keep the chloride (Cl-) channel open longer which
hyperpolarizes the cell (less excitable).
 Works QUICKLY because it is linked to an ion channel
 Patients like BDZ because when you’re feeling anxious, you want something
that works NOW.
 BDZ are allosteric modulators: they need GABA to enhance it, but they cannot
replace it i.e. they don’t work unless GABA itself is present.
 Flumazenil  antagonist

199. BENZO SUBUNITS
 Alpha-1 subunit: sedation, anticonvulsant, and amnesia effects
 Alpha-2 and alpha-3 subunit: anticonvulsant and muscle relaxant effect
 Alpha-5 subunit: cognitive effects

200. LIST THE MOST COMMON SIDE EFFECTS OF
BENZODIAZEPINES.
 Sedation (10%): caution when driving
 Dizziness or ataxia (<2%)
 Mild cognitive impairment (not the case for SSRI) - problem for elderly
 Greater rate of falls leading to hip fractures in the elderly on BDZ
 Where liver disease is present (eg alcohol withdrawal), or when the patient is
taking concomitant medications that compete for CP450 microenzymes, don’t
prescribe a benzo that has active metabolites
 → use lorazepam, oxazepam, or temazepam instead

201. WHICH BENZOS CAN BE GIVEN IM?
 Lorazepam and Midazolam

202. HYPNOTIC BENZODIAZEPINES
 For acute anxiety or insomnia, look for benzos with rapid onset of sedation and
anxiolysis
 Flurazepam
 Temazepam
 Quazepam

203. WITHDRAWAL, TOLERANCE, TAPER AND
TESTING FOR REBOUND ANXIETY
 Longer term usage of benzodiazepines can cause tolerance, requiring more of
the drug to achieve the same effect, and increasing the risk of abuse.
 Withdrawal symptoms are usually worse at the end of the taper due to a
conformational change of the receptor
 Waiting for some time to see if symptoms dissipate or remain the same will
distinguish between withdrawal and rebound anxiety
 Drugs with shorter effect and more rapid onset such as alprazolam (xanax) may
be more reinforcing and risky
 Lorazepam, librium and clonazepam are better for long term use.

204. BENZOS VS. SSRIS VS. THERAPY
 Benzos: Used for acute/short-term treatment (work rapidly) or as an adjunct
with other medications/therapies. Generally safe, but can cause sedation,
tolerance, or withdrawal symptoms.
 Antidepressants: Usually medications of choice for longer-term treatment of
anxiety disorders. Have delayed onset and can be anxiogenic before they are
anxiolytic
 CBT: useful in certain anxiety disorders, but often used adjunctively with
medications

205. LIST FIVE RISK FACTORS FOR BENZODIAZEPINE
DEPENDENCE THAT YOU SHOULD BE MINDFUL
OF WHEN PRESCRIBING BENZODIAZEPINES
 Personal or family history of alcohol dependence.
 Potency of medication (higher potency → higher risk)
 Duration of treatment (risk of dependence increases with longer-term
treatment).
 Rapidity of onset of CNS effects (increased risk of dependence for quicker
absorbed and more lipid soluble drugs).
 Agents with shorter-effect requiring more frequent doses to prevent withdrawal
symptoms (may be reinforcing if you can feel withdrawal and then take drug to
get that “ahh” effect).

206. MIDAZOLAM
Midazolam (Versed)
 Reliably absorbed IM and orally
 Shortest-half life (so shortest acting) → greater amnestic effects
 Used for surgical procedures, best drug for induction of anesthesia

207. LIBRIUM
 Chlordiazepoxide (Librium)
 Used for alcohol withdrawal/detoxification in hospital
 PO, least potent, very long half-life

208. CLONAZEPAM
Clonazepam (Klonopin)
 most potent, PO
 Very long half-life, so good for treating benzodiazepine withdrawal (would be
used to replace short-acting benzo, reduces intensity of rebound symptoms)
 Commonly used for seizure disorder

209. LORAZEPAM
 Lorazepam (Ativan)
 Reliably absorbed orally, IM, and IV
 Often given to acutely agitated patients due to its rapid and reliable absorption
(IV or IM)
 Best benzo for treating alcohol withdrawal with impaired liver function (has no
active metabolites)
 Also useful in patients taking concomitant meds (no active metabolites to
compete for cyt P450)
 Reasonable for routine use for anxiety treatment (less risk of dependence
compared to other benzos)

210. Z DRUGS
• Zolpidem (Ambien), zaleplon (Sonata), and eszopiclone (Lunesta) are BZ1-
selective agonists, and cause sedation with little disruption of REM sleep
– Rapid onset but short action: good for initial insomnia (but not middle or
terminal insomnia)
– Little residual AM sedation
– No disruption of normal REM sleep pattern
– No muscle relaxant or anticonvulsant effects

211. GAD TREATMENT
 Psychotherapy
 Psychodynamic
 Cognitive-behavioral
 Medication
 Benzos
 SSRIs
 Buspirone
 Start low and go slow
 Combination

212. GAD
 Characterized by excessive anxiety and worry (apprehensive expectation) about a
number of events or activities (such as work or school performance)
 Occurring more days than not for at least 6 months
 Must cause clinically significant distress or impairment in social, occupational, or
other important areas of functioning
 Must not be attributable to the physiological effects of a substance or another
medical condition
 Must not be better explained by another mental disorder
 Diagnostic Criteria: must have three or more of the following six symptoms
 1. Restlessness or feeling keyed up or on edge
 2. Being easily fatigued
 3. Difficulty concentrating or mind going blank
 4. Irritability
 5. Muscle tension
 6. Sleep disturbance

213. PANIC DISORDER
 Characterized by recurrent unexpected panic attacks
 Panic Attack: an abrupt surge of intense fear or discomfort that peaks within minutes
 Can occur from a calm state or an anxious state
 During which time four or more of the following symptoms occur:
 Palpitations, pounding heart, or accelerated heart rate
 Sweating, Trembling or shaking
 Shortness of breath, feelings of choking, chest pain or discomfort
 Nausea or abdominal distress, feeling dizzy, unsteady, light-headed, or faint
 Chills or heat sensations
 Paresthesias (numbness or tingling sensation)
 Derealization (feeling of unreality) or depersonalization (being detached from oneself)
 Fear of losing control or “going crazy”
 Fear of dying
 At least one of the attacks has been followed by 1 month or more of one or both of the
following events:
 Persistent concern or worry
 A significant maladaptive change in behavior (e.g., avoidance of certain situations)

214. HOW MIGHT PANIC DISORDER PRESENT IN THE
ED?
 Appears to be a heart attack

215. COMORBIDITIES OF PANIC DISORDER
 50-60% Major Depressive Disorder
 ⅓ depression comes first
 ⅔ panic disorder comes first (or they occur at the same time)
 NOTE: this association has a poorer prognosis with poorer response to
treatment, and twice the risk of suicide than from either one alone (14% vs 7-
8%)
 Substance Abuse: patients try to self medicate
 Social Phobia (15-30%)
 OCD (10%)
 GAD (25%)

216. RX OF PANIC DISORDER
 Education about disorder and support
 Cognitive and relaxation techniques
 Acute treatment
 Benzodiazepines
 Prophylactic treatment
 SSRIs: First choice
 TCA
 “start low, go slow”
 Behavioral treatment of agoraphobia and anticipatory anxiety when patient is
more stable.

217. PTSD
 Exposure to a traumatic event in which both of the following were present:
 Experienced an event or events that involved actual or threatened death or serious
injury, or a threat to the physical integrity of self or others.
 Event must have been violent or accidental
 Traumatic event is persistently re-experienced in one (or more) ways
 Recurrent and intrusive recollections of the event
 Dreams of the event
 Acting or feeling as if the traumatic event were recurring (includes a sense of reliving
the experience, illusions, hallucinations, and dissociative flashback episodes,
including those that occur on awakening or when intoxicated).
 Intense psychological distress at exposure to internal or external cues that symbolize
or resemble an aspect of the traumatic event.
 Three main categories of symptoms:
 Reexperiencing of the traumatic event  HALLMARK, other sx are nonspecific
 Avoidance of stimuli associated with the trauma
 Emotional numbing
 Increased arousal and autonomic hyperactivity, with symptoms similar to GAD.

218. ASD VS. PTSD
 ASD:
 Symptoms are noted within a month of the trauma
 Symptoms usually resolve over a period of weeks.
 PTSD:
 Symptoms persist beyond one month.
 50% of people exposed to a severe stressor experience ASD. 25% people
exposed to severe stressor develop PTSD. 12% develop chronic PTSD (longer
than 3 months).

219. RX FOR PTSD
 Multimodal therapy is required, since medications alone are not especially helpful
 Psychotherapy
 Treat comorbid psychiatric problems and substance abuse
 Medications:
 SSRIs generally used first
 Prazosin: Useful for treating nightmares and hyperarousal
 TCAs and MAOIs
 Help with depression, anxiety, hypervigilance, and reexperiencing
 Less effective for withdrawal and numbing
 Mood stabilizers (Lithium, carbamazepine, valproic acid) most useful for anger
outbursts
 Only use benzodiazepines with caution
 Can lead to behavioral disinhibition and also addiction in cases often already
complicated by substance abuse
 Little effect on numbing and reexperiencing symptoms.

220. OCD
 Obsession: persistent idea, thought, impulse or image that is experienced as
intrusive and inappropriate that causes marked anxiety or distress.
 The patient with obsessive thoughts or images or urges tries to distract himself
from them, but his anxiety level continues to build despite these efforts
 Compulsion: repetitive behavior or mental act that a patient engages in (often
involving rigid rules) in order to reduce anxiety associated with obsessions
 After engaging in the the compulsion, the obsessional anxiety does diminish
but, only temporarily

221. OCD COMORBIDITIES
 Common comorbidities include: major depressive disorder (80%), social phobia
(25%) or mood/anxiety disorders and substance abuse.
 Linked to Tourette’s disorder
 5% with OCD have Tourette’s
 2/3 with Tourette’s have OCD
 One theory: in OCD a positive feedback loop occurs between frontal lobes and
basal ganglia, perhaps a result of damage to an area that normally would
dampen this feedback

222. OCD SPECTRUM DISORDERS
 A variety of psychiatric disorders that involve impaired self perception and/or
impulse control, such as body dysmorphic disorder, eating disorder, compulsive
gambling, shoplifting or gambling, fall along the OCD-spectrum.
 All of these disorders share an obsessive concern or preoccupation with some
aspect of bodily functioning or appearance or stereotyped, compulsive or
impulsive behaviors.
 They all also demonstrate at least a partial response to SSRIs and may
respond to cognitive and behavioral strategies similar to those used to treat
OCD.

223. RX FOR OCD
 OCD responds preferentially to SSRIs
 may require higher dose and longer duration of trial than with depression
 symptoms return with stopping of drug
 Behavior therapy through exposure (to object of obsession) and response
prevention (resisting engaging in the compulsions)
 offers better long term results
 Neurosurgery in small fraction of cases
 Anterior cingulotomy, subcaudate tractotomy, their combination (called limbic
leukotomy) and anterior capsulotomy.
 90% response rate
 DBS to these same areas is another option.
 Electroconvulsive therapy is not effective for OCD.

225. DSM V SUBSTANCE ABUSE DISORDER
 A. A maladaptive pattern of substance use leading to clinically significant impairment or distress, as
manifested by 2 (or more) of the following, occurring within a 12-month period:
 1. Recurrent substance use resulting in a failure to fulfill major role obligations at work, school, or home
 2. Recurrent substance use in situations in which it is physically hazardous
 3. Continued substance use despite having persistent or recurrent social or interpersonal problems caused
or exacerbated
 4. Tolerance, as defined by either of the following:
 Need for markedly increased amounts of the substance to achieve intoxication or desired effect
 markedly diminished effect with continued use of the same amount of the substance
 5. Withdrawal, as manifested by either of the following:
 The characteristic withdrawal syndrome for the substance
 The same (or a closely related) substance is taken to relieve or avoid withdrawal symptoms
 6. The substance is often taken in larger amounts or over a longer period than was intended
 7. There is a persistent desire or unsuccessful efforts to cut down or control substance use
 8. A great deal of time is spent in activities necessary to obtain the substance, use, or recover
 9. Important social, occupational, or recreational activities are given up or reduced because of substance
use
 10. The substance use is continued despite knowledge of having a persistent or recurrent physical or
psychological problem that is likely to have been caused or exacerbated by the substance
 11. Craving or a strong desire or urge to use a specific substance