Neuroscience Notes

Medical Science 731







Neuroscience:

NOTES

Spring 2006

last updated 1/4/2007









Christopher B. Kolar

cbkolar@wisc.edu





This study guide has been created in the course of my studies at the University of Wisconsin

School of Medicine and Public Health. It is intended as an exam review of the required learning

objectives. It references a variety of course materials, including lecture, Power Point, assigned

readings, and sometimes outside sources. While I have attempted to make it as thorough, specific,

and accurate as possible, I cannot guarantee this, so use it at your own risk. If you have any

questions or comments, or have found an error within the text, please feel free to contact me.









COLOR KEY:

• red: diseases

• blue: medications

• orange: enzymes and compounds

• pink: microorganisms





FORMAT KEY:

• margins: 1”

• tab stops: 0.25”

• font: Times New Roman

• size: 10

Neuroscience: OBJECTIVES (page 2 of 117)









SPINAL CORD



Orientation

- imaging

- MRI: standing at the patient’s feet, with patient lying on back

- patient left: right side

- patient right: left side

- anterior: top

- posterior: bottom

- neurological section: standing at patient’s head, with patient lying on stomach (MRI with inverted AP)

- patient left: right side

- right: left side

- ventral: bottom

- dorsal: top

- spinal cord anatomy

- gray matter: inner layer, composed of cell bodies, and shaped like butterfly

- dorsal horn

- lateral horn

- ventral horn

- white matter: outer layer, composed of axons

- dorsal funiculus (column)

- lateral funiculus

- ventral funiculus









Dorsal Column

- function: conveys 2 point discrimination, vibration, and conscious proprioception from the body



- cells: peripheral processes: alpha-beta axons (6-12 μm diameter, myelinated) in medial dorsal root

- Meissner’s corpuscles: velocity detectors for movement across the skin

- Merkel’s discs: touch pressure receptors, for two point discrimination

- Pacinian corpuscles: velocity detectors, for vibration

- Ruffini corpuscles: may be involved in conscious proprioception

cell bodies: dorsal root ganglia

central processes: into CNS in medial dorsal root, ascend in ipsilateral dorsal funiculus

- fasciculus gracilis: T7 and below (leg); synapse in nucleus gracilis

- fasciculus cuneatus: T6 and above (arm); synapse in nucleus cuneatus



- somatotopy: lower levels are more medial (different than most other spinal pathways)



- lesions: deficits below the level of the lesion

- ipsilateral 2 point discrimination, vibration, conscious proprioception

- astereognosia, agraphestesia, ataxia, paresthesia



- diagnosis: Romberg sign: inability to maintain stability in absence of visual cues

stick and stamp: flinging of legs, elevated lift, and foot stamp during walking

L’Hermitte’s sign: parasthesia resulting from cervical column disease

- often described as the sensation of an electric shock

- flexion at the neck stretches demyelinated axons in cervical region of dorsal columns



- disorders: tabes dorsalis: neuronal wasting, often resulting in stick and stamp

Neuroscience: OBJECTIVES (page 3 of 117)









Spinothalamic Tract (Anterolateral System, or ALS)

- function: conveys pain and temperature



- pathway: neuron 1 (peripheral neuron)

- peripheral processes: delta, C fibers associated with naked nerve endings

- delta fibers: 1-5 μm, myelinated; cooling, first/pricking pain, crude touch

- C fibers: 0.2-1.5 μm, myelinated; warming, second/burning pain

- cell bodies: located in dorsal root ganglia

- central processes: into CNS in medial dorsal root

- ascend two levels in ipsilateral Zone of Lissauer

- synapse in ipsilateral dorsal horn on cells of the ALS

neuron 2 (ALS)

- cell bodies: dorsal horn cells on side of sensory data

- central processes: decussate, ascend in ALS, synapse in VPL of the thalamus

neuron 3 (thalamus to cerebral cortex): synapse in areas 3, 1, and 2 of cortex



- somatotopy: lower levels are more lateral



- lesions: Zone of Lissauer: ipsilateral deficit at affected level and caudal two levels

dorsal horn: ipsilateral deficit at affected level

ALS: contralateral deficit two levels below lesion and below



- diagnosis: deficit in pain and temperature

deficit in crude touch (can be masked if affected side dorsal columns are intact)









Dorsal Spinocerebellar Tract (DSCT)

- function: conveys unconscious proprioception, permits reflex responses



- pathway: neuron 1 (peripheral neuron)

- peripheral processes: Ia, Ib, II fibers associated with muscle receptors

- Ia: 12-20 μm, myelinated; nuclear bag, nuclear chain receptors (length, velocity)

- Ib: 12-20 μm, myelinated; Golgi tendon organs (tension)

- II: 12-20 μm, myelinated; nuclear chain receptors (length)

- cell bodies: located in dorsal root ganglia

- central processes: into CNS in medial dorsal root

- C8 to L3: synapse in ipsilateral Clarke’s nucleus

- below L3: ascend in fasciculus gracilis, synapse in ipsi Clarke’s nucleus at L3

- above C8: ascend in fasciculus cuneatus, synapse in ipsi accessory cuneate nucleus

neuron 2

- Clarke’s column: ascend in ipsi DCST, synapse in cerebellum (via inferior cerebellar peduncle)

- accessory cuneate nucleus: synapse in cerebellum (via inferior cerebellar peduncle)



- somatotopy: lower fibers are more lateral



- lesions: ipsilateral ataxia



- diagnosis: cerebellar ataxia: inability to stand steadily with feet together and eyes open

- because of this, determination of a Romberg sign is impossible

Neuroscience: OBJECTIVES (page 4 of 117)









Lateral Corticospinal Tract (LCST)

- function: conveys descending voluntary muscle instruction



- pathway: neuron 1 (upper motor neuron, LCST)

- cell bodies: located in motor cortex (area 4; precentral gyrus)

- axons

- brainstem: descend in corticospinal tract, form pyramids, decussate in caudal regions

- spinal cord: descend in lateral corticospinal tract, synapse at myotomal level

neuron 2 (lower motor neuron)

- cell bodies: located in ventral horn of myotomal level

- peripheral processes: exit via ventral roots, synapse at neuromuscular junction (NMJ)



- somatotopy: lower level targets are more lateral



- lesions: ipsilateral muscle weakness (UMN lesion) below level of the lesion; NOT paralysis

- hemiplegia: ipsilateral muscle weakness

- spasticity: increase in muscle tone seen when passively moving a limb

- hyperreflexia: heightened reflexive responses

- clonus: involuntary contractions (5-7 Hz) in response to abruptly applied, sustained stretch

- Babinski sign: dorsiflexion of big toe upon stroking plantar surface of foot

- Chaddock sign: dorsiflexion of big toe upon stroking lateral surface of foot

- Bing sign: dorsiflexion of big toe upon jabbing dorsal surface of big toe

- Hoffman sign: reflexive flexion of index finger, thumb upon flicking the middle finger

- hyporeflexia

- cremasteric reflex: cremasteric contraction upon stroking inner thigh (located at L1)

- abdominal reflex: movement of umbilicis upon scratching abdominal quadrant (T 6-T12)



- diagnosis: appearance: flexed arm, extended leg with complete hemiplegia

determination of spasticity, hyperreflexia, or hyporeflexia in UMN areas









Ventral Horn

- function: provides lower motor neuron function to muscle cells



- cells: inputs: LCST, reflex pathways

cell bodies: ventral horn at myotomal level

peripheral processes: exit via ventral roots, synapse at neuromuscular junction (NMJ)



- somatotopy: medially oriented cells: innervate more proximal muscles

laterally oriented cells: innervate more distal muscles (lateral = lower)



- lesions: ipsilateral muscle degeneration (LMN lesion) at level of the lesion

- atrophy: wasting and shrinkage

- flaccidity: lack of resilience

- atonicity: lack of firmness in response to stretch

- areflexia: lack of reflex in response to stretch

- fasciculation: visible twitching of dying muscles



- diagnosis: LMN symptoms and more specific muscular analysis

Neuroscience: OBJECTIVES (page 5 of 117)







- spinal shock: transient atonia, flaccidity immediately following UMN lesion

- can resemble LMN disease, but symptoms eventually replaced by those typical of UMN









Lateral (Intermediolateral) Horn

- function: autonomic sympathetic outflow

- smooth muscle of the dilator pupillae

- smooth muscle of the upper eyelid

- blood vessels, sweat glands, hair of the head



- pathway: hypothalamic control: descends in brain stem, spinal cord (medial LCST), synapse in lateral horn

preganglionic: cell bodies in lateral horn, axons to peripheral ganglia (white communicating rami)

- can synapse in sympathetic chain

- can travel up or down the sympathetic chain, synapse

- can pass through chain to form splanchnic nerves, synapse elsewhere

postganglionic: cell bodies in peripheral ganglia, axons travel with vasculature



- somatotopy: lateral horn located ONLY from T 1 to L2 in the spinal cord; must supply entire body from there



- lesions: hypothalamic control: ipsilateral Horner’s syndrome, complete ipsilateral loss of sweating

T1: ipsilateral Horner’s syndrome

below T1: loss of sweating in affected dermatome



- disorders: Horner’s syndrome: symptoms of the face caused by loss of sympathetic innervation

- ptosis: drooping eyelid, caused by loss of sympathetic innervation to the eyelid

- miosis: constricted pupil, caused by overriding effect of parasympathetics

- flushed face: caused by loss of vasoconstricting effects

- dry face: caused by loss of sweat control









Summary: Fiber Types

TABLE: Dorsal Root Fibers

Roman Greek size myelin structure modality

Ia Aα 12-20 μm yes nuclear bag receptors muscle length, velocity

nuclear chain receptors muscle length

Ib 12-20 μm yes Golgi tendon organs muscle tension

II Aβ 12-20 μm yes nuclear chain receptors muscle length

6-12 μm encapsulated receptors 2 pt, vibration, cons. prop.

III Aδ 1-5 μm light naked nerve endings cooling, first pain

--- B light visceral afferents

IV C 0.2-1.5 μm no naked nerve endings warming, second pain



TABLE: Ventral Root Fibers

Roman Greek size myelin target

Ia Aα 12-20 μm yes efferent: extrafusal muscle fibers

--- Aγ yes efferent: intrafusal muscle fibers

--- B light preganglionic autonomics

IV C 0.2-1.5 μm no postganglionic autonomics (not technically part of ventral root)

Neuroscience: OBJECTIVES (page 6 of 117)









SELF LEARNING: Spinal Levels

determining approximate spinal levels

- gray matter

- largest in cervical, lumbosacral enlargements due to massive innervation demands to limbs

- smallest in thoracic, upper lumbar levels due to minor innervation demands of thorax, abdomen

- white matter: absolute size increases with successively higher spinal segments

- lateral horn: present from T1 to L2

- fasciculus cuneatus, gracilis: both present above T7

- cervical vs. lumbosacral enlargements

- dorsal horn: narrower in cervical levels than in lumbar levels

- ventral horn: broad in both cervical levels and lumbar levels

summary

- cervical: balanced white, grey matter; both dorsal columns obvious

- thoracic: lots of white matter, very little grey matter; lateral horn

- lumbar: only one dorsal column, both dorsal and ventral horns are relatively thick

- sacral: lots of gray matter, very little white matter









SPINAL CORD (CLINICAL)



Lower Motor Neuron Diseases and Diagnosis

LMN anatomy

- anterior horn cell (cell body)

- somatotopic organization: lateral cells innervate distal muscles (lateral = lower)

- lesion specificity: single muscles or portions of muscles can be affected by anterior horn cell lesions

- peripheral nerve

- α-motor neurons: innervate extrafusal muscle fibers (primarily force-generating)

- γ-motor neurons: innervate intrafusal muscle fibers (primarily attached to reflex receptors)

- B fibers: preganglionic autonomics

- C fibers: postganglionic autonomics; not technically part of ventral root

- neuromuscular junction

- generation: nerve impulse generated at anterior horn cell

- conduction: AP propagated via saltatory conduction, ultimately reaching neuromuscular junction

- synapse: presynaptic: influx of Ca2+ causes fusion of ACh-containing vesicles, release into synaptic cleft

postsynaptic: binding of ACh generates end plate potential, generating AP in muscle fiber

- muscle

- motor unit: muscle fibers innervated by a single anterior horn cell

- territory spans 10-15 mm in a muscle

- generally, directly adjacent muscle fibers are not usually innervated by the same cell

- consequence: not part of the same motor unit

- purpose: damage to a motor unit is dispersed amongst muscle, allowing easier repair and recovery

- fiber types

- type Ia: slow-conducting (oxidative)

Neuroscience: OBJECTIVES (page 7 of 117)







- type Ib: intermediate (oxidative, glycolytic)

- type II: fast-conducting (glycolytic)





differential diagnosis of LMN subgroups

history and clinical examination

- history: onset, family history, consanguinity, pattern and progression, associated sensory deficits, fatigability

- examination: corroborate clinical history, document patterns of weakness, sensory loss, fatigability, reflex changes



histological examination of muscle or nerve biopsy specimens

- primary myopathy: degeneration of muscle

- non-specific features: necrosis, evidence of regeneration, structural abnormalities

- diagnostic features: nemaline rod formation, central core

- inflammation: may indicate a treatable disease

- muscle denervation: cannot distinguish between anterior horn cell disease or peripheral neuropathy

- type grouping: grouped adjacent type I or II fibers, resulting from denervation and reinnervation

- group atrophy: atrophied groups of muscle fibers, resulting from type grouping and subsequent denervation

- nerve damage

- axonal damage: bead-like disruption of the peripheral nerve (Wallerian degradation); disease of axon or body

- demyelination: shortened internodes with thinner myelin (does not affect axon cylinder)



electromyographic (EMG) examination

- process

- nerve conduction studies: stimulation of nerve, measurement of evoked responses, comparison to standards

- conduction speed: time taken from stimulation to generation of CMAP

- compound muscle action potential (CMAP): represents AP of all muscle fibers activated by nerve stimulation

- sensory nerve action potential (SNAP): represents AP of all sensory fibers activated by nerve stimulation

- repetitive nerve stimulation studies: repeated stimulation of nerve (2-3 Hz), recording of first 4 CMAPs



- nerve conduction findings in different LMN subgroups

- anterior (ventral) horn cell disease

- conduction velocity: normal

- CMAP amplitudes: low

- peripheral nerve cell disease

- axonal

- conduction velocity: normal

- CMAP/SNAP amplitudes: low

- demyelinating

- conduction velocity: low

- CMAP/SNAP amplitudes: normal

- neuromuscular junction (NMJ) disease

- conduction velocity: normal

- CMAP amplitudes: normal

- repetitive stimulation: decremental

- muscle disease

- conduction velocity: normal

- CMAP amplitudes: low



needle examination

- process

- needle activation: electrode is introduced into the muscle, recordings are made with moderate muscle activation

- motor unit potentials (MUPs): represent action potentials of a single motor unit, standardized to specific muscles

- findings

- large (neurogenic) MUPs: anterior horn disease, peripheral nerve damage (reinnervation, type grouping)

- small (myopathic) MUPs: primary muscle disease (muscle degeneration, weakness)

Neuroscience: OBJECTIVES (page 8 of 117)







- fasciculations and fibrillations

- fasciculations: visible contraction of a small group of muscle fibers; seen with muscle fiber reinnervation

- caused by spontaneous discharge of anterior horn cell or motor axon

- common in amyotrophic lateral sclerosis

- fibrillations: small potentials generated by single muscle fiber contraction; seen with muscle denervation

- ACh receptors lose localization, become sensitive to free ACh released from adjacent fibers

- disappear with reinnervation, and may aid in attracting new innervation

biochemical studies

- ACh antibodies: found in myasthenia gravis (neuromuscular transmission defect)

- creatine phosphokinase (CK): elevated in blood in primary muscle diseases where muscle breakdown occurs



genetic studies

- genetic defects: known for many neuromuscular diseases, can be detected in peripheral blood or muscle





abnormal findings in LMN disease subgroups

- anterior horn cell diseases

- clinical: selective involvement of muscles

- low CMAP: fewer total axons (group atrophy)

- large MUPs: reinnervation (type grouping)

- histology: type grouping, group atrophy

- fasciculations: present

- fibrillations: present



- peripheral nerve diseases

- axonal

- clinical: associated sensory deficits and autonomic abnormalities

- low CMAP: fewer total axons (group atrophy)

- low SNAP: frequently accompanied by sensory nerve damage

- large MUPs: reinnervation (type grouping)

- fasciculations: present

- fibrillations: present

- histology: type grouping, group atrophy

- demyelinating

- clinical: associated sensory deficits and autonomic abnormalities

- conduction: slow conduction velocity



- neuromuscular junction diseases

- clinical: abnormal fatigability

- dec. CMAPs: poor response to repetitive stimulation



- primary muscle diseases

- clinical: specific patterns of muscle weakness

- Duchenne muscular dystrophy: large calves, proximal muscle weakness

- myotonic dystrophy: myotonia (inability to relax muscles), muscle weakness

- low CMAP: fewer muscle fibers per motor unit

- myopathic MUPs: degenerated muscle leads to decreased responses

- histology: necrosis, inflammation, degeneration, increased fat and connective tissue

- blood CK: elevated



TABLE: Summary of Findings in LMN Subgroups

conduction CMAP SNAP repetitive MUPs blood CK histology fasciculation fibrillation

velocity amplitude amplitude stimulation

anterior horn ↓ large type grouping X X

disease group atrophy

peripheral ↓ ↓ large type grouping X X

nerve group atrophy

Neuroscience: OBJECTIVES (page 9 of 117)







(axonal)

peripheral ↓

nerve

(demyelin)

myasthenia ↓

gravis (NM)

primary ↓ small ↑ necrosis X

muscle inflammation

(active)

degeneration

fat, CT

UMN lesion





- general localization

- central lesion: increased reflex in affected limb

- peripheral lesion: decreased reflexes in affected limb

- spinal cord lesion: bilateral sensory, motor deficits below a horizontal level









Radiculopathy (Peripheral Nerve Disease)

- radiculopathy: irritation of one or more of the spinal cord roots

- symptoms: pain (“shooting,” “burning,” “sharp”), weakness, numbness, paresthesia

- causes: lateral spinal disc protrusion, bony spurs

- prevalence: 5-10% of cases of back pain

- treatment: physical rehab: similar outcomes to surgery, but much slower

surgery: rapid relief, but can cause loss of stability; required in 10% of cases



anatomy

- peripheral nervous system

- spinal nerve roots

- location: exit spinal cord at segmental levels, join to form the spinal nerve

- divisions: dorsal root: posterior, sensory

ventral root: anterior, motor

intervertebral foramina: location of nerve exit from vertebral column; more vulnerable

- rami (branches of the spinal nerves)

- divisions: dorsal rami: supply true back muscles, skin of the back

ventral rami: supply everything else (except the head)

- fiber types: sensory, somatomotor, visceromotor

- dermatomes

- dermatome: distribution of sensory fibers in each spinal nerve

- important dermatomes

- C4: shoulder

- C6: lateral forearm (includes thumb, index finger; shaped like a “6”)

- C8: medial forearm (includes digiti minimi)

- T 4: nipple line

- T10: navel

- T12: suprapubic region

- L2: anterior thigh

- L4: medial leg

- L5: lateral leg, medial foot (includes hallux)

- S1: lateral foot (includes digiti minimi)

- myotomes

- myotome: group of muscles primarily innervated by motor fibers in a single nerve

- upper limb: important myotomes

Neuroscience: OBJECTIVES (page 10 of 117)







- C5/6: shoulder: deltoid, biceps, brachioradialis, infraspinatus, supraspinatus

- C6/7: elbow: triceps

- C7/8: wrist: extensors and flexors

- C8, T1: hand: intrinsic muscles

- lower limb: important myotomes

- L2/3: hip: flexors (iliopsoas)

- L3/4: knee: extensors (quadriceps), adductors

- L4/5: ankle: dorsiflexors

hip: extensors and abductors

- L5, S1: knee: flexors

- S1/2: ankle: plantiflexiors

- reflexes

- biceps: C5

- brachioradialis: C6

- triceps: C7

- patellar: L3/4

- Achilles: S1/2

- cervical vertebrae

- C1: atlas (head rotation)

- C2: axis (head flexion; contains dens around which atlas rotates)

- spinal cord roots

- exit from the vertebral column

- lumbar roots: emerge below respective vertebrae

- thoracic roots: emerge below respective vertebrae

- cervical roots: emerge above respective vertebrae (note: one more root than vertebrae, numbers maintained)

- intervertebral disc: named for the levels between which it is situated



disorders

root compression

- characteristics of root compression

- pain: hallmark complaint, frequently accompanied by paresthesia and sensory loss

- dull pain: typically more proximal, difficult to localize

- sharp pain: typically localizes around dermatomal borders

- weakness: can occur in muscles innervated by the root

- intervertebral disc disease: most common cause of compressive radiculopathy

- herniated discs will compress the root of the lower number of the intervertebral disc

- L4/5: damages L5 (most common disc herniation, 50% of cases); large root, small foramen diameters

- L5/S1: damages S1 (second most common disc herniation, 46.3% of cases)

- treatment

- clinical: MRI, and in conjunction with symptoms (20-30% of asymptomatic people 8 mm

- area: varies 16-fold

- increases crispness of unfocused retinal images by reducing stray light contributing to blur

- small pupil reduces rays coming in on non-parallel angles

- increases depth of field due to blur reduction

- object appears darker, but clearer

- miosis: constriction of the pupil

- muscle: constrictor pupillae

- innervation: parasympathetic

- pupillary light reflex: constriction in response to light

- afferent: eye to pretectal nuclei to Edinger-Westphal nucleus via optic nerve (CN II)

- bilateral sensation: crosses via posterior commissure

- efferent: E-W nucleus bilateral to pretectum to constrictor pupillae muscle

- lesions

- optic nerve lesion: no direct response, but consensual response (loss of sensation)

- oculomotor lesion: no direct OR consensual response (loss of motor control)

- linkage between accomodation and pupillary constriction

- near response: actions that occur when gaze is shifted from a distant to a near object

- pupillary constriction

- lens accommodation

- eye convergence

Neuroscience: OBJECTIVES (page 45 of 117)







- Argyll-Robertson pupil: pupillary constriction is lost with light adjustment, but remains with accommodation

- can be seen in some patients with CNS syphilis

- lesion location: unknown; may be in the pretectum

- mydriasis: dilation of the pupil

- muscle: dilator pupillae

- innervation: sympathetic

- hypothalamic: descending control

- preganglionic: lateral horn at T1 to the superior cervical ganglion

- postganglionic: SCG, coursing with carotid, opthalmic arteries, through ciliary ganglion, via nasociliary nerve,

to dilator pupillar muscle

- lesions: Horner’s syndrome

- constriction of the pupil due to unopposed action of the parasympathetics

- ptosis due to loss of innervation of Mueler’s muscle (superior tarsal), a muscle that helps open upper eyelid

- pharmacology of the iris

- parasympathetic system

- function: miosis (constriction)

- transmitter: cholinergic

- agents: cholinergic agonists (pilocarpine, carbochol)

noradrenergic antagonists (phentolamine)

- sympathetic system

- function: mydriasis (dilation)

- transmitter: noradrenergic

- agents: noradrenergic agonists (epinephrine, phenylephrine, cocaine)

cholinergic antagonists (atropine, tropicamide)









Retinal Structure and Function

retinal anatomy

- layers

- types

- nuclear layers: those containing cell bodies

- plexiform layers: those containing axonal and dendritic processes

- retinal structure: sclera to vitreal chamber

- photoreceptor layer: light transducing cells

- external limiting membrane

- outer nuclear layer: nuclei of photoreceptors

- outer plexiform layer

- inner nuclear layer: bipolar cells, other integrative neurons of the retina

- inner plexiform layer

- ganglion cell layer: ganglion cells

- nerve fiber layer: ganglion cell processes, destined for the optic disc to form the optic nerve

- orientation: inverted retina

- specializations to preserve visual image

- axons are thick and unmyelinated

- retina is thin (0.4 mm thick) with few structural supporting elements

- advantage: metabolic supply to photoreceptors

- disadvantage: fragile structure

- structural elements

- optic disc: location of exiting retinal ganglionic axons, blood vessel access to the eye

- fovea: pit-shaped area in central retina (1.5 mm wide) where retina is reduced in thickness

- specialized for visual acuity

- direct fixation focuses light on fovea

Neuroscience: OBJECTIVES (page 46 of 117)







- macula lutea (macula): larger area in which the fovea is located

- yellow compared to the rest of the retina (due to a protective absorptive pigment)

- “foveal vision” and “macular vision” are interchangeable

cell types in the retina

- photoreceptors

- photoreceptor: unique cells in the retina that transduce light energy into a neural signal

- rod: specialized for sensitivity (black and white vision, night vision)

- cone: specialized for acuity (color vision)

- outer segment: functional region at the distal portion of the cell

- packed with light-sensitive molecules in a series of membrane invaginations that resemble discs

- respond to light with a graded potential

- most direct neural path from eye to brain: two synapses

- photoreceptors: light-sensitive cells

- bipolar cells: integrative cells

- ganglion cells: integrative cells

- other retinal cell types

- horizontal cells: located in outer nuclear layer, and can contact numerous photoreceptors

- interplexiform cells: form neural circuits with bipolar, ganglion cells as initial processing of visual signals

- amacrine cells: form neural circuits with bipolar, ganglion cells as initial processing of visual signals

- Muller cells: large glial cells that provide metabolic support

- retinal astrocytes: provide metabolic support

retinal pigment epithelium (RPE)

- structure: layer of melanin-containing cells on the internal side of the choroid

- tips of photoreceptors contact RPE

- function: melanin: absorbs light not captured by the photoreceptors

- prevents reflection and scatter of light that would degrade the visual image

- helps cool the photoreceptors from the heat of the absorbed light

metabolic function

- photoreceptor discs are shed (3/hr) from the top of the outer segment while new ones are generated

- turnover depends critically on the retinal pigment epithelium

- clinical: problems with RPE can cause progressive vision degradation and, ultimately, blindness

specializations in the retina

- fovea: focal point of the retina that mediates acute color vision

- shape: depression in the retinal layer due to loss of ganglion, bipolar cell layers, and vasculature

- function: highest density of cone photoreceptors in the retina

- rod and cone-mediated vision

- rods and cones are distributed differently across the retina

- cones are greatest in number in the fovea (drop off substantially by 15° away)

- rods are absent from the fovea

- rods are the primary receptor in non-foveal regions of the retina

- perifovea: peak distribution of rods in the retina (20° away from fovea)

- rods are more sensitive to light than are cones

- scotopic vision: nighttime vision

- convergence: synapse of numerous rods onto one bipolar cell

- increases sensitivity

- decreases acuity

- the most sensitive rods respond to a single photon of light

- cones have better acuity than rods

- photopic vision: daytime vision

- specializations for acuity

- dense packing in the fovea

- direct connections (sometimes one to one) with bipolar cells

- rods are much more common than cones

- rods: 120 million

- cones: 6 million

- ganglion cells: 1 million

Neuroscience: OBJECTIVES (page 47 of 117)







- cones convey color information, while rods don’t

- rhodopsin: light-sensitive pigment found in all rods

- cones: three pigments that respond to different wavelengths of light

- blue: shortwave-sensitive

- green: middlewave-sensitive

- red: longwave-sensitive

- deficiencies: can lead to color blindness

- frequently male due to X-linkage

- still see in color, but in different or fewer hues than people with typical color vision



TABLE: Comparison of Rod- and Cone-Mediated Vision

rods cones

number 120 million 6 million

type scotopic (night) photopic (day)

organization convergent direct

location best in perifovea best in fovea

acuity low (20/200) high (20/20)

light sensitivity high low

color sensitivity black and white color (trichromatic)



- peripheral vs. central vision

- peripheral retina: image locator (can detect new stimuli)

- central retina: image analyzer (can fixate on, analyze data)

optic disc and optic nerve

- structures

- optic disc: point of passage for ganglionic cells, eye vasculature

- optic nerve: bundling of ganglionic cells, covered in dural sheath, that continues towards the brain

- lamina cribosa: barrier at the base of the optic nerve made of specialized sclera

- composition: dense collagen with fenestrations through which axons, neuroglia pass

- function: maintains fluid and pressure difference between eye and the rest of the brain

- organization

- ganglion cells first become myelinated in the optic nerve (oligodendrocytes)

- axons are grouped into small bundles after the lamina cribosa (astrocytes, microglia)

- most axons from a particular quadrant are grouped into the same region of the nerve

- central retinal locations: central locations in the optic nerve

- peripheral retinal locations: peripheral locations in the optic nerve

- consequence: damage to a small portion of the optic nerve can be localized

- infections

- endophthalmitis: eye infection

- by traveling through the optic disc, this can become meningitis or encephalitis

- blind spot

- natural blind spot due to optic disc

- scotoma: pathological blind spot caused by a lesion in the eye or in part of the visual pathway

blood supply

- retina

- central retinal artery

- origin: branch of the opthalmic artery

- course: enters eye through the optic disc

- distribution: inner 2/3 of retina, optic nerve

- posterior ciliary artery

- origin: branch of the opthalmic artery

- course: enters outside of eye through choriocapillaries

- distribution: outer retina, photoreceptors, optic nerve (supply from external to dural sheath)

Neuroscience: OBJECTIVES (page 48 of 117)









Central Visual Pathways

- visuotopy: visual mapping

- visual areas of the brain contain an organized map of the world

- understanding this is important to understanding central projections of visual neurons

visual fields and retinal coordinates

- visual fields

- visual field: in the eye. entire extent of the external world that can bee seen without moving the eye

- nasal field: medial half-visual field

- temporal field: lateral half-visual field

- superior field: upper half-visual field

- inferior field: lower half-visual field

- monocular and binocular visual fields

- fields

- monocular field: visual field as seen by an individual eye

- binocular field: combination of the two monocular fields

- monocular segments (crescents): areas in the far temporal fields seen only by one eye or the other

- localizing a visual deficit: coordinate systems

- visual field coordinates: location of the image in the field of vision

- retinal coordinates: location of the image on the retina (anatomical location)

- retinal relationships

- image is inverted as it passes through the lens

- diplopia: double vision caused by poor correspondence of individual monocular fields

- topographic organization

- visual receptive field: region in visual space in which a visual stimulus can excite or inhibit a visual neuron

- visual field: sum of all of the individual visual receptive fields

- retinotopic organization: topographic organization of the visual system (maintained in central visual pathways)

retinal projections

- retina to optic tracts

- pathway

- optic nerve: projection from the retina back to the optic chiasm

- optic chiasm: location of decussation of some optic fibers

- optic tract: continuation of optic nerve

- crossing pattern

- axons from the nasal retina cross to the contralateral optic tract

- axons from the temporal retina remain in the ipsilateral optic tract

- central visual structures receive afferent input from the contralateral visual field

- overview: targets

- thalamus (lateral geniculate body): pathway for conscious visual perception

- superior colliculus: involved in saccadic eye movements and orienting responses

- pretectum: involved in pupillary light reflex and optokinetic nystagmus (a primitive eye movement)

- hypothalamus (suprachiasmatic nucleus): regulation of circadian rhythms

- retino-geniculo-cortical pathway

- lateral geniculate body (LGB): thalamic nucleus involved in relaying conscious visual proprioception

- retinal ganglion cells synapse on thalamocortical cells in the dorsal LGB

- partial decussation causes each nucleus to receive information from the contralateral visual field

- structure of the LGB

- organization: six well-defined layers

- innervation: topographically-innervated by both eyes

- axons from the two eyes remain segregated

- each layer of LGB receives input from one eye only (single cells innervated by single eye)

- functions

- initial topographic alignment of retinal projections

- complete map of the contralateral visual field contained in each layer

Neuroscience: OBJECTIVES (page 49 of 117)







- six maps in precise register

- line normal to curved layers passes through cells that map the same visual field location

- segregation of visual signals into separate streams destined for different types of visual processing

- optic nerve contains different functional classes of cells that carry different types of visual information

- different classes of neurons are segregated into different layers of the LGB

- gateway to control flow, character of visual signals that reach cortex

- geniculocortical projection through the optic radiations

- pathway of optic thalamic projections

- LGB

- retrolenticular limb of the internal capsule (caudal to the lenticular nucleus)

- optic radiations

- optic lobe

- optic radiations: retinotopic organization

- lower visual field: axons travel directly back to occipital cortex

- upper visual field: axons swing out laterally to the temporal lobe forming an arc (Meyer’s loop)

- visual cortex

- primary visual cortex: alternate names

- V1 in the occipital lobe (primary visual cortex)

- area 17 (Brodmann’s cytoarchitectural maps)

- striate cortex (prominent stripe, or stria of Gennari, that can be seen with the naked eye)

- calcarine cortex (most of the cortex is confined to superior, inferior banks of the calcarine sulcus)

- retinotopic organization of the primary visual cortex: complete representation of contralateral visual field

- foveal representation: posterior (enlarged; 1/3 of primary visual cortex)

- upper visual field: ventral bank of the calcarine fissure

- lower visual field: dorsal bank of the calcarine fissure

- extrastriate visual cortex (secondary visual areas)

- secondary visual areas: other cerebral cortical areas concerned with vision

- Brodmann areas 18, 19 in the occipital lobe, other cortical areas

- each contains a retinotopically-organized map of the contralateral visual hemifield

- over half of the cerebral cortex is involved in visual processing

- includes portions of occipital, temporal, and parietal lobes

- parietal regions: where is it?

- temporal regions: what is it?

- frontal cortex: also involved visually in production of eye movements

- blood supply for the central visual structures

- optic nerve: opthalmic branches (central retinal artery, posterior ciliary arteries)

- optic chiasm: anterior cerebral arteries

internal carotid arteries

- optic tract: posterior communicating artery

anterior choroidal artery

- LGB: branches of posterior cerebral artery

branches of anterior choroidal artery

- optic radiations: branches of anterior choroidal artery (minor from middle cerebral, posterior cerebral)

- area 17: posterior cerebral artery (considerable anastomosis with middle cerebral)

lesions

- definitions

- anopsia: loss of vision

- homonymous: affects same part of visual field in each eye

- visual pathways

- optic nerve: ipsilateral total blindness

- optic chiasm

- crossing fibers: bitemporal hemianopsia (lateral visual field loss)

- ipsilateral fibers: unilateral nasal hemianopsia

- optic tract: contralateral homonymous hemianopsia (contralateral visual field loss)

- LGB projection

- Meyer’s loop: contralateral upper quadrant hemianopsia

Neuroscience: OBJECTIVES (page 50 of 117)







- straight fibers: contralateral lower quadrant hemianopsia

- primary visual cortex: contralateral homonymous hemianopsia with macular sparing

- even a large lesion of area 17 on one side of the brain can spare the macular region

- if both cortices are affected, with macular sparing on both sides, tunnel vision results

- reason is poorly understood

- NOTE: everything after the optic chiasm is homonymous

- small area 17 lesions

- scotoma: minor deficit of the visual field

- corresponds to retinotopic location in the calcarine fissure

- frequently not noticed by patients

- secondary visual field lesions: subtle deficits affecting an aspect of vision (as opposed to a portion)

- inferior temporal lobes: prosopagnosia: inability to recognize previously-familiar faces

- posterior parietal lobes: neglect: ignored or unrecognized objects in the contralateral hemifield

- parietal lobes: spatial deficits: poor spatial understanding









Visual Testing

visual acuity testing

- visual acuity: the ability to tell an object from its background

- limited part of the visual system – does not measure color vision, contrast, sensitivity, or other functions

- tests only cones at the fovea

- method

- each eye is tested alone, with the opposite eye covered

- patient is asked to read standardized letters of gradually-decreasing size

- lowest recognizable letter size is deemed the visual acuity

- indication: acuity relative to a “normal” person standing at 20 feet

- numbers refer to size of the letters and the corresponding size on the retina

- 20/20: arc of 5 minutes from 20 feet away

- 20/40: arc of 10 minutes from 20 feet away

- direct relationship between viewing distance and arc subtended

- distance chosen as to not require accommodation (rays are “infinitely” far away)

- modifications for viewing distance: acuity = 20/(20·x) | x = (lowest line read / viewing distance)

example: viewing distance = 100 feet

lowest line read = 20/20

acuity = 20/(20·(20/100))

= 20/4



confrontational visual field testing

- method

- patient and examiner each cover one of their eyes, and open eyes are aligned

- examiner holds fingers up in various parts of the visual field, and the patient is asked to identify the number

- typically 1, 2, or 5 fingers are used

- results from complaints in difficulty of discerning 3 and 4 fingers

- indication: rough acuity relative to the examiner

- works well in gross EM screening, but not for detailed detection

- machines designed to test visual field provide better control

- documentation

- charted from patient perspective (left on left, right on right)

- abbreviations

- OS: oculus sinister (left eye)

- OD: oculus dexter (right eye)

Neuroscience: OBJECTIVES (page 51 of 117)







visual testing machines

- overview: the hill of vision

- peripheral visual testing: creates a geographic map of visual areas working well, areas working poorly

- retinal responsiveness

- central retina has more cones, more ganglion cells, and is thus able to discern more attributes of stimuli

- in photopic conditions, sensitivity peaks at the fovea, gradually diminishes in the periphery

- described as a “hill of vision in a sea of darkness”

- optic nerve

- optic disc: location where ganglion cells exit, blood vessels enter eye

- does not have retinal cells, so vision in that area is artificially filled in by sensory systems

- during peripheral visual testing, there is an abrupt decrease in sensitivity at that area

- hill of vision: shape

- parabolic, fairly constant between people

- function of:

- mesopia

- photoreceptor density

- ganglion cell density

- alterations

- cataract: causes decrease in sensitivity at every point along the curve

- retinal scar: causes abrupt loss of sensitivity in a particular area

- methods

- design

- setup: hemispherical bowl containing a point of fixation

- lighting: low level, adapted for mesopic conditions (where rods and cones can both respond)

- process: patient presses a thumb switch when the stimulus has been flashed

- method

- Goldmann Visual Field testing

- mobile light stimulus

- fixed intensity light is moved in from periphery by examiner

- patient indicates when light becomes visible

- analogy: flying a plane into the side of the hill at a certain altitude, determining when it hits

- use: infrequent in modern visual field testing

- computerized visual field testing

- fixed light stimulus

- brightness is gradually increased

- patient indicates when light becomes visible

- analogy: dropping a ball onto top of hill, measuring how far it falls

- use: common in modern visual field testing, due to increased objectivity

- lights are presented in the same order each time

- no variability in speed of object movement by the technician

- allows a better, more graphic interpretation of patient’s field of vision

- reading results: normal eyes

- sensitivity

- increased central, decreased peripheral

- decreased nasal (presence of nose)

- blind spot: causes abrupt loss of sensitivity

- localization

- optic nerve: nasal retina

- blind spot: temporal vision

- the blind spot is on the same side as the eye

- the hill of vision: correspondence with rod and cone distribution

- localization

- cones: predominate in fovea

- rods: predominate in periphery

- mesopic: between photopic (high luminance) and scotopic (low luminance)

- allows both rods and cones to function well during the test

Neuroscience: OBJECTIVES (page 52 of 117)







- shape of the hill of vision is a function of:

- receptor density

- response sensitivity of the rods and cones to test stimuli

- thus visual field testing does not match total density of photoreceptors, but is as close as can be expected



pupillary light reflex

- visual pathway

- photoreceptor

- ganglion cell

- nerve fiber layer

- optic nerve

- optic chiasm

- lateral geniculate body

- optic radiations

- visual cortex

- pupillary light reflex pathway

- pathway

- afferent: fibers do not synapse on the LGB, but instead synapse bilaterally on the pretectum

- integrator: pretectum fibers synapse bilaterally on Edinger-Westphal nucleus

- efferent: EW fibers synapse unilaterally on ciliary ganglia, which then synapse on constrictor pupillae

- characteristics: EW nuclei receive sum of ocular sensation at all times

- pretectal input is bilateral: input to pretectal nuclei is based on the visual field, not on one eye

nuclei communicate and share inputs

- pretectal output is equal: EW nuclei receive equal input

- implications

- degree of constriction is dependent on intensity of light

- in normal individuals, light shone in an eye will cause equal constriction of both pupils

- relative afferent pupillary defect testing

- relative: only functions as a comparison between a “good” eye and a “bad” eye

- afferent: assumes that efferent arm of the loop is intact

- pupillary: determination of pupillary function

- defect: implies positive (loss of normal reaction) finding

- method

- if efferent system is intact:

- establish that the right eye iris is working (right eye first: convention)

- note pupil size in darkness

- shine light on right eye and determine if pupil constricts

- establish that the left eye iris is working

- note pupil size in darkness

- shine light on left eye and determine if pupil constricts

- compare the two eyes to each other

- begin with light on right eye

- move attention to left eye; swing light to left eye and note what the pupil does

- move attention to right eye; swing light to right eye and note what the pupil does

- positive: difference in constriction between the eyes

- light on normal eye: both eyes slightly more constricted

- light on abnormal eye: both eyes slightly more dilated

- if efferent system is nonfunctional in one eye:

- establish that the right eye iris is working (right eye first: convention)

- establish that the left eye iris is working

- compare the two eyes to each other

- ignore the defective eye for the swinging test

- if relative dilation happens when light is over bad eye, then there is also a defect in visual signal

Neuroscience: OBJECTIVES (page 53 of 117)









Disease States

retinal detachment

- etiology: physical attachment of the retina to the retinal pigment epithelium (RPE) is weak

hole in the retina allows fluid to invade the interdigitating space, causing progressive separation

separation causes loss of photoreceptor metabolic source

- incidence: 1/1000 people per year

- age: all ages are equally effected

- predisposition: near-sighted more likely affected, due to longer ocular dimensions

- symptoms: flashing lights: irritation of nerves due to physical traction

floaters: floating opaque bodies caused by blood clots

loss of vision: seen as a shade in a fairly defined area

- physical exam: retinal tissue movement within the vitreous fluid

- examination: visual acuity

- normal if central retina is uninvolved

- extremely poor if central retina is involved

confrontational visual field testing

- undetached areas: responses are rapid, accurate

- detached areas: responses are slow, and may or may not be accurate

formal visual field testing

- may be relative (able to detect only bright, large lights in affected areas)

- may be absolute (unable to detect any light in affected areas, no matter how strong)

- steep defect: edge is frequently sharp between affected, unaffected areas

relative afferent pupillary defect test

- for examiner to notice difference, half of light – relative to other eye – must be lost

- for retinal detachment, half of the retina must be detached to give a positive test

- treatment: urgent: requires immediate treatment to prevent progression

- if fovea is still attached, treatment is done on the same day as evaluation

- if fovea is detached, treatment can be done in the next day

process

- cut a hole in the sclera to drain the fluid that has seeped between the two layers

- seal a hole in the retina

approximation: retina must be held close to RPE for healing to occur

- use a bubble of gas in the eye to push the retina out to the sclera

- use a scleral buckle to push the eye into the retina

outlook

- fovea not detached: final acuity is unchanged from pre-detachment levels

- fovea detached: rare to achieve final vision better than 20/100



optic nerve trauma

- etiology: direct trauma

rupture of blood vessels within the optic nerve sheath

- incidence: typically only associated with severe damage to the head and face

- optic canal is well-fortified

- rarely is only the optic nerve affected

- symptoms: significant, obvious craniofacial trauma

- frequently comatose in ICU for several days/weeks before vision change can be documented

- in rare clinical presentations, visual symptoms are bad enough for patient to seek emergent care

- physical exam: possible damage to the eye itself

- hyphema: blood in aqueous humor (caused by break in iris blood vessels)

- tears in iris sphincter muscle causing irregular or immobile pupil

- rupture of lens attachments to ciliary body

- retinal detachment

- choroidal rupture: bleeding under the retina in the choroid

Neuroscience: OBJECTIVES (page 54 of 117)







- optic nerve avulsion: optic nerve rears from the eyeball at the lamina cribosa

possible damage to the bony socket

- blood pooling beneath the periosteum

- blowout fracture: rupture of the orbital walls

- bone fragments capable of shearing the optic nerve

direct physical exam and imaging (ultrasound, CT, MRI) important for evaluation

- examination: visual acuity

- blindness: can result from complete avulsion or laceration through the entire nerve

- barely affected: can result from minor compression of the nerve by hematoma

confrontational visual field testing

- frequently abnormal in areas corresponding to areas of greatest nerve damage

- requires an alert patient: frequently cannot be done until some time after the injury

formal visual field testing

- abnormalities in areas corresponding to areas of nerve damaging

- requires an alert patient: frequently cannot be done until some time after the injury

relative afferent pupillary defect test

- if afferent only is damaged: will be blatantly positive

- if efferent is damaged: more difficult to determine

- treatment: remove cause for further progression

high dose steroids to minimize edema and further compression

not possible to restore nerve function (part of CNS; do not regenerate)



optic nerve / tract compression

- etiology: tumor

aneurism

- incidence: extremely low (1:100,000)

- symptoms: slow growing tumors

- eye/orbital pain

- difficulty with eye movements

- decreasing vision

fast growing tumors

- protrusion of the eye

- pain

pituitary tumor: endocrine symptoms

- physical exam: altered pallor of optic nerve (not cupping, as in glaucoma)

decreased ocular motility

protrusion of the eye compared to the contralateral eye

unusual curvature of the eyelid

increased eye pressure

signs of indentation from behind

congestion of blood vessels in the conjunctiva, scleral wall

sometimes, “bad vision” is the only symptom

- examination: visual acuity

- occurs only late

- not very sensitive at detecting subtle visual loss in chronic optic nerve compression cases

confrontational visual field testing

- more sensitive than acuity

- not sensitive enough to reliably pick out subtle defects of vision if this is the only test used

formal visual field testing

- reliable methodology to map the area of the compression

- bitemporal hemianopia: pressure on the optic chiasm

- loss of crossing fibers causes loss of nasal fibers, temporal vision

- can be caused by pituitary tumor

relative afferent pupillary defect test

- frequently normal

- positive test requires change in one eye RELATIVE to the other eye

Neuroscience: OBJECTIVES (page 55 of 117)







- treatment: optic nerve sheath tumors: monitoring (poor risk-benefit with removal)

pituitary tumors: should be removed, due to effects on endocrine system

aneurysm: should be repaired before rupturing, neurologic problems occur



cortical stroke

- etiology: blood vessel rupture due to elevated blood pressure

emboli from roughened internal vessel walls

cortical function: highly active metabolically, and full function lost within minutes

- incidence: stroke: sudden decrease in cortical function due to alteration of blood flow to the cortex

- ischemic stroke: sudden decrease in flow

- hemorrhagic stroke: rupture of blood vessel with associated intracortical hemorrhage

occurs frequently in older patients with high blood pressure, diabetes, or high cholesterol

- symptoms: small stroke: frequently goes unnoticed

large stroke: symptoms corresponding to damaged areas

- in these cases, patients are frequently referred to the opthalmologist

- assessment is done to determine damage to the visual system

in general, symptoms are determined by the extent of the location

- physical exam: no two patients present with the same findings

- alteration of speech

- loss of cranial nerve function VII-XII

physical damage to the eyeballs ONLY secondary to vascular disease

- small aneurysms of blood vessels

- thickening of the muscular wall of the arteries

- small hemorrhages of capillaries within the retinal surface

- examination: visual acuity: not significantly effected

- cortical strokes are usually localized to either side of the brain

- performance on acuity tests is still good due to strong human pattern recognition

confrontation visual field testing

- indicates an abrupt asymmetry at the vertical meridian

- advantage: can be performed with bedridden patients

- patients must be conscious and alert

- frequently, even if speech is affected, other means of communication can be utilized

formal visual field testing

- similar restrictions to performance as in confrontational testing

- necessarily MUST respect the vertical midline

relative afferent pupillary defect test

- NEVER positive: reflex fibers split off prior to LGB

- treatment: supportive

- drainage

- dissolution of clots

- protection from aspiration (if other CNs are affected)

preventive: minimization of further events

- lower blood pressure

- institute aspirin to avoid clots or emboli

- rectify the source if embolism is assumed

some function can be regained by other cells



cataracts

- etiology: cataract: any opacity of the natural “crystalline” lens

- progressive accumulation of epithelial stromal proteins in the lens structure

- proteins become opaque, causing problem in vision

- incidence: 100% if people live long enough

50% by the age of 70

number one surgical expense of Medicare patients in the US

number one cause of treatable blindness (≤ 20/200 in the better of the two eyes) in the US

number one cause of blindness worldwide

Neuroscience: OBJECTIVES (page 56 of 117)







- symptoms: decreased acuity: frequently reported as problems with reading

increased glare: frequently reported as problems with driving

- physical exam: abnormal appearance of the lens

- irregularities and opacities seen as reflections in what should be transparent

- black specs against the red background if the light is shone directly in

most common type: generalized, uniform darkening of the center of the lens

- focal areas of opacity can be central (marked visual effects)

- focal areas of opacity can be peripheral (little effect except in dim light)

- examination: visual acuity

- progressive loss of color vision with visible change in lens color

- progressive smearing of light by diffraction, causing decreased acuity

confrontational visual field testing: negative

- even dense cataracts are usually diffuse or smaller than the test object

formal visual field testing

- no focal defects are detected

- diffuse defect is detected as a loss of sensitivity over the entire “hill of vision”

relative afferent pupillary defect test: negative

- does not block sufficient light as to cause an afferent pupillary defect

- treatment: surgery

- anterior capsule is partially removed

- lens material is broken apart with an ultrasonic tip

- lens material is removed with suction

- inert plastic lens is inserted into capsular remnant

prognosis

- surgery can markedly improve long vision, even returning to 20/20

- risk/benefit: 1-2% chance of worsened vision after 5 years



age-related macular degeneration (ARMD)

- etiology: accumulated UV damage in RPE cells

- rods and cones get less metabolic support and function progressively worse

- metabolic waste products accumulate beneath RPE cells

- deposits can be seen upon examination as spots in the macula

- initially do not interfere with vision

generally worse in macula

- macula is the most metabolically active area

- note: there is a familial form that affects peripheral retina

- incidence: more prevalent in elderly people (duh…)

- leading cause of irreversible severe visual loss in white Americans over 50

- exceedingly rare in African Americans

- ~750,000 people over 65 years old have severe impairment secondary to ARMD

- symptoms: absolutely no symptoms in early forms

only after loss of large clumps of rods, cones does the patient experience decreased vision

other processes (such as cataract) can confound the test results

- physical exam: clumping of pigment in the RPE beneath the retina

whitish scar (in cases where there has been leakage of blood)

frequently seen in patients who also have a mild cataract

- examination: visual acuity

- early stages: rarely drops below 20/30

- late stages: can be worse than 20/200; will only rarely leave patients completely blind to stimuli

confrontational visual field testing

- early stages: undetectable

- late stages: easily detectible due to large-scale loss

formal visual field testing

- though the test is sensitive, the results could also frequently be explained by a cataract

- knowing if cataract or AMD is causal factor is speculation unless cataract is removed

relative afferent pupillary defect test: negative

Neuroscience: OBJECTIVES (page 57 of 117)







- typically only central retina is effected

- much less than 50% loss needed to be detected with this test

- treatment: replacement or reversal of damaged cells is impossible

treatment focuses on slowing/halting progression

- thought that antioxidant group (A, C, E, zinc, and selenium) might help

- however, this has only been demonstrated to have a benefit in only the most advanced eyes



glaucoma

- etiology: elevated intraocular pressure

- aqueous humor production

- secretion at the ciliary body

- flow through the pupil into the anterior chamber between the iris and cornea

- exit from the eye at the trabecular meshwork

- elevated pressure

- fluid production is constant

- fluid clearance is poor

- mechanism is unknown

damage

- lower ganglion cells are more sensitive to increased pressure

- atrophy occurs, tissue is lost, and the difference is seen as “cupping”

- cupping: thinning of the optic rim disc

- some amount (less than 50%) is normal

- >50% cupping patients are studied with visual field tests to detect glaucoma

- incidence: second-leading cause of blindness in the US

- 5 million people in the US have the disease

- 1-3% of white people between 60-80

most common cause of blindness in African Americans

- symptoms: none

- physical exam: abnormal appearance of the optic nerve

- examination: visual acuity: not affected until the final stages

- longer (peripheral vision) fibers are more sensitive to compression

- smaller number of peripheral ganglion cells makes their loss more noticeable

confrontation visual field testing

- early stages: typically, only small “pockets” form, and are frequently not detected

- late stages: pockets become larger and coalesce, and so can cause positive result

formal visual field testing

- most sensitive test for glaucoma

- can be mapped over time, giving an indication if treatment is working

relative afferent pupillary deficit test

- only occurs late (and is therefore clinically useless for detection)

- treatment: decrease eye pressure

- make the ciliary body produce less fluid

- assist the trabecular meshwork to drain the fluid at lower pressures

medications, laser procedures exist for each method

as a last resort, surgery can be used to connect anterior chamber to subconjunctival space

- bypasses trabecular meshwork altogether









AUDITION

Neuroscience: OBJECTIVES (page 58 of 117)









Mechanisms of Sound Transmission

sound

- origin: vibration

- structure

- alternating undulation of air particles causing transient pressure increases and decreases

- condensation: pressure increase

- rarefaction: pressure decrease

- individual particles do not move significantly, but instead simply propagate energy of motion

- velocity of propagation

- air: 340 m/s

- water: 4X faster than in air

parameters of sound

- velocity (v): speed at which sound is propagated

- frequency (f): number of cycles per second in Hertz (translates to pitch)

- amplitude: strength of sound, translating to intensity or loudness (expressed in dB)

- period (T): time required for one complete cycle

- wavelength (λ): distance between two successive peaks on the wave

- mathematics

T=1/f

λ=v/f

measuring strength of sound

- sound pressure: deviation above and below atmospheric pressure due to propagated wave compression/rarefaction

- hearing uses a logarithmic scale

- range of hearing: dynamic range is 1,000,000 to 1

P1

- expression: dB  20 log 10

P2

- dB: decibel

- P1: sound pressure

- P2: reference pressure

- for hearing, taken as the sound pressure level at the normal threshold of hearing (20 μPascals)

- references average hearing threshold to 0 dB



TABLE: Sound Pressure Level of Common Environmental Sounds

dB sound

140 pain threshold

130 jet engine

120

110

100 rock concert

90

80 heavy traffic, concert hall

70

60 soft background music

50 quiet conversation

40 whisper

30

20

10

0 hearing threshold (young males)



the sensitivity of hearing

- the threshold for hearing varies as a function of the frequency of the sound

- 400-4000 Hz: range of greatest sensitivity of sound

Neuroscience: OBJECTIVES (page 59 of 117)







- 4000 Hz: peak auditory sensitivity (here, motion of ear drum is 10 -9 m, less than diameter of H ion)

- threshold values

- 0 dB: hearing

- 120 dB: risk for damage

- 140 dB: pain threshold









The Ear

- major parts of the ear

- external ear

- middle ear

- inner ear

the external ear

- structures

- auricle (pinna): big floppy thing on the outside

- external auditory meatus: ear canal

- tympanic membrane: ear drum

- function

- auricle: sound collector

- auditory canal: sound transmission, protective functions

- auditory: focuses sounds towards tympanic membrane

- protective: lined with epithelium containing hair and ceruminous wax glands

- aids in desquamation (shedding of skin)

- aids in preventing entry of foreign bodies into the ear

- tympanic membrane: sound transduction

the middle ear

- anatomy

- middle ear: tympanic cavity

- narrow, air-filled chamber lined with mucous membrane

- situated between external acoustic meatus (bounded by tympanic membrane) and the inner ear

- auditory ossicles: connection between tympanic membrane, inner ear

- malleus: hammer

- incus: anvil

- stapes: stirrup

- muscles: function in sound regulation

- tensor tympani muscle: (CN V) attaches to malleus, regulates tension on the tympanic membrane

- stapedius muscle: (CN VII) attaches to stapes, regulates range of motion

- Eustachian tube: connects middle ear with pharynx, and aids in equalizing external and internal pressures

- function of the middle ear: transmits sound from air to fluid

- complications

- inner ear is an underwater sound receiver

- sound between air and water theoretically loses 99.9% (30 dB) of its energy due to reflections

- solution: impedance matching

- diameter of tympanic membrane is 21X diameter of the oval window

- length of arm of malleus is 1.3:1 with respect to the arm of the stapes

- summation: 27.3X increase in pressure (29 dB) from tympanic membrane to oval window

- middle ear matches acoustic impedance between air and fluid, maximizing energy flow

- Eustachian tube

- structure: tube connecting middle ear and nasopharynx

- function: opens and closes periodically to keep middle ear static pressure equal to atmospheric pressure

- failure to open

- negative pressure builds up due to absorption of trapped air

Neuroscience: OBJECTIVES (page 60 of 117)







- results in increased stiffness, reduction in hearing of low frequency sounds

- attributes of a vibrating system: mechanical resonance

- elements of a vibrating system

- mass

- stiffness

- friction/damping

- resonance frequency: frequency at which amplitude of vibration is maximal

- based on a “preferred” frequency of oscillation

- example: guitar string vibrates based on mass of string and stiffness (governed by L and T)

- in the ear

- contraction of muscles, decreased middle ear air pressure

- increased stiffness

- rightward shift in amplitude relative to frequency

- suppression of sound transmission for low frequency sounds

- accumulation of puss during infection, pathological bone growth of ossicles

- increased mass

- leftward shift in amplitude relative to frequency

- suppression of sound transmission for high frequency sounds

- reflex contractions of the middle ear muscles

- contraction of muscles increases stiffness, reducing transmission up to 15 dB

- tensor tympani: (CN V) attaches to malleus

- stapedius: (CN VII) attaches to stapes, more effective at sound reduction

- function

- protection from damage due to intense sound (latency of 10 msec; cannot protect from impulsive sounds)

- improve discrimination of speech sounds (via reduction of low frequency of transmission)

inner ear

- anatomy of the inner ear

- labyrinth: designation for the inner ear due to complex shapw

- osseous (bony) labyrinth: hollow in the temporal bone

- temporal shell bone of the inner ear; one of the hardest bones in the body

- perilymph: fills bony labyrinth

- composition: closely resembles cerebrospinal fluid, other extracellular fluids

- high [Na+]

- osmolality similar to blood plasma

- labyrinth lined with periosteum

- membranous labyrinth: series of communicating, membrane-bound sacs and ducts

- composed of six mechanoreceptive structures

- semicircular canals (3): sense of equilibrium

- utricle: sense of equilibrium

- saccule: sense of equilibrium

- cochlea: contains sensory elements specialized for detection of sound waves

- endolymph: fills membranous labyrinth

- composition: closely resembles intracellular fluids

- high [K+]

- structure of the cochlea

- morphology: hose-pipe analogy, coiled into the characteristic shape

- bony portion: steel pipe closed at one end

- membranous portion: closed rubber hose, extending almost to end, glued to either side

- structures

- scala vestibuli: upper chamber, receives pressure waves from oval window

- scala media (cochlear duct): middle chamber, containing organ of Corti (sensory aspect)

- scala tympani: lower chamber, sends pressure waves to round window

- helicotrema: space at the end of the spiral connecting the upper, lower chambers

- oval window: separates stapes footplate from scala vestibuli

- round window: structure allowing for fluid displacelemt

- cochlear mechanics and the traveling wave

Neuroscience: OBJECTIVES (page 61 of 117)







- basilar membrane deforms in response to fluid pressure (traveling wave)

- propagates along the length of the basilar membrane

- amplitude reaches a maximum at some point that depends on the frequency of the tone

- the basilar membrane is tonotopically organized

- basilar membrane is a resonance structure

- each location along basilar membrane responds best to a small range of sound frequencies

- base of the cochlea: high frequencies (thin, stiff)

- apex of the cochlea: low frequencies (thick, floppy)

- primary determinant of tone response: thickness/stiffness of basilar membrane

- hair cells are the receptors of the inner ear

- hair cells: receptor cells of hearing

- found in the organ of Corti

- same morphology as vestibular hair cells

- stereocilia: bundle of sensory hairs linked near the apex by tip links

- kinocilia: single large stereocilia that provides basis of polarity

- mechano-electrical transduction by hair cells

- receptor potential: electrical signal produced in response to movement of a hair cell bundle

- excitation: deflection towards the kinocilium

- inhibition: deflection away from the kinocilium

- all hair cells are oriented in the same direction within the cochlea

- hair cells are extraordinarily sensitive to displacement

- analogy: hair cell as the Sears Tower

- movement at the threshold of hearing is equivalent to a 2” displacement of the tip of the tower

- movement

- tectorial membrane is in contact with stereocilia of hair cells

- vertical displacement of the basilar membrane causes shearing motion between tectorial membrane, hair cells

- innervation: CN VIII

- inner hair cells: cells innervated by afferent fibers of the cochlea (3500 in a human)

- mechanism

- upon excitatory displacement, increase in gK and gCa, causing depolarization and neurotransmitter release

- upon inhibitory displacement, decrease in gK and gCa, and ion channel closure

- the place principle of hearing

- Place Code: characteristic frequency of a nerve fiber is directly related to a location along the basilar membrane

- very little divergence of auditory fibers

- each auditory nerve fiber contacts only one IHC

- each IHC can be contacted by as many as 20 auditory nerve fibers

- auditory nerve fibers are most sensitive to the frequency that reflects position of the contacted hair cell

- outer hair cells

- numbers

- inner hair cells: 3500, arranged in one row

- outer hair cells: 12000, arranged in three rows

- function: not well understood

- receive efferent innervation via CN VIII

- brain stem: 5% of cell bodies

- spiral ganglion: 95% of cell bodies

- innervation causes OHCs to change shape, which affects mechanical action of the tectorial membrane

- OHCs are more susceptible to aging, toxins, and over-stimulation

- otoacoustic emissions

- otoacoustic emissions: naturally-occurring vibrations in response to sound generated by healthy cochlea

- origin: thought to arise from movement of OHCs

- can be recorded with a specialized microphone

- basis of some non-invasive tests of the integrity of the cochlea

- common in screening processes in newborns and infants

- clinical: acoustic neuroma (schwannoma)

- etiology: tumor of CN VIII

- can be associated with NF2 gene (chromosome 22)

Neuroscience: OBJECTIVES (page 62 of 117)







- symptoms: ipsilateral CN VIII deficits

- sensorineural hearing loss

- contralateral nystagmus

- ipsilateral caloric deficits

ipsilateral CN VII deficits (if tumor impinges on CN VII)

- facial muscle weakness

- loss of taste

- loss of tearing

ipsilateral cerebellar symptoms (if tumor impinges on cerebellum)









Central Auditory System

overview

- central auditory system: pathways by which auditory information is relayed from the cochlea to the cortex

- nuclear groups in:

- medulla

- pons

- midbrain

- thalamus

- cerebral cortex

- redundancy

- many auditory nuclei between the cochlea and auditory cortex

- nuclei are interconnected by large array of crossed, uncrossed, and bilateral projections

- tonotopic organization

- tonotopic organization: orderly spatial distribution of frequencies within nuclei

- high frequencies: base of the cochlea

- low frequencies: apex of the cochlea

- tonotopic organization is maintained in all major auditory nuclei

central auditory pathways

- vestibulocochlear nerve (cochlear portion)

- input: hair cell sensory afferents (cell bodies in the spiral ganglion)

- output: orderly bifurcation into dorsal, ventral cochlear nuclei

- cochlear nuclei (dorsal, ventral)

- input: cochlear portion of vestibulocochlear nerve

- output: ipsilateral superior olivary nucleus (via trapezoid body)

ipsilateral inferior colliculus (via lateral lemniscus)

- superior olivary complex (SOC)

- function: location of first convergence of sound information

location where interaural cues for sound location are first used

- input: ipsilateral cochlear nuclei

- output: contralateral inferior colliculus (via trapezoid body, contralateral lateral lemniscus)

trapezoid body: area of crossing that provides major input to both superior olivary nuclei

- inferior colliculus

- input: information traveling via ipsilateral lateral lemniscus

- output: brachium of the inferior colliculus to medial geniculate body

- medial geniculate body (MGB)

- function: auditory relay nucleus of the thalamus

- input: cells of the inferior colliculus

- output: axons: sublenticular portion of internal capsule

target: auditory portions of the cerebral cortex

- primary auditory cortex

- location: dorsal surface of superior temporal lobe, on gyri of Heschl (Brodmann areas 41, 42)

Neuroscience: OBJECTIVES (page 63 of 117)







- blood supply: middle cerebral artery

- input: cells of the medial geniculate body

types of hearing loss

- conductive hearing loss: impairment of sound wave arrival at the inner ear

- etiology: buildup of cercumen (ear wax)

infection

fluid in the middle ear

punctured eardrum

fixation of the ossicles (as in otosclerosis)

scarring

narrowing of the ear canal

tumors in the middle ear

perforation of the tympanic membrane

- treatment: removal or treatment of the block

- prognosis: usually leads to restoration

- sensorineural hearing loss (nerve deafness): impairment of hair cells or cochlear nerve

- causes presbycusis: aging process leading to gradual hearing loss in both ears

tumors (e.g. acoustic neuromas)

viral infections, Meniere’s disease, or meningitis

overexposure to repeated, loud, continuous noises

toxic medications (e.g. ibuprofen, gentamycin)

heritable conditions

- prognosis: generally non-reversible

- treatment: current genetic research is working on some therapies, but treatment is still limited

auditory tests

- types of conduction

- air conduction: sound energy sent through the air that stimulates the ear drum

- bone conduction: sound energy sent through vibrations in the skull (bypasses middle ear)

- comparison of thresholds vs. method of conduction can help determine site of hearing loss

- audiogram

- audiogram: graph showing hearing threshold as a function of frequency

- variables

- frequency (Hz)

- intensity (dB HL)

- method (air or bone conduction)

- dB HL scale

- recalibrates sound intensity such that auditory threshold is zero at each frequency

- 0 dB: normal hearing

- hearing loss: reflected in threshold value

- mild hearing loss: ~20 dB

- moderate hearing loss: ~60 dB

- severe hearing loss: ~100 dB

- clinical: gentamycin

- gentamycin: antibiotic that, as a side effect, can kill outer hair cells at the cochlear base

- audiogram: declining function with higher frequencies

- tuning fork tests

- Weber test

- technique: place tuning fork at forehead midline

- result: normal: sound radiates to both ears equally

abnormal: sound louder in one ear than in the other

- ipsilateral ear: conductive hearing loss (pathology on same side as “louder ear”)

- contralateral ear: sensorineural hearing loss (pathology on opposite side of “louder ear”)

- Rinne test

- technique: bone conduction

- vibrating tuning fork on mastoid

- patient covers opposite ear with hand

Neuroscience: OBJECTIVES (page 64 of 117)







- patient signals when sound ceases

air conduction

- vibrating tuning fork moved immediately over ear canal

- patient indicates when sound ceases

- results: normal: air conduction better than bone conduction

- patient hears tuning fork through the ear

- typically persists twice as long as bone conduction (~40 seconds after)

abnormal: bone conduction is better than air conduction

- patient doesn’t hear, or only momentarily hears, sound via air conduction

- suggests conductive hearing loss

- electroencephalography (EEG)

- technique: scalp electrodes applied to head to record waves of electrical activity

- auditory evoked brainstem response (ABR) records waves along auditory pathway

- timing or positive, negative waves can be compared to other ear or clinical normative measures

- readings

- early latency brainstem components

- I: cochlea, distal portion of CN VIII

- II: cochlea, CN VIII, cochlear nuclei

- III: superior olive

- IV: rostral pons, midbrain near inferior colliculus

- middle and late latency components

- negative: N0 Na, Nb, N1, N2

- positive: P0, Pa, P1, P2

- difficult to distinguish between brainstem, thalamus, and higher auditory centers

- note: y-scale is reversed by convention

- abnormal: due to high temporal precision of auditory system, any delayed or missing cues are significant

- acoustic neuroma: increased latency from I to III

- brainstem infarction: increased latency from III to V

- brainstem tumor: no clear components after I

- conductive deficit: increased absolute latencies of all waves









INTEGRATION



Sensory Plasticity

- introduction

- sensory systems

- static to some extent

- dynamic (plastic) to some extent

- plasticity: capacity to make functionally-appropriate adjustments in neural connection patterns

- postnatal modification of sensory systems

- reorganization and rewiring during normal development

- reorganization and rewiring subsequent to injury

plasticity during development

- plasticity in vision

- natural history

- infants at birth are legally blind by adult acuity standards

- incomplete color vision

Neuroscience: OBJECTIVES (page 65 of 117)







- incomplete 3D stereovision

- poor control of eye movement

- by 8 months, vision approaches normal adult levels

- demonstration: development of ocular dominance columns in monkey visual cortex

- layer 4: primary visual cortex layer that receives LGB innervation

- experimental results

- birth: mixed input in layer 4 of the visual cortex

- six weeks: segregation into alternating, equal-sized columns of input from each eye

- six weeks (w. R eye occluded): unequal segregation

- representation of deprived eye is significantly reduced relative to good eye

- long-term perceptual consequences

- implications

- well-used sensory pathways firmly establish neural connections with central sensory structures

- poorly-used sensory pathways become weakened, lose representation in central sensory structures

- normal sensory experience is necessary for normal development

- critical period: time during development when neural connections are forming

- time when system is most vulnerable to damaging effects of abnormal sensory input

- persistent defects can be permanent if not corrected before the end of the critical period

- critical periods

- vision: first six years, with first 2-3 as the most crucial

- audition: less well-defined, but seems to last longer

- early intervention is critical to ensure best-possible outcome

- sensory deprivation can affect other cognitive functions

- speech discrimination: begins within hours of birth, firmly established by 12 th month after birth

- loss of audition can thus permanently affect speech discrimination if not corrected

- vision, hearing assessments can be performed early in young children, infants

- fundamental concepts

- sensory systems immature at birth

- normal, post-natal development of sensory systems depends on normal sensory experience

- uncorrected sensory deprivation during critical period (esp. first 2-3 years) can lead to permanent deficits

plasticity in adulthood

- plasticity in adulthood

- previously believed that once sensory nerve pathways were firmly established, restructuring could not occur

- now apparent that sensory neural reorganization can take place in adults in certain circumstances

- reorganization after peripheral lesions

- cortical maps: subjacent regions take over and fill in denervated zone

- previously believed that peripheral nerve lesions would result in areas of absent input (silent zone)

- cortical mapping experiments have shown that to be untrue

- timing: over several months, but can occur to some extent within minutes

- areas of demonstrated reorganization

- cortex

- VPL

- dorsal column nuclei (medulla)

- dorsal horn (spinal cord)

- visual system

- reorganization after central lesions

- cortical reorganization: somatotopic location of lesioned area shifts to adjacent areas

- stroke recovery: one possible mechanism

- plasticity with learning

- natural cortical representation based on amount of fine control/discrimination required

- cortical representation increases following training of certain areas

Neuroscience: OBJECTIVES (page 66 of 117)









Thalamus

- pineal gland

- pineal gland: small midline mass that secretes the hormone melatonin

- melatonin: central control of diurnal rhythms (day/night cycling of hormones) in lower mammals

- pineal gland in humans

- part of diurnal control has been assimilated by hypothalamus

- melatonin has been implicated in certain human processes

- sleep

- tumor reduction

- aging

- other possible roles

- onset of puberty

- marker for midline of brain on x-rays (due to frequent partial calcification)

- diencephalon: divisions

- hypothalamus

- ventral thalamus: contains subthalamic nucleus

- epithalamus: primarily made up of the pineal body

- dorsal thalamus: generally referred to as thalamus

introduction to the thalamus

- functions of the thalamus

- relay: “gateway to the cortex”

- integration: integrates and regulates data transfer in complex ways

many functions cannot be considered as simply “sensory” or “motor”



- internal medullary lamina

- structure: thin sheet of white matter running longitudinally through the thalamus

separates thalamus into medial, lateral, anterior nuclear masses

- divisions: medial nuclear mass: medial nuclear group

lateral nuclear mass: lateral nuclear group

ventral nuclear group

anterior: anterior nuclear group

intralaminar: intralaminar nuclear group



- thalamic radiation

- structure: portions of the internal capsule (anterior and posterior limbs)

- function: corticothalamic projection



nuclear groups

- ascending pathways headed to the thalamus

- brachium of the inferior colliculus

- origin: ipsilateral inferior colliculus

- target: medial geniculate body (MGB)

- function: sensory: hearing

- medial lemniscus

- origin: contralateral nucleus gracilis, nucleus cuneatus

- target: ventral posterolateral nucleus (VPL)

- function: sensory: 2 pt. discrimination, vibration, and conscious proprioception

- anterolateral system

- origin: contralateral dorsal horn

- target: ventral posterolateral nucleus (VPL)

- function: sensory: pain, temperature from the body

- trigeminothalamic tract

- origin: contralateral spinal nucleus V

- target: ventral posteromedial nucleus (VPM)

Neuroscience: OBJECTIVES (page 67 of 117)







- function: sensory: pain, temperature from the face

- solitariothalamic tract

- origin: ipsilateral nucleus solitarius

- target: ventral posteromedial nucleus (VPM)

- function: sensory: taste

- cerebellothalamic fibers

- origin: contralateral deep cerebellar nuclei (esp. dentate nucleus)

- target: VA/VL

- function: motor: coordination



ventral nuclear group

- lateral geniculate body (LGB)

- location: caudal thalamus, lateral to the MGB

- input: bilateral retinal ganglion cells (contralateral visual field)

- output: retrolenticular limb of the internal capsule to primary visual cortex (area 17)

- function: visual relay nucleus

- medial geniculate body (MGB)

- location: caudal thalamus, ventral to the pulvinar

- input: ipsilateral inferior colliculus fibers via brachium of the inferior colliculus

- output: sublenticular portion of the internal capsule to primary auditory cortex (areas 41, 42)

- function: auditory relay nucleus

- ventral posterolateral nucleus (VPL)

- location: thalamus, lateral to internal capsule, caudal to VA/VL

- input: dorsal column system (via medial lemniscus)

anterolateral system (lateral spinothalamic tract, or LSTT)

- output: project to primary sensory cortex (areas 3, 1, 2)

- function: sensory (body) relay nucleus

- ventral posteromedial nucleus (VPM)

- location: thalamus, within VPL

- input: trigeminothalamic tract (TTT), solitariothalamic tract (STT)

- output: project to primary sensory cortex (areas 3, 1, 2)

- function: sensory (head) relay nucleus, taste relay nucleus

- VA/VL

- location: thalamus, most anterior aspect of ventral nuclear group

- input: basal ganglia: globus pallidus, via ansa lenticularis and lenticular fasciculus

cerebellum: deep nuclei, via superior cerebellar peduncle

substantia nigra

- output: motor-related cortex

- function: motor relay nucleus

medial group

- medial dorsal nucleus (MD)

- location: long, cigar-shaped nucleus on medial aspect of thalamus

- input: pain afferents from the LSTT (anterolateral system) and TTT

olfactory inputs from primary cortex

- in general, thalamus gets input prior to cortex

- here, thalamus receives initial input, possibly due to evolutionary origin

- output: pain: prefrontal cortex

olfactory: insular and orbitofrontal cortex

- function: pain response, olfactory integration functions

anterior nuclear group

- anterior nuclear group

- location: most anterior aspect of thalamus

- input: mammilothalamic tract (MTT), limbic system

- output: cingulate gyrus (“motor cortex of the limbic system”)

- function: visceral, emotional relay system

intralaminar group

Neuroscience: OBJECTIVES (page 68 of 117)







- centro-median nucleus (CM)

- location: dorsal to red nucleus, medial to VPM

- function: not known with certainty

- major connections to the motor system basal ganglia

- role in pain perception

- control of sleep-waking cycle

lateral group

- pulvinar nucleus

- location: just lateral to the posterior internal medullary lamina

- inputs: diverse areas of the major sensory systems

- outputs: association areas of cortex in parietal, occipital, and temporal lobes

- secondary visual areas (18, 19)

- function: directs attention to a particular stimulus

- lateral dorsal nucleus: not well characterized

- lateral posterior nucleus: not well characterized



symptoms of thalamic lesions

- diagnosing lesions of the thalamus

- thalamic nuclei are small: lesions producing highly specific effects are uncommon, but do occur

- thalamus occupies a central area immediately bounded by the internal capsule

- close proximity to deep motor nuclei of the cerebral hemisphere

- striatum (caudate, putamen)

- globus pallidus

- implication

- thalamic lesions frequently accompanied by damage to these structures

- frequently results from hemorrhage of the striate arteries

- symptoms of thalamic lesions

- contralateral hemianesthesia

- lesion: damage to VPL, VPM

- diagnosis: affects all somatic sensory modalities

- modalities

- light touch

- conscious proprioception

- 2 point discrimination and vibration

- pain and temperature

- lesions of the internal capsule or cortex generally are more selective, leaving pain unchanged

- hyperalgesia, causalgia

- lesion: damage to VPL, VPM with recovery (days to months)

- hyperalgesia: exaggerated unpleasant or painful sensation resulting from mild cutaneous stimulation

- causalgia: spontaneous pain with no apparent stimulation

- symptoms do not occur with lesions of cerebral hemispheres (internal capsule, cortex, or deep nuclei)

- causalgia: red flag for thalamic syndrome

- contralateral homonymous hemianopsia

- lesion: damage to the LGB

- eliminates contralateral visual field

- movement disorders

- lesion: damage to the VA/VL

- ataxia, intention tremor: reminiscent of cerebellar damage

- choreoathetoid movements: reminiscent of basal ganglia damage

- problems occur contralateral to side of lesion



summary: thalamic nuclei

- overview

- anterior group: anterior nucleus

- medial group: mediodorsal nucleus (MD)

- lateral group: pulvinar

Neuroscience: OBJECTIVES (page 69 of 117)







lateral dorsal (LD)

lateral posterior (LP)

- ventral group: ventral anterior / ventral lateral (VA/VL)

ventral posterior (VPL, VPM)

medial geniculate body (MGB)

lateral geniculate body (LGB)

- intralaminar group: centromedian (CM)



TABLE: Summary of Thalamic Nuclei

group/function nucleus input cortical connections

anterior --- limbic system (including cingulate gyrus

(limbic) mamillary bodies)

medial mediodorsal (MD) olfactory cortex pain: prefrontal cortex

(pain, olfaction) spinothalamic afferents olfaction: insular, orbitofrontal cortex

lateral lateral dorsal (LD) limbic system cinguate gyrus

(attention) lateral posterior (LP) numerous association cortex

pulvinar numerous association cortex

ventral VA / VL cerebellum motor, pre-motor, supplementary

(specific receiving globus pallidus motor cortex (4, 6)

nuclei) substantia nigra

VP: VPL medial lemniscus somatic sensory cortex (3, 1, 2)

ALS motor cortex (4)

taste: to insular cortex

VP: VPM TTT

STT

MGB inferior colliculus auditory cortex (41, 42)

LGB retinal ganglion cells primary visual cortex (17)

intralaminar sheet-like spinothalamic diffuse

(pain, sleep cycle) reticular formation

centromedian (CM) globus pallidus motor cortex

substantia nigra striatum (to some extent)









Cortex

cortical anatomy

- blood supply

- cortical arteries (branches of the Circle of Willis)

- anterior cerebral

- middle cerebral

- posterior cerebral

- anastomoses between branches of cerebral, dural arteries are insufficient to prevent damage after blockage

- blockage of a cortical artery produces a rapid, irreversible destruction of a large region of cortex

- extent of damage depends on individual extent of anastomoses

- blood supply: by cortical region

- visual cortex (17, 18, 19): posterior cerebral

- somatosensory (3, 1, 2) and motor cortex (4, 6): anterior cerebral (foot and leg)

middle cerebral (rest of body)

- auditory cortex (41, 42): middle cerebral

- Wernicke’s (22) and Broca’s (45) areas: middle cerebral (cortical representations)

anterior cerebral (underlying white matter)

- medial temporal lobe (including hippocampus): posterior cerebral

Neuroscience: OBJECTIVES (page 70 of 117)







- blood supply: by artery

- anterior cerebral: somatosensory, motor cortex (foot, leg of areas 3, 1, 2, and 4, 6)

auditory areas (underlying white matter)

- middle cerebral: somatosensory, motor cortex (trunk, head of areas 3, 1, 2, and 4, 6)

primary auditory cortex (41, 42)

auditory areas (cortical areas 22, 45)

- posterior cerebral: medial temporal lobe and limbic structures

visual cortex (17, 18, 19)

- watershed zone: areas of brain most susceptible to infarct

- cortical locations

- landmarks

- central sulcus: boundary between frontal and parietal lobes

- Sylvian/lateral fissure: boundary between temporal, frontal lobes

- areas

- somatosensory cortex: areas 3, 1, 2 in front of central sulcus

- motor cortex: areas 4, 6 behind central sulcus

- parietal association area (PPC): area 5, 7 behind somatosensory cortex

- frontal eye fields: area 8 frontal lobe, in front of area 6

- visual cortex: areas 17, 18, 19 back of brain, on ventral aspect

- Wernicke’s area: area 21, 22 below auditory cortex, behind Sylvian fissure

- auditory cortex: areas 41, 42 behind Sylvian fissure

- Broca’s area: area 44, 45 frontal lobe, in front of Sylvian fissure

- venous drainage

- anastomoses are extensive, so blockage typically will not lead to infarction

- rupture of large veins can be clinically significant

anatomy of the internal capsule

- internal capsule

- contains all fibers entering, leaving cerebral cortex from thalamus, brainstem, and spinal cord

- only fibers to the striatum bypass the internal capsule

- descending fibers

- fiber types

- corticospinal

- corticobulbar

- corticopontine

- corticothalamic

- corona radiata: area of cerebral hemisphere where descending fibers collect prior to entering internal capsule

- descent

- corticothalamic: from internal capsule directly into thalamus

- corticospinal, corticobulbar, corticopontine: from internal capsule into cerebral peduncle

- ascending fibers

- fiber types

- thalamocortical (vast majority of ascending fibers)

- monoamine neurotransmitter brainstem fibers (project into cortex without relaying in thalamus)

- ascent: from internal capsule through corona radiata to cortical areas

- capsular radiations

- main body: to frontal and parietal lobes

- sublenticular limb: to temporal lobe (contains auditory radiations)

- retrolenticular limb: to occipital lobe (contains visual radiations)

- structure: V-shaped

- anterior limb: between thalamus, lenticular nucleus

- posterior limb: between caudate, lenticular nucleus

- somatotopic organization: longest fibers are most posterior

- corticopontine: anterior limb

- corticobulbar: genu (bend)

- corticospinal: posterior limb

- upper extremities: anterior aspect

Neuroscience: OBJECTIVES (page 71 of 117)







- trunk: intermediate aspect

- lower extremities: posterior aspect

- blood supply to the internal capsule

- general

- medial striate: branches of the anterior cerebral artery

- lateral striate: branches of the middle cerebral artery

- anterior choroidal: branch of the internal carotid

- unnamed: minor branches of the internal carotid

- by target

- anterior limb: medial striate arteries

- genu: dorsal aspect: lateral striate arteries

ventral aspect: anterior choroidal artery, unnamed branches

- posterior limb: branches of the anterior choroidal artery

- retrolenticular limb: posterior cerebral

- by artery

- medial striate: anterior limb

- lateral striate: genu, dorsal aspect

- anterior choroidal: genu, ventral aspect

posterior limb

- posterior cerebral: retrolenticular limb

- lesions

- consequences

- combined sensory and motor deficits

- pure motor deficit (contralateral hemiparesis)

- may have different effects based on somatotopic organization

- small lesions in internal capsule can have relatively large effects

- fairly common

- blockage of the internal carotid

- blockage of the middle cerebral

- hemorrhage of the striate arteries

- striate arteries: arteries of stroke

- particularly susceptible to hemorrhage, primarily in people with hypertension

- tends to affect larger area of internal capsule and adjacent structures than what is supplied by the arteries

fiber systems

- fiber systems of the cerebral cortex

- ascending fibers: cortical afferents

- descending fibers: cortical efferents

- association fibers: connect different cortical areas on the same side of the brain

- commissural fibers: connect the two halves of the cortex

- primarily run in corpus callosum

- to a lesser extent, run in the anterior commissure



- association fibers

- superior longitudinal fasciculus: connects cortex of all four lobes (largest association bundle)

- inferior longitudinal fasciculus: connects temporal, occipital lobes

- uncinate fasciculus: connects frontal lobe to rostral temporal lobe (runs deep to Sylvian fissure)

- arcuate fasciculus: connects Wernicke’s, Broca’s areas (connects speech with intended)

- cingulum: runs in cingulate and parahippocampal gyri (part of lymbic system)

- short bundles: connect adjacent gyri

- corpus callosum: fiber bundle that connects hemispheres of the brain

- in people with seizure disorders, this may be severed to reduce potency of seizures

- incredibly, this produces only minor deficits that generally require detailed tests to elucidate

- left hemisphere: generally directs speech

- right hemisphere: generally directs perception, manipulation of spatial relationships

association areas of neocortex

- association cortex: areas without predominantly sensory or motor functions

Neuroscience: OBJECTIVES (page 72 of 117)







- found in all four major lobes

- assemble information from various sources to aid in carrying out complex tasks

- association axons: inputs from thalamic nuclei, other cortical areas to association cortex

- overlap

- overlap in function of sensory, motor areas

- overlap in association, sensory/motor areas



pathology

- complexity of symptoms

- lesions: generally affect complex relationships

- recognition of complex spatial patterns (e.g. faces)

- language functions

- perception of spatial relationships

- integration of complex movements

- decision making

- control of social interactions

- result: dysfunctions in higher order processes such as thought, speech, emotion, or memory

- pure sensory or motor deficits are rarely seen

- primary sensory and motor areas are only a small fraction of the cortex

- surrounded immediately by association areas that frequently see damage

- categories of deficit

- aphasia: disruption of speech functions

- agnosia: loss of object recognition, spatial relationship perception in absence of major sensory impairment

- apraxia: loss of ability to perform complex motor tasks in absence of paralysis

- variability of symptoms

- damage of identical topographical areas may cause vastly different symptoms

- differences in cortical representation

- differences in extent of plasticity of adjacent areas

- few patients have small, well-localized lesions in the cerebral cortex

- asymmetry of symptoms

- speech, language: left hemisphere in vast majority of people

- right hemisphere: 4% of right-handed people

- left hemisphere: 17% of left-handed people

- bilateral: rare cases

- language centers

- Broca’s area: area 45; associated with nonfluent aphasia

- Wernicke’s area: area 22; associated with fluent aphasia

- aphasia: disturbance of speech

- personality

- prefrontal cortex: large, poorly defined area anterior to motor areas in the frontal lobe

- includes cortex on the medial and ventral aspects of the lobe as well

- associated with emotion and personality

- lesions: associated with dramatic alteration in emotional expression and personality

- loss of social awareness, judgment, initiative, concentration

- can so profoundly alter someone that the person becomes difficult to live with



disorders of cortical function

- cortical lesions

- major categories of deficit

- aphasia: disruption of speech functions

- agnosia: loss of object recognition, spatial relationship perception in absence of major sensory impairment

- apraxia: loss of ability to perform complex motor tasks in absence of paralysis

- study of cortical functions

- primarily based on study of individuals with lesions (stroke, tumor, trauma)

- seldom discreet: effects tend to be diffuse, making difficult the study of localization of abilities

aphasia

Neuroscience: OBJECTIVES (page 73 of 117)







- non-fluent aphasia (Broca’s aphasia)

- symptoms: awkward articulation

restriction of vocabulary, grammar to the most simple, well learned forms

relative preservation of auditory comprehension

mild reading impairment

severely impaired written language

hemiplegia frequently present

- etiology: lesion of Broca’s area (45)

- third frontal convolution of the left hemisphere

- subcortical white matter

- extends posteriorly to inferior portion of motor strip (prerolandic gyrus)

asymmetry: involves hemisphere responsible for language

- left hemisphere: language-dominant in vast majority of all individuals

- right hemisphere: language-dominant in only 1-2% of neurologically-normal population

memory device: “Broca’s (area 45) is B4 Wernicke’s”

- fluent aphasia (Wernicke’s aphasia)

- symptoms: impaired auditory comprehension

fluent, easily articulated but paraphasic speech (paraphasia)

- paraphasia: production of unintended syllables, words, or phrases during effort to speak

- literal paraphasia: words with similar sounds, or speech out of order

- semantic paraphasia: words with similar meanings

disorders of reading and writing

- dyslexia: disorder of reading

- dysgraphia: disorder of writing

little awareness of deficit

memory device: “Wernicke’s is worse”

- etiology: lesion of Wernicke’s area (22)



TABLE: Characteristics of Fluent and Non-Fluent Aphasia

non-fluent (Broca’s) fluent (Wernicke’s)

speech awkward easily articulated

fluency non-fluent fluent, paraphasic

grammar restricted normal

auditory comprehension preserved impaired

reading impairment mild minimal

writing impairment severe severe

awareness of deficit present limited

hemiplegia usually rare





agnosia

- visual agnosia

- visual form agnosia

- deficit: inability to recognize objects or body parts, but can be recognized when touched

- lesion: bilateral damage to visual association cortex (areas 18, 19)

- prosopagnosia

- deficit: limited or absent ability to recognize familiar faces, though facial discrimination is okay

- lesion: bilateral occipitotemporal gyrus

- auditory agnosia: pure word deafness / auditory agnosia for speech

- deficit: inability to comprehend spoken language, but can read, write, speak normally

comprehension of non-oral sound is intact

- lesion: bilateral symmetric cortical-subcortical lesions of anterior portion of superior temporal gyri

(spares Heschl’s gyrus)

- somatosensory agnosia: asteroagnosia / tactile form agnosia

- deficit: inability to recognize object by sight alone, but can identify with sight

Neuroscience: OBJECTIVES (page 74 of 117)







- lesion: temporal-parietal junction (implicated)



apraxia

- characterization

- apraxia: disorder in which there is a loss of ability to perform an earlier learned skilled movement

- frequently associated with aphasia

- divisions

- ideational apraxia

- deficit: conception

- incorrect object used to perform correct action

- does not improve based on presence or absence of object (pantomime)

- lesion: left temporal-parietal junction

- ideomotor apraxia

- deficit: execution

- problems with sequencing or performance of an action

- improves if object is present

- lesion: circuit including inferior left parietal lobe, supplementary motor cortex



- dysarthria: poor articulation, frequently resulting from neurological injury

- frequently affects control over other motor areas

- can be an early symptom of stroke, or characteristic of certain diseases (ALS, Parkinson’s)









Hypothalamus

anatomy

- location

- general: ventral-most part of the diencephalon, on either side of the third ventricle

- borders: dorsal: hypothalamic sulcus

ventral: exposed on the base of the brain

rostral: optic chiasm (rostral limit)

caudal: mammillary bodies (caudal limit)

- regions

- supraoptic: anterior, at the level of the optic chiasm

- tuberal: middle, at the level of the tuber cinereum (or median eminence)

- mammillary: posterior, at the level of the mammillary bodies



hypothalamic nuclei

supraoptic region

- supraoptic nucleus

- location: above lateral aspect of the optic chiasm

- function: secretion of vasopressin (ADH, antidiuretic hormone)

secretion of oxytocin

- clinical: diabetes insipidus

- symptoms: rapid water loss from the kidney

- etiology: insufficient response or supply of ADH

- pathology: can be caused by lesions to the anterior hypothalamus

- paraventricular nucleus (PVN)

- location: medial aspect of the hypothalamus, bordering third ventricle

- function: secretion of vasopressin (ADH, antidiuretic hormone)

secretion of oxytocin

secretion of corticotropin-releasing hormone (CRH)

- clinical: diabetes insipidus

- suprachiasmatic nucleus

Neuroscience: OBJECTIVES (page 75 of 117)







- location: medial aspect of the hypothalamus, just above the optic chiasm

- function: involvement in daily rhythms

- hypothalamus contains biological clock that temporally regulates body functions

- projection from retina to suprachiasmatic nucleus supplies day-night information

- helps synchronize diurnal (daily, or circadian) rhythms

- anterior hypothalamic area

- location: supraoptic region

- function: thermoregulation (heat dissipation)

tuberal region

- lateral hypothalamic area (LHA)

- location: lateral to fornix in tuberal hypothalamus

- function: feeding center

- bilateral lesions result in anorexia (loss of appetite)

- can be severe enough to cause the organism to die of starvation

- ventromedial nucleus

- location: ventromedial to fornix in tuberal hypothalamus (most prominent nucleus)

- function: satiety center

- bilateral lesions result in hyperphagia and extreme obesity

- also result in aggressive behavior (hypothalamic rage) and chronically irritable mood

- clinical: set point theory of weight control

- body weight is thought to be controlled, to some extent, by the LHA and ventromedial nuclei

- below set point, LHA is activated

- above set point, ventromedial is activated

- supported by recent experimental evidence involving metabolite response relationships

- arcuate nucleus (infundibular, periventricular nucleus)

- location: loops below third ventricle posterior to optic chiasm

- function: regulatory control of adenohypophysis

- contain hormone releasing factors or release-inhibiting factors

- secreted from median eminence and infundibulum into portal system

- major hormones regulated:

- growth hormone

- ACTH

- thyrotropin

- gonadotropins (LH, FSH)

- prolactin

mammillary region

- posterior hypothalamic nucleus

- location: mammillary region

- function: thermoregulation

- heat generation via:

- shivering

- vasoconstriction

- blockage of perspiration

- mammillary nuclei

- location: posterior hypothalamus

- function: memory consolidation (long term memory formation)



hypothalamic fiber tracts

- fornix

- course: bidirectional

- hippocampal formation

- mammillary nuclei

- function: memory

- mammillothalamic tract (MTT)

- course: bidirectional

- mammillary nuclei

Neuroscience: OBJECTIVES (page 76 of 117)







- anterior nucleus of the thalamus

- function: limbic system relay

- stria terminalis

- course: unidirectional

- origin: amygdala

- target: hypothalamus

- function: parasympathetic autonomic functions

- medial forebrain bundle

- location: courses through lateral hypothalamic area

- course: numerous ascending, descending components

- ascending monoamine cell group fibers

- descending olfactory cortex fibers that may play a role in appetite control

- descending fibers from other basal forebrain structures

- function: physiological: functions such as sleep

behavioral: traits such as depression and pleasure



functions of the hypothalamus

- endocrine: release of 8 major hormones

- thermal: temperature regulation

- anterior lesions: cause hyperthermia

- posterior lesions: cause hypothermia

- autonomic: high level input to sympathetic

high level input to parasympathetic (dorsal motor nucleus X)

- behavioral: food and water intake

sexual behavior and reproduction

control of daily cycles in physiological state and behavior

mediation of emotional responses

- bilateral ventromedial lesions: expressions of rage

- stimulation of other hypothalamic nuclei can cause numerous other emotions



- hypothalamus as an integrative organ

- functions under autonomic, hormonal control are largely influenced by emotions

- hypothalamus is involved with both emotion and hormonal release, and is thus thought to be a mediator



summary

- major hypothalamic nuclear groups

- medial region

- supraoptic

- tuberal

- mammillary

- lateral hypothalamic area

TABLE: Summary of Major Hypothalamic Nuclear Groups and Nuclei

region division nucleus function

medial region supraoptic paraventricular ADH, oxytocin, CRH

supraoptic ADH, oxytocin

suprachiasmatic daily rhythms

tuberal ventromedial satiety center

arcuate releasing factors

mammillary mammillary memory

posterior heat production

lateral region --- --- hunger center

Neuroscience: OBJECTIVES (page 77 of 117)









Olfactory Pathways

structures

- olfactory receptors

- location: roof of the nasal cavity, embedded in specialized patch of mucous membrane

- structure: bipolar neurons with modified, non-motile cilia

- course: pass through perforations in the cribiform plate and enter olfactory bulb

- clinical: anosmia: loss of sense of smell

- nerve bundles can be severed by skull fractures or other pathology in the region

- because of the association between taste and smell, this can cause severe deficits in taste

- olfactory bulb

- location: ventral aspect of the frontal lobes

- structure: mitral cells

- receive synaptic input from olfactory receptors

- project directly to olfactory cortex

- almost all other sensation first passes through thalamus before reaching cortex

- olfactory information goes directly to cortex before reaching thalamus

- reason: evolutionarily, olfaction developed prior to the thalamus

- olfactory tract

- location: connection between olfactory bulbs and olfactory cortex

- structure: axons of mitral cells

- anterior commissure

- location: between hemispheres, anterior to optic chiasm

- function: connects two halves of the olfactory system

cortical areas

- olfactory cortex

- medial aspect of the temporal lobe

- location: overlies rostral portion of the parahippocampal gyrus, including uncus

- function: primary part of olfactory cortex

- clinical: uncus (uncinate gyrus): medial bulge of the temporal lobe

- uncinate fits: seizures frequently originate from uncus

- uncal herniation: displacement of the uncinate gyrus

- caused by tumors, hemorrhage, edema, or trauma

- can cause contralateral pressure on the brainstem, resulting in nerve damage

- base of the frontal lobe

- location: overlies anterior perforated substance

- function: additional portion of olfactory cortex

- clinical: location where striate arteries enter the interior of the brain

- insular cortex

- location: buried in Sylvian fissure

- function: flavor

- receives taste input from medial part of VPM

- believed to be the location where olfactory and taste information is integrated

- orbitofrontal cortex

- location: base of the frontal lobe

- function: unknown role in olfactory perceptoin

clinical: testing for olfactory impairment

- unilateral testing for anosmia

- nasal cavities, olfactory pathways up to the level of the anterior commissure are completely separate

- each nostril must be tested separately to detect a unilateral anosmia

- pungent odors

- free endings of trigeminal nerve located within nasal cavity that respond to irritating or pungent odors

- odors of this type cannot be used when testing for anosmia

Neuroscience: OBJECTIVES (page 78 of 117)









Limbic System

anatomy

- components

- limbic lobe: ring of cortex on the medial aspect of the cerebral hemisphere

- cingulate gyrus

- parahippocampal gyrus

- septal cortex

- hippocampal formation, fornix

- amygdala

- septal area

- mammillary bodies (in some accounts, the entire hypothalamus is included)

- anterior nuclei of the thalamus

- interconnecting tracts

- fornix

- mammillothalamic tract (MTT)

- stria terminalis

- cingulum: connects areas of the limbic lobe

- Papez circuit

- alternate name for structures of the limbic system

- named for the anatomist that first pointed out their circular nature

- hippocampus to hypothalamus, mammillary bodies

- mammillary bodies to thalamus

- thalamus to cingulate gyrus (which connects to neocortex)

- cingulate gyrus to entorhinal cortex

- entorhinal cortex to hippocampus



components of the limbic system

hippocampal formation

- location: beneath external surface of cerebral hemisphere

- phylogenetically old part of the cerebral cortex

- location is a consequence of the overgrowth of the surface of the neocortex

- associations: fornix: fiber bundle connecting hippocampus to mammillary bodies, septal nuclei

- fibers converge on fornix proper and follow a C-shaped course with lateral ventricle

- enter hypothalamus anteriorly, terminate in target tissues

- function: memory consolidation: process of converting recent memory into long term storage

categories of amnesia

- anterograde amnesia: loss of memory of events occurring after the lesion

- retrograde amnesia: loss of memory of events occurring before the lesion

bilateral lesions to the hippocampus damage consolidation, resulting in 1-2 minute memory

- blood supply: branches of the posterior cerebral artery

- pyramidal cells have unique features that make it highly susceptible to damage from anoxia

- one of the first sites in the brain to be irreversibly damaged

- clinical: lesions of the fornix or mammillary bodies: associated with recent memory deficit

Korsakoff’s syndrome

- etiology: thiamine deficiency associated with alcoholism

- pathology: grossly-visible destruction of mammillary bodies

- in these patients, damage has been found to extend to the medial thalamus

- unknown if memory deficit requires thalamic involvement

amygdala

- location: immediately rostral to the hippocampus, within the temporal lobe

- anatomically grouped with the basal ganglia

Neuroscience: OBJECTIVES (page 79 of 117)







- functionally grouped with the limbic system

- structure: almond-shaped large nuclear complex

- associations: stria terminales: fiber bundle connecting amygdala to hypothalamus

- leaves amygdala caudally

- course approximately parallels that of fornix

other projections: to thalamus, neocortex

- function: control of emotions, especially fear and anger

control of sexual behavior

control of food and water intake

septal area

- location: anterior to the hypothalamus

- structure: septal nucleus

septum pellucidum: thin membrane between the two lateral ventricles

small portion of neocortex that forms part of limbic lobe

- associations: hypothalamus, hippocampus

- function: implicated in control of emotions and memory function, though this is uncertain

cingulate gyrus

- location: portion of limbic lobe overlying corpus callosum

- associations: anterior nuclear group of the thalamus (via thalamic radiations)

parahippocampal gyrus, septal area (via cingulum)

- function: implicated in generation of emotional, visceral responses, though this is uncertain



limbic structures as a system

- complexity of visceral (eating, drinking, SEEEEX!) and emotional behavioral patterns

- food intake requires:

- integration of information from blood levels of metabolites, distention of GI tract, etc.

- initiation of appropriate motor patterns to find food

- analysis of sensory information to identify food

- consumption of food

- control of digestion via autonomic nervous system

- fear response requires:

- analysis of sensory information to determine when emotional response is appropriate

- activation of somatic musculature to produce appropriate movements

- coordination of autonomic effects

- difficulty in studying limbic system

- complexity of behavioral responses requires connections with sensory, motor, and autonomic systems

- stimulation of specific components of the system can therefore give misleading results

- stimulation frequently causes changes in autonomic control and movement

- this only indicates that limbic system has interconnections, not that it is a primary integrator of movement

- design of the limbic system

- a single brain system is involved in both emotional-visceral and memory functions

- reason: emotions and visceral sensations strongly affect learning

- ability to learn evolved to allow profiting from experiences in reproduction, food, and pain avoidance

- thus it makes sense that one system orchestrates emotions, visceral functions, and has roles in memory



- Kluver-Bucy syndrome

- etiology: bilateral damage to the rostro-ventral portion of the temporal lobes

- hippocampal formation

- amygdala

- inferotemporal neocortex

- symptoms: behavioral deficits

- docility

- hypersexuality

- hyperphagia

visual agnosia

recent memory deficits

Neuroscience: OBJECTIVES (page 80 of 117)







- clinical: complete syndrome is rarely observed, but elements are frequently encountered









HIGHER FUNCTION



Sleep

- overview

- distribution: universal to every animal species studied

- significance: encompasses 1/3 of human life

- function: unknown, but necessary for survival

prolonged deprivation leads to severe physical, cognitive impairment and death

- clinical: found in many psychiatric illnesses

frequently part of diagnostic criteria for specific disorders

definition of sleep

- sleep: state of decreased awareness of environmental stimuli

- distinguished from coma, hibernation by rapid reversibility

- individuals tend to move little, adopt stereotypical postures

- types of sleep

- REM: rapid eye movement sleep

- name derived from characteristic eye movements during sleep

- paradoxical sleep: electroencephalogram shows brain activity remarkably similar to waking

- NREM: non-rapid eye movement sleep

- orthodox sleep: decreased activation of EEG

- quiet sleep: in infants, relative lack of motor activity

stages of sleep

- scoring

- electroencephalogram EEG brainwave activity

- electrooculogram EOG eye movement

- electromyogram EMG motor movement



- awake

- eyes open: beta waves (18-25 cps)

- EEG: low voltage, fast activity, activated pattern

- EOG: obvious voluntary eye movements, blinks

- EMG: high tonic activity, phasic activity related to voluntary movements

- eyes closed: alpha waves (8-13 cps)

- NREM sleep

- stage 1: theta activity (3-7 cps)

- EEG: loss of alpha activity, occasional vertex waves

- EOG: eye movements become slow and rolling

- EMG: skeletal muscle tone relaxes

- perception: awake, decreased awareness of sensory stimuli, dreamlike mental activity

- hypnic jerks: benign sudden muscle contractions; exacerbated by deprivation

- stage 2: sleep spindles (12-14 cps)

- EEG: K complexes (high amplitude negative sharp waves  positive slow waves)

- EOG: eye movements cease

- EMG: muscle activity further decreases

- perception: asleep

- SWS: delta waves (≤ 2 cps)

Neuroscience: OBJECTIVES (page 81 of 117)







- slow wave sleep: delta sleep, deep sleep; composed of NREM stage 3 and stage 4

- stage 3: 20-50% of epoch time occupied by slow waves

- stage 4: >50% of epoch time occupied by slow waves

- EOG: eye movements are not present

- EMG: muscle activity further decreases

- REM sleep

- EEG: theta activity (3-7 cps) with sawtooth waves

- tonic (persistent) components

- EEG: reminiscent of stage 1, with increased activity in theta band

- EMG: generalized atonia of skeletal muscles (except extraocular muscles, diaphragm)

- phasic (episodic) components

- EOG: irregular bursts of rapid eye movements

- EMG: muscle twitches



- summary: EEG

- awake, eyes open: beta waves (18-25 cps)

- awake, eyes closed: alpha waves (8-13 cps)

- stage 1: theta activity (3-7 cps) vertex waves, hypnic jerks

- stage 2: theta activity (3-7 cps) sleep spindles (12-14 cps), K complexes

- SWS: delta waves (≤ 2 cps)

- REM: theta activity (3-7 cps) sawtooth waves



organization of sleep

- amount: generally 7-9 hours per night, though some need less than 5 or greater than 12

- proportion: fairly consistent in normal adults

- stage 1: 5%

- stage 2: 50%

- SWS: 20-25%

- REM: 20-25%

- order: occurs in cycles of NREM-REM sleep, each lasting 90-110 minutes

- SWS: prominent early, diminishes as the night progresses

- REM: prominent late, with more intense phasic activity and dreaming later in the night



circuitry and neurotransmitters underlying wakefulness, NREM and REM sleep

wakefulness

- ascending reticular activating system (ARAS): system maintaining an activated EEG/cortex

- composed of ascending projections from the medulla, pons, and midbrain

- pass directly to cortex to activate EEG/cortex

- transmitters and cells of origin

- cholinergic: origin: lateral dorsal tegmental (LDT)

pedunculopontine tegmental (PPT)

nucleus reticularis pontis (NRP; oralis and caudalis)

clinical: Alzheimer’s patients lose cholinergic cells in nucleus basilis of Meynert

anticholinergic drugs (tricyclic antidepressants, atropine) can cause sedation

nicotine: cholinergic agonist that enhances arousal

neostigmine: anticholinesterase inhibitor that enhances arousal



- serotonergic: origin: midbrain-pons junction

dorsal raphe (DR)

medulla (MRFs)

clinical: selective serotonin reuptake inhibitors (SSRIs) decrease sleep, increase arousal



- norepinergic: origin: locus coeruleus (LC)

medulla (MRFn)



- dopaminergic: origin: substantia nigra pars compacta

Neuroscience: OBJECTIVES (page 82 of 117)







ventral tegmental area

target: striatum (caudate, putamen)

frontal cortex (via mesocorticolimbic projections of VTA)

caudal hypothalamus

clinical: drugs such as amphetamine and cocaine work to enhance DA response



- histamine: origin: tuberomammillary nucleus (TM) in the posterior hypothalamus

target: thalamus and cortex posterior hypothalamus



- glutamate: origin: widespread throughout brainstem, thalamus, cortex

target: widespread throughout brainstem, thalamus, cortex



- hypocretin: origin: cells in the hypothalamus

(orexin) target: excitatory to locus coeruleus (LC)

clinical: functional loss in narcolepsy



- other neurotransmitters, neuromodulators

- substance P

- neurotensin

- epinephrine

- hypothalamic peptides

- corticotropin-releasing factor (CRH)

- vasoactive intestinal peptide

- thyrotropin-releasing factor

- cortisol



non-REM sleep

- ventrolateral preoptic area (VLPO): inhibitory site that initiates NREM sleep

- location: rostral to the optic chiasm within the hypothalamus

- sleep-active: selectively increase discharge at sleep onset



- transmitters and factors in the VLPO

- GABA: origin: VLPO cells

target: serotonergic, noradrenergic, cholinergic cell groups in brain stem reticular formation

histonergic cell groups in the TM (caudal hypothalamus)

role: inhibition of ARAS wake-promoting cells

- ARAS cells feed back, inhibit VLPO region

- enables cells to decisively switch back and forth between sleep, waking

GABA: released in highest concentrations during NREM sleep



- adenosine: role: sleep factor that directly or indirectly regulates activity of VLPO neurons

clinical: blocked by caffeine



- hypocretin: role: excitatory input to all components of the ARAS

clinical: animal models of narcolepsy related to defects in hypocretin system



- other neurotransmitters, neuromodulators

- GABA-ergic neurons from other brain areas

- rostral hypothalamus

- pre-optic area

- nucleus basilis

- barbituates



REM sleep

- pons: contains areas primarily responsible for REM sleep generation

Neuroscience: OBJECTIVES (page 83 of 117)







- transmitters and factors in REM sleep generation

- GABA: origin: poorly characterized

role: inhibits cells of LC and DR

- cholinergic: origin: nucleus reticularis pontis (NRP)

target: brainstem and spinal cord

role: inhibits movement during tonic phase of REM



- clinical

- REM behavior disorder

- lack of paralysis during REM sleep, resulting in acting out dreams

- exhibit normal behavior during wakefulness, NREM sleep

- cataplexy

- REM sleep paralysis that can erupt during wakefulness

- experience a sudden withdrawal of motor activity, can literally collapse to the floor



- summary: sleep stages and neurotransmitters

- ↑NREM: GABA: VLPO, nucleus basalis of Meynert, hypothalamus

adenosine



- ↑REM: GABA (pons) turns off LC, DR

- disinhibits NRP

- ↑ACh in thalamus and cortex gives REM



- ARAS: ACh pons, nucleus basalis of Meynert

5-HT dorsal raphe, medulla

NE: locus coeruleus, medulla

DA: substantia nigra, ventral tegmental area (VTA)

histamine: tuberomammillary region (caudal hypothalamus)

cortisol

CRH



physiological changes associated with sleep

- autonomic activity

- NREM: increase in parasympathetic activity relative to sympathetic activity

- tonic REM: increase in parasympathetic activity relative to sympathetic activity

- phasic REM: autonomic instability: brief surges of both sympathetic and parasympathetic activity

- blood parameters

- decreases in: blood pressure

heart rate

cardiac output

- NREM: decreased relative to normal

- SWS: lowest average values during sleep

- REM: peak average values during sleep, but still decreased relative to normal

- temperature parameters

- decreases in: brain and body temperature

- SWS: particular decreases in temperature due to reduced hypothalamic set point, heat loss

- clinical: experienced as prematurely waking up feeling warm after going to bed feeling cold

REM: decreased ability to regulate temperature through sweating, shivering

- hormonal parameters

- TSH: before sleep inhibited by sleep, stimulated by sleep deprivation

- GH: early in the night enhanced by SWS, positive feedback to enhance SWS

- prolactin: middle of the night enhances REM sleep

- cortisol: before waking contributes to morning arousal

- ACTH: before waking contributes to morning arousal

- memory device: “Tim gets phat chicks always!”

Neuroscience: OBJECTIVES (page 84 of 117)







- HPA axis: hypothalamic-pituitary adrenal axis

- most inactive at nocturnal sleep onset

- genital parameters

- REM sleep can bring on:

- penile erections

- clitoral erection and vaginal blood flow

- not necessarily linked to sexual content in associated dreams

developmental course of sleep

- total sleep

- factors determining extent of human sleep

- age: most important factor

- other factors

- gender

- psychiatric illness

- physical illness

- age in human sleep

- newborn: 16-18 hours/day

- reflects demand of dramatic aging

- remains relatively constant for first year

- 3-5 years: 10-12 hours/day

- 10 years: 10 hours

- adulthood: 7-8 hours

- elderly: 6-7 hours

- sleep tends to be fragmented, susceptible to disruption from noise

- decrease in amount may be offset by increase in daytime napping

- REM sleep

- proportion: decreases with age

- newborn: 50%

- 2 years: 20-25%

- adulthood: 20-25%

- interval: increases with age

- newborn: 50-60 minute intervals

- infants may pass directly from wakefulness to REM sleep

- bypasses first NREM cycle at beginning of the night

- adulthood: 90-100 minute intervals

- clinical: Alzheimer’s disease

- condition associated with pathological aging, among other things

- indications that REM sleep may be reduced, reflecting the known decline in cholinergic function

- slow wave sleep (stage 3, 4)

- proportion: steady decrease with age

- 3-5 years: abundant high amplitude (synchronized) delta wave sleep

- adolescent: gradual decline, generally replaced by NREM stages 1, 2

- elderly: may be virtually absent

- significance: may represent early indication of aging of the CNS

- clinical disorders

- narcolepsy: intermittent episodes of uncontrollable sleep

- onset: adolescence

- incidence: 1 in 10,000

- insomnia: inability to sleep

- onset: adulthood

- incidence: 25% at age 30

50% at age 70 (with elderly people particularly susceptible to awakening during the night)

- nocturnal myoclonus: periodic leg movements (affects 20-30% of people over 65 years old)

- sleep apnea: cessation of breathing for 15-30 seconds (affects 20-30% of people over 65 years old)

temporal regulation of sleep and wakefulness

- periodicity in mammals

Neuroscience: OBJECTIVES (page 85 of 117)







- cycle: periods of increased and decreased activity occurring at various intervals

- period: cycle time between successive peaks or troughs

- circannual rhythm: rhythms of about a year

- circadian rhythm (diurnal): rhythms of about a day (24 hours)

- circadian rhythms in humans

- temperature: early morning at 96°

mid-afternoon at 100°

- hormones: cortisol

growth hormone

prolactin

- urine production

- heart rate

- blood pressure

- characteristics of diurnal rhythms

- persist in absence of environmental time cues (collectively termed “zeitgebers”)

- in absence of environmental cues, period is never precisely 24 hours

- rhythm is intrinsic to the organism

- suprachiasmatic nucleus: principal mammalian circadian clock

- inputs: direct projections from retina

- free-running period: ~25 hours

- in absence of environmental time cues, circadian period averages approximately 25 hours

- temporal isolation experiments: ~25 hours

- forced desynchrony experiments: ~24.5 hours

- effect on body temperature

- in free-running system, phase relationship to sleep cycle changes

- normal: low point near end of sleep

- free-running: low point near beginning of sleep

- reason

- greatest circadian propensity for sleep coincides with temperature minimum

- also time of greatest REM sleep propensity (recall: longer early REM periods)

- regulation of sleep

- two components

- circadian component: cyclic variation over a day

- homeostatic component: increasing drive with being awake

- sleep onset: point of greatest difference between regulating components

- waking: point of intersection between regulating components (shortly after circadian trough)

sleep pathology

- narcolepsy

- incidence: 0.03-0.1%

- symptoms: sleep attacks: sudden-onset REM sleep lasting 5-30 minutes

excessive daytime sleepiness

cataplexy: sudden paralysis, often precipitated by sudden emotional stimulus

sleep paralysis: inability to move while just falling asleep or waking up

hypnagogic hallucinations: visual or auditory hallucinations

- diagnosis: demonstration of REM-onset sleep in a person not REM-sleep-deprived

- etiology: frequently traced to human leukocyte antigen defect (HLA DR2 subtype)

- periodic limb movements

- symptoms: sleep-time movements usually involving lower extremities, sometimes upper

- Babinski-like response

- extension of the big toe, dorsiflexion of the ankle, flexion of the knee and hip

- etiology: mediated by brain stem or other lower centers active during wake-sleep transitions

- can rouse patient or partner

- common cause of insomnia

- treatment: GABA-ergic drugs (benzodiazepines, gabapentin)

L-DOPA

dopamine agonists

Neuroscience: OBJECTIVES (page 86 of 117)







opiates

- restless leg syndrome

- symptoms: unpleasant crawling sensation occurring in the legs

- increases with age

- interferes with falling asleep

- associated with other problems: uremia, arthritis, peripheral neuropathy

- association: frequently occurs along with periodic limb movements









Reward and Reinforcement

general principles

- the four “reward” humours

- food

- sex

- attachment

- drugs

- motivational systems: located in central nervous system

- involved in motivated behaviors necessary for survival of the individual or species

- many motivated behaviors lead to reward and reinforcement

- overstimulation of reward-reinforcement

- psychoactive drugs

- intake of sweet and rich foods

motivation, reinforcement, and operant conditioning

- motivation

- motivation: goal-directed behavior dependent on specific arousal state or drive of the organism

- factors in motivation

- internal environment (specific state)

- external environment (sensory information)

- learned response (acquired)

- behavior: external action in response to a motivation

- appetitive behavior: arousal, approach/avoidance of goal

- consummatory behavior: eating, drinking, mating

- reward: sensory stimulus or event that is perceived as pleasurable or desired by the organism



- operant conditioning

- operant conditioning: association of a stimulus with a behavior

- factors in operant conditioning

- behavior: action

- consequence: result of the action

- discriminative stimulus: situation overlying the system



- reinforcement

- reinforcement: process by which probability of behavior changes in response to an environmental event

- reinforcers and punishers

- reinforcer: stimulus that increases response rate

- positive reinforcer: increases response rate when presented

- negative reinforcer: increases response rate when withdrawn

- punishment: stimulus that decreases response rate

- positive punishment: decreases response rate when presented

- negative punishment: decreases response rate when removed



TABLE: Reinforcement and Punishment

positive reinforcer negative reinforcer

Neuroscience: OBJECTIVES (page 87 of 117)







reinforcer presented positive reinforcement positive punishment

- application of something desirable - application of something undesirable

- increases response rate - decreases response rate



- raise head to leave class - spank the child

- press lever to get food - receive hangover after drinking

reinforcer removed negative punishment negative reinforcement

- removal of something desirable - removal of something undesirable

- reduces response rate - increases response rate



- accident leads to no car - response removes shock

- time out for bad behavior - information reduces sentence





factors influencing the effectiveness of a reinforcer

- overview

- schedule of reinforcement

- availability of other reinforcers

- extinction

- individual differences



- schedule of reinforcement

- pairing

- continuous reinforcers: always paired with the behavior

- intermittent reinforcers: only occasionally paired with the behavior

- after acquiring a behavior, animals will work hard for even intermittent reinforcement

- immediacy

- availability of other reinforcers

- presence or absence influences likelihood of establishment of reinforcement

- examples

- availability of sweet solution will decrease a rat’s lever pressing for drug reinforcers

- availability of social reinforcers may decrease a child’s risk of using drug reinforcers

- extinction

- extinction: teaching an animal not to respond to a learned cue due to lack of reinforcement

- example

- rat presses lever and nothing happens, when action was associated with food reward

- poor luck at a slot machine after initial good luck

- behavioral responses rewarded for a long time or with a potent reward may take longer to extinguish

- all emotion may be related to reward/reinforcement, according to some hypotheses

- euphoria: positive reinforcement

- frustration: extinction

- individual differences

- individuals differ in sensitivity to various rewards/reinforcers

- in some cases, sensitivity has been shown to be genetically inherited



neurological basis for reinforcement

- mesocorticolimbic dopaminergic (DA) system

- linked to positive reinforcement

- components

- “mesocorticolimbic”

- meso: VTA, nucleus accumbens

- cortico: prefrontal cortex

- limbic: amygdala, hippocampus

- ventral tegmental area (VTA)

- location: midbrain, close to the substantia nigra pars compacta

- target: nucleus accumbens, prefrontal cortex, and other more rostral areas

Neuroscience: OBJECTIVES (page 88 of 117)







- function: involved in reward and motivation systems

- inputs: locus coeruleus

pedunculopontine tegmental nucleus (PPT: cholinergic cell group in the pons)

amygdala

prefrontal cortex

- nucleus accumbens

- location: ventral and medial to the head of the caudate and putamen

- function: involved in reward and motivation functions

- at each level, system has connections to other brain regions

- dopamine and positive reinforcement

- striatum

- caudal region (caudate, putamen)

- innervation: substantia nigra pars compacta

- function: motor (deficits can cause Parkinson’s disease)

- ventral region (nucleus accumbens)

- innervation: ventral tegmental area (VTA)

- function: reward, motivation functions

- evidence for involvement of dopamine in positive reinforcement

- self-stimulation of the VTA or mesocorticolimbic system (rat electrode studies)

- increased extracellular DA in nucleus accumbens assoc. with sweet nutrition consumption (rat microdialysis)

- comparable electrical brain stimulation in humans associated with pleasure (various human studies)

- DA release

- associated with primary reinforcing stimuli

- associated with conditioned stimuli (and may thus be useful in learning about predictive value of stimuli)

- DA release smaller with a well-learned stimulus

- implication: DA seemingly more important in learning than in simple reinforcement

- opiates and the VTA

- opioids: morphine-like substances

- enkephalins

- endorphins

- dynorphins

- pharmacology: activate VTA cells, causing DA release in nucleus accumbens

- opiate receptors

- some located on GABA processes that terminate on VTA terminals

- activation of receptors blocks GABA release, leading to release of DA

- can be directly injected into the blood stream, as in heroin

- function: associated with stages of positive affect

- may regulate food intake and affective response to sweet taste

- sweet foots activate endogenous opoid circuits, increasing DA in nucleus accumbens

- opiate blockers (e.g. naltrexone) reduce palatability of food without reducing hunger drive

- may regulate emotional responses in relation to stress

- opioids in areas such as amygdala, hypothalamus

- pain: opoids protect organism from pain until escape is possible

- anxiety: administration of opiates to infant monkeys reduces separation anxiety



clinical correlates

- binge eating and the relationship to substance abuse problems

- deprivation of one reinforcer results in increased intake of alternative reinforcers

- food-deprived rats increase lever-pressing for drug rewards

- rats with strong preference for sweet solutions foods more likely to develop preference for morphine, alcohol

- binge eating is frequently associated with increased intake of alcohol, drug use

- binge eating: intake of large amount of food in a short period of time

- dieting: the attempt to refrain from eating food (deprivation of a natural reinforcer)

- many report that binge eating started after a period of dieting or worsened after dieting

- women who diet most severely are most likely to binge eat, drink heavily, smoke, or use marijuana

- binge eating presents in 25-30% of people entering a weight loss program

Neuroscience: OBJECTIVES (page 89 of 117)







- drugs of abuse activate the ascending mesocorticolimbic dopamine system

- affect critical components of the brain’s reinforcement system

- may exert long-term alterations in gene expression, protein synthesis, and synaptic function

- addiction: diagnostic criteria (DSM-IV)

- loss of control over use of the substance

- impairment in daily functioning and continued use despite adverse consequences

- physical or emotional adaptation to the drug

- self-administration as a model for drug dependence in humans

- animal self-administration model: use of animal subjects with drug administration associated to a response

- animals will not self administer human hallucinogens

- LSD

- mescaline

- animals will self administer numerous other human psychotropic drugs

- cocaine

- amphetamine

- nicotine

- caffeine

- alcohol

- opiates

- sedatives (barbituates, Halcion, Xanax)

- findings from the self administration model

- animals learn to perform an operant response for IV delivery of a drug

- animals will self-administer cocaine to death

- forego food and water to get cocaine

- models self-destructive behavior in human cocaine addicts

- dopamine involvement in drug abuse

- euphoria drugs: cocaine, amphetamine

- lesions of the mesolimbic system reduce or abolish response for IV cocaine or amphetamine

- euphoric drugs increase amount of synaptic dopamine

- differential effects

- many drugs of abuse activate the nucleus accumbens-dopamine system

- drugs that rats do not self administer do not have an effect on DA levels

- mechanisms

- cocaine: competitively binds nucleus accumbens dopamine reuptake site, increasing synaptic DA

- amphetamine: competitively binds nucleus accumbens dopamine reuptake site, increasing synaptic DA

- alcohol: affects endogenous opiate system to effect DA release from nucleus accumbens

- may bind opiate receptors on VTA cells

- may affect direct opiate paths to the nucleus accumbens

- nicotine: binds nicotinic ACh receptors on DA nerve cells

- directly increases dopamine levels

- also enhances learning system, thus increasing addiction

- heroin: binds opoid receptors on VTA cells

- marijuana: binds cannabinoid receptors on VTA cells

- morphine: blocks pain systems that inhibit dopamine release (dis-inhibition)



conditioning and learning models of addiction

- models for conditioning

- unconditioned stimulus: stimulus directly causing response

- unconditioned response: response resulting from administration of UCR

- conditioned stimulus: stimulus indirectly linked to response

- conditioned response: response resulting from administration of CR



TABLE: Factors in Conditioned Learning: Pavlov’s Dog

stimulus response

reflexive response UCS (unconditioned stimulus): UCR (unconditioned response):

food in dog’s mouth salivation

Neuroscience: OBJECTIVES (page 90 of 117)







learned response CS (conditioned stimulus): CR (conditioned response):

bell paired with meat salivation





- drugs: unconditioned stimulus



TABLE: Factors in Conditioned Learning: Drugs

stimulus response

reflexive response UCS (unconditioned stimulus): UCR (unconditioned response):

drug positive effects of drugs

learned response CS (conditioned stimulus): CR (conditioned response):

presence of drug environment craving for drugs

- conditioned response ≠ unconditioned response

- UCR: desired effects of the drug

- CR: respiratory depression, analgesia, increased temperature, drug-seeking behavior





TABLE: Factors in Conditioned Withdrawal: Opiate Addiction

stimulus response

reflexive response UCS (unconditioned stimulus): UCR (unconditioned response):

lack of drugs withdrawal symptoms

learned response CS (conditioned stimulus): CR (conditioned response):

presence of drug environment withdrawal symptoms

- conditioned response = unconditioned response





adaptation to drugs: tolerance and physical dependence

- neuroadaptation

- neuroadaptation: biological changes in the brain resulting from repeated or chronic exposure to a drug

- one exposure: causes a specific effect

- repeated exposures: frequently causes adaptation and desensitization

- desensitization

- desensitization: reduction in sensitivity to a particular response

- reflects nervous system efforts to maintain homeostasis

- consequences

- progressively more drug needed to obtain same effect

- may or may not be accompanied by physical dependence, which can lead to withdrawal syndromes

- withdrawal syndrome

- common symptoms

- changes in body temperature or heart rate

- seizures

- tremors

- vomiting

- symptoms of opiate withdrawal

- nausea

- GI disturbance

- chills

- dysphoria

- sympathetic arousal

- symptoms of cocaine/nicotine withdrawal: may be more difficult to observe

- severe depression

- irritability

- craving

- motivation for drug use

- early use: effects of drug

Neuroscience: OBJECTIVES (page 91 of 117)







- chronic use: avoidance of withdrawal

cellular and molecular effects of drug exposure

- neurofilaments

- drugs cause decreases in neurofilament numbers in VTA cells

- causes VTA cell shrinkage

- consequences

- alterations in neuronal structure

- decreases in axonal caliber

- decreases in axonal transport rate in these cells

- may result in lower dopaminergic transmission to nucleus accumbens

- tyrosine hydroxylase: enzyme involved in dopamine synthesis pathway

- TH increased in VTA cell bodies, decreased in dopaminergic terminals of nucleus accumbens

- implication: less DA transmission from nucleus accumbens, despite increased synthesis in VTA

- intermediate early genes (IEGs)

- intermediate early genes: genes and protein products responsible for regulating activity, expression, cell activity

- inputs to IEGs

- G proteins

- second messengers

- protein phosphorylation

- nuclear transcription factors

- drugs affect IEGs, which can lead to long-term changes in cells

- cyclic-AMP response-element binding protein (CREB)

- CREB: nuclear transcription factor that, when phosporylated by PKA, activates target genes

- may be a component of long-term memory

- amphetamine: activates phosphorylation of CREB, with subsequent adaptation to this response



- other biochemical findings

- conditioned stimuli can turn on IEG expression in certain brain regions

- example: conditioned stimuli associated with cocaine can activate c-fos in:

- amygdala

- prefrontal cortex

- implication: pairing of drug states with environmental cues actually changes long-term cellular activity

- N-methyl-D-aspartate (NMDA) receptors

- critical component in brain’s learning and plasticity mechanisms

- drugs blocking these receptors (e.g. MK-801) block many of the behavioral, adaptive effects of drug exposure

- amphetamine: activates IEG zif/268

- MK-801: blocks activation by amphetamine

- zif/268: gene implicated in long term potentiation, along with NMDA receptors









Memory and Cognition

- memory testing in the mini mental status exam (MMSE)

- working memory: ask the patient to repeat the name of three unrelated items

- recent memory: after a delay (3-5 minutes), ask the patient to recall the three unrelated items

- remote memory: ask the patient about historical or verifiable personal events of the past

overview of memory

- sensory memory (sensory store)

- types: visual (iconic)

auditory (echoic)

- capacity: very big

- duration: visual: 0.5-1.0 seconds

auditory: slightly longer

Neuroscience: OBJECTIVES (page 92 of 117)







- storage: unlabeled, non-meaningful

- loss: decay over time

masking by novel stimuli

- short term memory (working memory)

- capacity: 7 ± 2 chunks

- bit: smallest piece of information (“A” in LSATACTSAT)

- chunk: meaningful piece of information (“ACT” in LSAT ACT SAT)

- duration: without rehearsal: 15-30 seconds

with rehearsal: indefinite (persists with attention)

- processing: serial

- storage: meaningful, explicit, conscious

- loss: interference

competition

replacement

- location: pre-frontal cortex (PFC)

- convergence zone for visual, auditory sensory systems

- receives information from other areas involved in long term memory

- retrieval: process of finding, retrieving, bringing long term memory into working memory

- long term memory

- capacity: virtually unlimited

- duration: virtually unlimited, especially after learning language

- once encoded, some believe it may remain infinitely

- loss of memory may simply be loss in retrieval

- processing: non-serial (branched, network, or hierarchical)

- anatomy: convergence

- parahippocampal cortex: convergence zone receiving projections primarily from parietal lobe

- perirhinal cortex: convergence zone receiving projections primarily from temporal lobe

relay

- through entorhinal cortex

- to hippocampus

encoding

- hippocampus: participates in reinstatement of pattern of cortical activation of original experience

- each restatement changes cortical synapses a little, resulting in learning

- cortical representations become self-sufficient, become independent of hippocampus

- types: explicit memory: memory that is consciously considered

- semantic: memories about general factual information (e.g. George Bush is a bad president)

- episodic: personal, autobiographical memories (e.g. first day of school)

implicit memory: memory that is not conscious but still influences behavior

- procedural: memories for how to do things (e.g. playing a trombone)

- conditioning: memories formed through conditioning (e.g. dinnertime salivation)



neural systems of explicit memory: patients with memory deficits

- memory consolidation takes place in the hippocampus

- hippocampus is not:

- the location or method of retrieval of long term memories

- the location of short term memories

- hippocampus is:

- involved in converting short term memories to long term memories

- crucially involved in memory, which is one of our most important cognitive functions

patient HM

- history

- patient underwent voluntary bilateral temporal lobe resection

- surgeon: Dr. William Scoville

- date: 23 August, 1953

- reason: attempt to stop epileptic surgeries

- removed tissue was found to include bilateral hippocampus

Neuroscience: OBJECTIVES (page 93 of 117)







- due to unexpected memory effects, has been studied to aid in memory research

- deficit: recent memory deficit (inability to consolidate new information into long term stores)

- perception: normal

- IQ: above average

- memory: short term: preserved in both verbal, non-verbal tasks

long term: anterograde amnesia, accompanied by 11 year retrograde amnesia

- language: mostly normal

- examination

- impairments

- problems with any learning task in which there is a delay between presentation and recall

- severely impaired with memory of daily life

- where he is

- who cares for him

- what he ate at his last meal

- normal function

- intact short term working memory

- intact procedural memory (demonstrated with mirror-drawing task)

- implication: encoding of explicit memory has unique circuitry, with involvement of hippocampus

patient RB

- history

- global ischemia complications from heart bypass surgery

- survived for five years

- deficit: amnesia

- examination

- histological examination revealed bilateral loss of cells in CA1 of Ammon’s horn

- CA1 pyramidal field of hippocampus especially vulnerable to excitotoxic effects of glutamante

- implication: ischemia can have significant effects on memory



neural systems of implicit memory

- poorly characterized

- involved structures

- cerebellum

- basal ganglia

- caudate

- putamen

- globus pallidus

- process

- information from basal regions is passed to the VA/VL

- VA/VL projects to premotor areas (PM1) and supplementary motor areas (SMA)



clinical correlations: disorders involving memory deficits

retrograde amnesia

- amnesia

- anterograde: loss of ability to form new memories

- retrograde: loss of previous memory

- mechanisms of retrograde amnesia

- loss of synapses in cortical areas involved in storing features

- loss of association synapses

- loss of pathways in retrieval into working memory

- deficit in working memory

- hippocampus: establishment of association synapses

- defining an apple

- taste: sweet and sour

- smell: sweet

- touch: crisp, hard, and smooth

- sight: round, red

Neuroscience: OBJECTIVES (page 94 of 117)







- associative: grows on a tree, great in pie

- recalling an apple

- thought about an apple involves numerous sensory modalities

- each modality leaves a trace, so memories of an apple are scattered throughout the cortex

- storing an apple

- hippocampus: binds traces with the same object

- thus allows activity in any of those pathways to elicit the memory of an apple

normal aging

- cellular degeneration

- degeneration

- with increasing age, brain undergoes reduction in weight and protein content

- etiology: loss of neurons

- different areas of brain lose neurons at different rates

- hypothalamus: very little loss

- substantia nigra: substantial loss

- locus coeruleus: substantial loss

- locus coeruleus: norepinergic cell body region involved in arousal functions

- loss of these cells may impair ability to learn complex information

- hippocampus: substantial loss (20% of hippocampal neurons lost during 2 nd half of life)

- cortex: some loss or atrophy

- basal forebrain: some loss in structures projecting to hippocampus, basal forebrain

- especially profound in nucleus basalis of Meynert

- secrete ACh that plays important role in memory

- internal cellular alterations

- neurofibrillary tangles

- with increased age, found in larger neurons such as those of the hippocampus, amygdala

- composition

- poorly soluble hyperphosphorylated isoforms of tau

- tau: microtubule-binding protein (normally soluble

- relevance

- normal aging: unknown

- pathological aging (Alzheimer’s disease): found in substantial amounts post-mortum

- senile plaques

- with increased age, found in extracellular space

- beta-amyloid protein: forms core of the plaques

- amyloid precursor protein (APP): precursor to beta-amyloid protein

- manufactured on nerve cells

- normal function: unknown



pathological aging

- dementia: steady decline in cognitive functions such as memory and intellectual skills

- prevalence: 11% of population over age 65

+2% for each year of life after age 75

- etiology: dementia with Lewy bodies

Huntington’s disease

atherosclerosis

multiple sclerosis

head injury

prion disease

Parkinson’s disease

- proportion: Alzheimer’s: 70%

stroke: 15%

neurodegenerative diseases: 15%

- Huntington’s

- Parkinson’s

- Alzheimer’s disease: memory and cognition syndrome with unknown etiology

Neuroscience: OBJECTIVES (page 95 of 117)







- symptoms: early

- forgetfulness

- untidiness

- restlessness

- confusion

- loss of working memory (esp. digit span)

late

- loss of interest in events

- loss of control over body functions

- mental emptiness

- diagnosis: postmortem examination of the brain

- senile plaques, neurofibrillary tangles

- scattered throughout the brain

- high densities in amygdala, hippocampus

- neuronal cell loss and alterations in neuronal morphology

- reduced weight

- cortical atrophy in more anterior lobes

- cell loss in hippocampus, amygdala, olfactory system

- cell loss in nucleus basalis (major cholinergic cell group at base of forebrain)

- role of the cholinergic system

- nucleus basalis of Meynert: cholinergic output to hippocampus and cortex

- location: beneath globus pallidus

- function: integrates various subcortical functions important for memory

- Alzheimer’s disease: severe loss of neurons in nucleus basalis

- pharmacology

- attempts to administer high cholinergic precursors (e.g. choline) have been successful

- attempts to decrease breakdown of acetylcholine (e.g. Aricept) have been more successful

- note: involvement of norepinephrine

- losses in cortical norepinephrine activity are also evident in the Alzheimer brain

- correcting imbalance in one neurotransmitter system may not be sufficient

- other speculations

- neurotrophic (growth) factor may be reduced, or affected neurons may become less responsive

- in this manner, there may be a way to slow or stop the associated degradation

- role of beta-amyloid protein

- amyloid precursor protein (APP) gene

- function: may be involved in regulation of cell growth, length of dendrites/axons

- pathology: mutations in gene have been associated with increased β-amyloid plaques

- location: chromosome 21

- Down syndrome (trisomy 21) patients manifest β-amyloid plaques at an early age

- small amounts in teenage years, substantial amounts in 4 th and 5th years

- other genes linked to Alzheimer’s disease

- early onset

- presenilin 1 (chromosome 14)

- 80% of cases of familiar Alzheimer’s disease (can attack at 40)

- may lead to excess β-amyloid production

- presenilin 2 (chromosome 1)

- closely related to the chromosome 14 gene

- may lead to excess β-amyloid production

- late onset

- apolipoprotein E (APOE)

- located on chromosome 19

- occurs in three different alleles

- note: more than 90% of Alzheimer’s disease are sporadic and late onset

- current thinking on Alzheimer’s disease

- clinically highly heterogeneous

- gradual accumulation of β-amyloid protein, neurofibrillary tangles leads to degeneration of function

Neuroscience: OBJECTIVES (page 96 of 117)







- over time, limbic communication is compromised, leading to Alzheimer’s









Stress

- stress: any perturbation of homeostasis

- physical: heat, cold, physical trauma

- psychosocial: fear, anger, surprise

- stress response

- can be both beneficial and detrimental to the organism

- adaptive: beneficial, leading to resilience

- maladaptive: detrimental, leading to dysfunction

- key components

- hypothalamic-pituitary-adrenal system (HPA axis): secretion of hormones from pituitary, adrenal cortex

- locus coeruleus-norepinephrine (LC-NE) system: major brain pathway encoding stress response

- corticotropin releasing hormone (CRH) system: major brain pathway encoding stress response

- general mechanism: sympathetic activation for “fight or flight” response

- increased flow of glucose and O2 to the muscles and brain

- adrenomedullary discharge of epinephrine

- vasoconstriction

- increased heart rate and blood pressure

- enhanced arousal

- focused attention

stress response: anatomy

- components of the stress response

- HPA axis: regulation of secretion of pituitary ACTH secretion, modulating endocrine stress response

- LC-NE system: promotes activation of peripheral autonomic responses, vigilance

- extrahypothalamic CRH system: activates LC-NE system



hypothalamic-pituitary-adrenal system (HPA axis)

- paraventricular nucleus

- location: medial aspect of the hypothalamus, bordering third ventricle

- input: amygdala (amygdala receives multimodal sensory input)

lateral hypothalamus (lateral hypothalamus receives input from higher sensory cortical areas)

locus coeruleus

prefrontal cortex

hippocampus

brain stem (reticular formation carrying pain, temperature, auditory, visual,

vibration, respiration, and cardiovascular data)

- output: HPA: CRH release into the portal system ( ACTH)

autonomic: brain stem autonomic ganglia in dorsal motor nucleus X (inhibitory)

sympathetic preganglionics in lateral column of the spinal cord (excitatory)

LC: CRH output to the locus coeruleus

- function: hormonal regulation

- secretion of vasopressin (ADH, antidiuretic hormone)

- secretion of oxytocin

stress response

- secretion of corticotropin-releasing hormone (CRH)



- involvement in the stress response

- paraventricular nucleus: releases corticotropin releasing hormone (CRH) into portal capillary plexus

- anterior pituitary: releases adrenocorticotropic hormone (ACTH) in response to CRH

- adrenal cortex: releases glucocorticoids (cortisol) in response to ACTH

Neuroscience: OBJECTIVES (page 97 of 117)







- modulation: feedback inhibition

- primary mechanism for controlling general HPA activity

- glucocorticoids inhibit precursor release from anterior pituitary, hypothalamus, and limbic brain regions



- cortisol

- diurnal rhythm

- peak: onset of wakefulness (most stressful time of day)

- nadir (trough): 12 hours after waking

- role in learning and memory

- memories of emotional events are typically more vivid and stable than those of other events

- evolutionary function: stressful events are useful to recall

- hippocampus: dense amounts of glucocorticoid receptors

- problems of chronic exposure

- can cause hippocampal neuronal cell death, resulting in memory impairment

- especially prevalent during aging process



locus coeruleus-norepinephrine (LC-NE) system

- locus coeruleus

- location: rostral pons

- “blue spot”: color in staining of brain sections

- 20,000 LC cells in the human brain

- input: medullary reticular formation (collaterals from TTT, STT, ML, ALS)

prefrontal cortex

amygdala

hypothalamus

paraventricular nucleus (via CRH)

- output all areas of neocortex

thalamus

limbic system

hypothalamus

other brain stem nuclei

spinal cord

- transmitter: norepinephrine

- function: adaptive global brain functions

- behavioral, sensory stimuli elicit activation of LC-NE neurons

- LC integrates, orchestrates adaptive CNS response to stimuli

- loud clicks or bright flashes

- noxious stimuli

- physiological challenges (hypoxia, hypoglycemia)

- terminal regions alter global brain functions such as vigilance, attention, arousal



- biosynthesis of catecholamines

- tyrosine hydroxylase: L-tyrosine  L-DOPA

- DOPA decarboxylase: L-DOPA  dopamine

- dopamine-β-hydroxylase: dopamine  norepinephrine

- phenylethanolamine N-methyl transferase (PNMT): norepinephrine  epinephrine



extrahypothalamic CRH systems

- location: amygdala

paraventricular nucleus (PVN)

- output: locus coeruleus

- transmitter: CRH

- function: stress response

- increased arousal (LC activation of autonomic response)

- increased vigilance (LC activation of cortex)

Neuroscience: OBJECTIVES (page 98 of 117)







stress response: adaptability

- psychological factors modulating stress response

- predictability

- controllability

- evidence

- shock two animals, giving one animal ability to stop shock for both animals

- controllable stress: normal cortisol and norepinephrine

- less likely to experienced reduced NE in future uncontrolled stressor

- uncontrollable stress: elevated cortisol, decreased norepinephrine, adrenal hypertrophy

- place previously shocked animals in situation where, for either one, jumping hurdle decreases shock

- controllable stress: rapid adaptation

- uncontrollable stress: learned helplessness

- inability to respond adaptively to new situations after uncontrollable stress

- may be similar to mechanisms underlying depression

- positive experience can have protective effects on stress response

- adult rats with more attachment contact during infancy showed reduced adrenocortical response to stress

- implication: early life experiences during critical period may participate in shaping adult stress reactivity

- relationship to depression

- noncontingency: lack of a relation between responding and outcome

- shapes individual’s ability to deal with aversive, stressful events

- undermines ability to respond positively, cope effectively, or believe that behavior can affect outcome

- perceived or actual loss of control over important life events may be a major precipitation of depression

post-traumatic stress disorder (PTSD)

- etiology: exposure to a traumatic event

- experienced events involving actual or threatened death or serious injury or personal threat

- response involved intense fear, helplessness, or terror

- symptoms: re-experience of the event

- recurrent or intrusive distressing recollections of the event

- recurrent distressing dreams of the event

- acting or feeling as if the traumatic event were occurring

- intense psychological distress or reactivity at exposure to cues reminding of the event

avoidance of stimuli associated with trauma, numbing of general responsiveness

- efforts to avoid activities, places, or people that arouse recollection of the trauma

- inability to recall an important aspect of the trauma

- diminished interest or participation in significant activities

- feelings of detachment or estrangement from others

- restricted range of affect

- sense of foreshortened future

increased arousal

- difficulty falling asleep

- irritability or outbursts of anger

- difficulty concentrating

- exaggerated startle response

- physiology: increased levels of NE in the blood and urine

increases in heart rate, blood pressure

abnormal responses to yohimbe (α2-NE antagonist)

lower cortisol levels

- brain becomes hypersensitive to cortisol

- increase in cortisol receptors on ACTH-producing cells, increasing negative feedback

- evidence for altered function of HPA axis in people with PTSD

- clinical: β blockers: frequently used to block effects of increased NE



- neural damage in PTSD

- damage to the hippocampus

- hyperactivity of locus coeruleus may damage hippocampus

- causes improper integration or memories, resulting in:

Neuroscience: OBJECTIVES (page 99 of 117)







- nightmares

- flashbacks

- physical symptoms

- damage to commissural fibers (communication between hemispheres)

- specialized areas of the cerebrum

- right brain: typically associated with emotions, development of social skills

- left brain: typically associated with reason

- communication deficit

- results in memories or emotions that cannot be verbalized, worked through easily

- events may become trapped in the subconscious









Emotion

overview

- primary emotions

- anger

- fear

- pleasure

- sadness

- disgust

- stimulus relevance

- stimulus relevance: function of external stimuli in guiding appropriate, adaptive behavior

- guides behavior in many spheres

- consumption

- sexuality and reproduction

- defense

- approach/avoidance

- fight/flight

- function of emotions

- primitive

- achievement of homeostasis

- facilitation of adaptive behavior and equilibrium

- cognitive-emotional interactions

- emotional significance of diverse stimuli, events

- assignment of emotional valence

- alteration of emotional value previously assigned to a stimulus

- factors in emotional response

- evaluation of the stimulus

- past experience

neuroanatomy of emotion

limbic system

- amygdala: key structure involved in evaluating emotional valence of stimuli

- lesion: difficult with associations between environmental stimuli, emotional states

- failure to learn that a stimulus predicts reward or danger

- falling in social rank

- decreased affiliative behavior

- damage to other limbic structures can produce similar changes in emotional behavior

- interactions between cortical brain regions and limbic system

- interconnections



cortex (pre-frontal, temporal)

↑↓

limbic system (hypothalamus, amygdala, hippocampus)

Neuroscience: OBJECTIVES (page 100 of 117)







↑↓

brainstem (parabrachial nucleus, nucleus solitarius, dorsal motor X, etc.)

autonomic nuclei



- implications

- complex sensory processing in the cortex can directly influence limbic system

- limbic processing can strongly influence higher-level cognitive integration

monoaminergic systems

- monamine systems

- serotonin

- norepinephrine

- dopamine



- serotonin system

- origin: raphe nucleus (dorsal raphe-serotonin)

- projection: all areas of the cerebral cortex

temporal lobe structures (amygdala, hippocampus, hypothalamus)

midbrain

cerebellum

brain stem

spinal cord

- dopamine system

- origin: ventral tegmental area (VTA-dopamine)

substantia nigra pars compacta

- projections: basal ganglia

limbic system

frontal, temporal cortex

- norepinephrine system

- origin: locus coeruleus (LC-NE)

- projections: all areas of the cerebral cortex

cerebellum

spinal cord



neural substrates of fear and anxiety

- fear response

- fear response: defensive or protective acts

- withdrawal (fleeing)

- freezing

- fighting

- function: essential for survival

- development: largely innate

- development of fear

- developmental

- behavioral responses associated with fear are evident within first few months of human life

- selective fear response to unfamiliar situations develops later in human life

- genetic: inherited predisposition to express intense fear, stress responses

- instinctive

- rhesus monkeys have a learned fear of snakes

- this fear comes much more easily than fear of flowers

role of the amygdala

- anatomy

- lateral nucleus: receives all sensory inputs, projects to other three nuclei

- basal nucleus: projects to central nucleus

- accessory basal nucleus: projects to central nucleus

- central nucleus: contains output cells of the amygdala

connects to other areas of brain concerned with emotional responses

Neuroscience: OBJECTIVES (page 101 of 117)







- function: moderates fear reactions and learning of fear

- lesion: absence of appropriate behavioral response to fear-eliciting stimuli (psychic blindness)

- stimulation: defensive, flight reactions in cats

fear, anxiety in humans

- inputs: conditioned fear stimulus

sensory thalamus

polymodal sensory cortex

hippocampus

- outputs: numerous (see table)

- process of emotional fear response in the amygdala

- input: direct, multimodal sensory input from cortex

- association: associative process takes place in amygdala

- output: various target tissues expressing the various symptoms of fear

- breadth of amygdala: dramatic effects on mental life, behavior of the individual

- reaction to both conditioned and unconditioned stimuli

- imprinting of stimuli with highly charged emotional context (emotional memory)

- recognition of emotional stimuli

- Urbach-Wiethe disease: genetic disorder that results in calcification, atrophy of the amygdala

- such patients have difficulty rating intensity of various facial expression, though facial learning is not impaired



TABLE: Role of the Amygdala in Various Target Tissues

target effect of stimulation sign of fear or anxiety

hypothalamus sympathetic activation rapid heartbeat, galvanic skin response, paleness,

pupil dilation, BP elevation

parabrachial nucleus increased respiration panting, respiratory distress

(solitarius complex)

ventral tegmental area, activation of DA, NE, ACh behavioral and EEG arousal

locus coeruleus increased vigilance

reticular formation increased reflexes increased startle

(brain stem)

periaqueductal grey cessation of behavior freezing, conditioned emotional response

(different than SPA) social interactions

trigeminal motor nerves mouth open, jaw movements facial expressions of fear

facial motor nerves

paraventricular nucleus ACTH release corticosteroid release

(hypothalamus) (stress response)

- amygdala is centrally positioned to influence a wide array of systems



role of corticotropin-releasing hormone (CRH) systems in fear and anxiety

- features of the central nucleus of the amygdala (CeA)

- contain CRH

- exhibit CRH receptors

- target locus coeruleus neurons

- function: aid in onset of fear and anxiety

- administration of CRH into cerebral ventricles induces anxiety responses

- hypervigilance

- enhancement of freezing posture

- decreased exploration of behavioral responses

- administration of CRH antagonist produces reduction in occurrence of anxiety responses

- stimulation of CeA with CRH increases release of NE and epinephrine from the adrenal medulla

- hypothesis: dis-regulation of CRH systems may underlie or contribute to a state of chronic fear/anxiety

clinical correlation: panic attack and panic disorder

- panic disorder

- prevalence: 2-3% of people over lifetime

twice as many women affected

Neuroscience: OBJECTIVES (page 102 of 117)







- symptoms: extreme fear

intense urge to flee

intense autonomic arousal

- light-headedness

- racing heart

- difficulty breathing

- chest discomfort

- generalized sweating

- weakness

acute attack symptoms may last several minutes to an hour

- etiology: hypersensitive autonomic nervous system involving overly reactive LC-NE system

- acute panic attacks generated by abnormal neural circuitry

- generally experienced as storms of autonomic activity

- yohimbine: mild hallucinogen extracted from South African tree bark

- α2-NE receptor antagonist

- such receptors tend to serve as autoreceptors

- agonists: negative feedback signal to reduce release of NE

- antagonists: block negative feedback, producing more constant NE

- Yohimbe thus causes LC cells to continually release NE

- laboratory findings

- administration of yohimbine to panic-prone patients mimics panic attack

- administration of clonidine (α2-NE receptor agonist) reduces panic attack (and firing of LC neurons)

- implication: NE system may be oversensitive or hyperactive in individuals predisposed to panic disorder

role of carbon dioxide in the etiology of panic attacks

- patients with panic disorder may have sensitive brain stem CO2 receptors

- inhalation of 5% CO2 found to potentiate rapid increase in ventilation before panic attack

- CO2 produces a dose-dependent increase in LC firing rates

- hypotheses on etiology of panic attacks

- physiological: functions, sensations, and metabolic demands occurring in the periphery

- cortical: fearful perceptions and thoughts emanating from cerebral cortex

- hormonal: cholecystokinin (CCK): neuropeptide

- panic attacks may begin with excitation of CCK in brain stem

- stimulate noradrenergic neurons of LC, beginning panic attack

sadness and negative affect

- sadness: internal state signaling need for affection

- functions to motivate individuals to seek supportive social relationships

- present form birth, alerts caregiver to infant’s needs

- laboratory model: mother-infant separation

- infants separated from mothers characterized by:

- loss of interest in environment

- reduced food intake

- huddling in the corner

- profound impact on subsequent behavior

- those isolated at an early age showed extremely antisocial behavior

- when forcibly made into mothers, showed anti-maternal behavior (including infant tossing)

clinical correlation: depression and alterations in brain monoamines

- depression

- symptoms: depressed mood

loss of interest in previously-pleasurable activities

weight alterations

sleep problems

motor problems

loss of energy

feelings of guilt

loss of concentration

suicidal thoughts

Neuroscience: OBJECTIVES (page 103 of 117)







- prevalence: affects 5% of adult population at any one time

20% of individuals will experience an episode at any one time



- monoamine hypothesis of depression: depression results from deficit in brain norepinephrine, serotonin, or both

- depression in patients taking reserpine

- reserpine: antihypertensive agent previously used in treatment of hypertension

- mechanism: long-standing depletion of monoamines

- examination of metabolites in depressed patients

- 3-methoxy-4-hydroxyphenylglycol (MHPG)

- major metabolite of norephinephrine

- reduced in CSF in depressed patients

- 5-hydroxyindoleacetic acid (5-HIAA)

- major metabolite of serotonin (5-HT)

- reduced in CSF in depressed patients

- memory device: NM, S5

- antidepressants: increase level of biogenic amines

- monoamine oxide (MAO) inhibitors: block enzyme responsible for oxidation of monoamines

- tricyclic drugs: block presynaptic reuptake of NE and serotonin

- selective serotonin reuptake inhibitors (SSRIs): block presynaptic reuptake of serotonin

- selective norepinephrine reuptake inhibitors (SNRIs)

- example: reboxetine (mesylate)

- relatively new class of drugs with unique mechanism, benign side effects

- may be particularly useful in patients with decreased energy

- summary: disruption of brain serotonin (5-HT) and NE contributes to depressive syndrome

- correlation of lowered brain serotonin and suicide

- suicide

- incidence: 30,000 people per year in the United States

- etiology: depression?

- difficult to determine who will successfully take their life by suicide

- size of stress is not a good predictor

- neurophysiology of depression

- consistent reduction of serotonin and 5-HIAA (metabolite) in those who commit suicide

- low serotonin may predispose individuals to commit suicide

- low brain 5-HT produces increase in impulsive behavior

- impulsive behavior is a better predictor of suicide

- etiology: unknown

- heritable factors

- neurological insults during development









Thought and Perception

overview

- goals of perception

- selectively attend to specific information

- filter out irrelevant information

- systems mediating thought and perception

- prefrontal cortex (PFC)

- temporal lobe: temporal cortex

amygdala

hippocampus

- VTA-mesocorticolimbic system: dopamine system

Neuroscience: OBJECTIVES (page 104 of 117)







prefrontal cortex

- prefrontal cortex

- location: rostral to supplementary motor cortex

- dorsolateral PFC: lateral wall of the hemispheres

- ventromedial (orbitomedial) PFC: medial wall, ventral surface (above the orbits)

- connection: cortical association connections

- parietal

- temporal (and auditory association cortex)

- occipital (and visual association cortex)

associations with deep structures

- hippocampus

- hypothalamus

- thalamus

- limbic structures

- function: executive information

- prioritize, integrate sensory input from multiple sensory modalities into perception

- compare new and old complex perceptions

- assign emotional significance and control emotional reactions

- sub-regions: dorsolateral PFC: working memory, planning, behavioral flexibility

orbitofrontal PFC: emotional modulation

- clinical: decreased PFC activity in schizophrenia



- dorsolateral prefrontal cortex: function in working memory

- working memory: limited, short-term store of currently relevant information

- eliciting deficiencies in working memory

- delayed task response

- in view of subject, reward hidden under one of several possible objects

- screen is lowered and raised after a delay

- test: determine if subject can recall where the object was hidden

- Wisconsin Card Sort Test

- presentation of reward associated with cards using various sorting rules (shape, size, color)

- deficiencies indicate damage in working memory

- evidence of PFC function in working memory

- impairment of delayed response task associated with poorly developed PFC

- infant humans, infant monkeys, and monkeys with PFC damage show perservation in delayed task response

- perseveration: repetition of a previous response when no longer appropriate

- impairment of working memory tasks correlated with abnormal dopamine levels in PFC

- present if dopamine levels are either too high or too low

- reflects need for normal DA levels for normal memory

- PFC lesions associated with poor memory performance tasks

- localization: dorsolateral PFC

- decreased regional blood flow to dorsolateral PFC in schizophrenia patients during Wisconsin Card Sort Test

- symptoms of schizophrenia possibly involving working memory

- disjointed, illogical sentence structure

- poor hygiene

- repetitive behaviors

- thus schizophrenia associated with PFC damage

- orbitofrontal (medial prefrontal) cortex: function in affective / emotional response

- injuries to orbitofrontal cortex associated with docile apathy, lack of spontaneity

- Phineas Gage

- railroad foreman that sustained damage after a tamping rod was propelled through his skull and brain

- localization: through modern analysis, localized to bilateral medial frontal (orbitofrontal) region

- consequence

- maintained intelligence, physical capabilities, and precision of memory

- profoundly changed in thought and behavior (rude, irreverent, profane, inattentive)

- prefrontal leukotomy

Neuroscience: OBJECTIVES (page 105 of 117)







- procedure: cutting of the white matter of the frontal lobe

- originator: Egas Moniz

- clinical: previously used to treat people with severe anxiety and violent behavior

- subsequently linked to epilepsy, severe ethical concerns

- now nearly abandoned as treatment for aggression



temporal lobe

- temporal lobe

- function: regulation of information processing, perception

- sub-regions: amygdala: emotion, affect

hippocampus: long term memory

specialized neocortex

- primary, secondary auditory cortex

- olfactory cortex

- visual association areas

- language association area (Wernicke’s [22])

- development: phylogenetically new cortex: lateral surface

phylogenetically old cortex: medial surface (archicortex, paleocortex)

- amygdala

- hippocampus

- uncus

- parahippocampal gyrus

- clinical: temporal lobe abnormalities frequently found in brains of schizophrenics



- temporal lobe: function in thought and perception

- damage associated with varying manifestation of disorders of thought, perception, emotion, memory

- sources of damage

- post-traumatic damage

- destruction following viral diseases (herpes, encephalitis)

- neoplasms

- cerebrovascular lesions

- manifestations

- organic psychosis

- delusions

- temporal lobe association with past experience

- Walter Penfield: surgeon who applied systematic electrical stimulation to awake humans (1950s)

- findings

- phenomena related to patient’s past experience (esp. visual, auditory hallucinations)

- unique to temporal lobe; virtually never occurred with electrical stimulation to other areas

- syndromes associated with temporal lobe deficits

- Capgras syndrome: belief that people they know have become imposters or changed faces

- temporal lobe epilepsy (TLE): disorder in which epileptic focus is in the temporal lobe

- generally lack motor convulsions associated with grand mal seizure

- altered mental state which may or may not be remembered, with variable manifestation

- hallucinations (auditory, olfactory, visual)

- illusions of memory

- deja vu

- familiarity of the unfamiliar

- feelings of emotion such as fear or pleasure

- associations with schizophrenia

- some association of TLE with schizophrenic-like psychosis

- study: 12 of 24 patients with EEG-based TLE diagnosis met criteria for schizophrenia

- hallucinations

- hallucination: false or mistaken idea

- perception without external stimulus that maintains compelling sense of reality

- types

Neuroscience: OBJECTIVES (page 106 of 117)







- visual

- auditory

- tactile

- olfactory

- gustatory

- associated with several psychiatric disorders, including schizophrenia

- neuroanatomical correlation

- changes in temporal lobe glucose metabolism, esp. left hemisphere over auditory area

- delayed auditory evoked action potentials during hallucinations

- associated with auditory cortex, not brainstem potential

- relevance: found in normal experimental subjects distracted by non-target sounds

- reduction in temporal lobe volume, varying with severity of hallucinations



VTA-mesocorticolimbic system

- dopamine systems

- origin: ventral tegmental area (midbrain)

- target: other components of the mesocorticolimbic system

- prefrontal cortex

- limbic structures

- temporal lobe



- implication of dopamine system in abnormal thought and perception

- dopaminomimetic drugs:

- exacerbate pre-existing psychotic symptoms

- induce psychotic symptoms in normal individuals

- antipsychotic medications: all work by blocking dopamine receptors



- dopaminomimetic drugs: drugs that mimic the action of dopamine (amphetamine, cocaine, L-DOPA)

- L-DOPA

- clinical: Parkinson’s disease: alleviates motor symptoms

- origin: metabolic precursor of dopamine

- mechanism: functionally increases CNS dopamine levels

- side effects: behavioral disturbance due to psychotic symptoms

- amphetamine, cocaine

- clinical: produce psychotic symptoms similar to schizophrenia when taken in high doses

- mechanism: competitively binds nucleus accumbens dopamine reuptake site, increasing synaptic DA

- dopamine may be associated with attention to salient events

- overactivity may produce attention abnormalities

- stimuli which would normally be ignored are interpreted as salient

- this would explain many of the delusions of schizophrenics

- antipsychotic effect of dopamine blockers

- chlorpromazine (Thorazine): first antipsychotic drug

- introduced in the 1950s

- mechanism: dopamine antagonist

- neuroleptic: effective in reducing or eliminating thought disorder, delusions, and hallucinations

- D2 receptor: dopamine receptor subtype targeted by antipsychotic medications

- receptor localization

- D1 receptors: striatal cells projecting to the internal segment of the GP (direct pathway)

- D2 receptors: striatal cells projecting to the external segment of the GP (indirect pathway)

- clinical potency

- correlation between antipsychotic clinical potency and D2 receptor affinity

- no similar correlation to binding serotonergic, adrenergic, histaminergic, or D1 receptors



schizophrenia

- schizophrenia: psychiatric disorder related to perceptual difficulties

- symptoms

Neuroscience: OBJECTIVES (page 107 of 117)







- disorder in thought

- disorganization

- perservation

- inability to formulate or sustain plans

- emotional blunting

- lability: gliding, moving from point to point over the surface, unstable, fluctuating

- psychosis

- hallucinations

- paranoia

- delusions

- perceptual abnormalities

- defects associated with schizophrenia: areas of thought and perception

- prefrontal cortex

- temporal lobe

- dopaminergic systems

- brain abnormalities

- ventricular enlargement: especially evident in temporal horn of lateral ventricle

- indicative of atrophy

- not pathognomic (characteristic or diagnostic) to schizophrenia

- gross volume changes: reduced size of temporal lobe structures

- localization: can be bilateral, but are more commonly found in the left hemisphere

- severity of psychosis correlated with severity of psychotic symptoms

- likely related to the schizophrenic disorganization of thought and language

- cytoarchitectural changes: frontal, temporal (limbic) regions

- example: parahippocampal gyrus have incorrect cellular arrangement and location relative to layers

- schizophrenia may represent a genetically-influenced disturbance of neural migration









Consciousness

- consciousness: awareness/perception of self and environment

- definitions

- wakefulness

- self-awareness, awareness of environment

- working memory and memory retrieval

- decision-making

- thought

- state in which we can respond appropriately to our environment

- condition of self-awareness that includes abstract thought processing

- electroencephalogram (EEG) as a measurement of consciousness

- stage 3-4 sleep: delta 0-4 Hz

- drowsiness: theta 4-8 Hz

- awake, eyes open: alpha 8-13 Hz

- awake, eyes closed: beta 13-25 Hz

- perception: gamma >25 Hz

- importance of the thalamus

- modes of firing

- awake: transfer mode (tonic) steady trains of spikes

- asleep: burst mode (hyperpolarized) slow bursts of action potentials

- certain neurotransmitters control movement between modes

- norepinergic: locus coruleus (LC-NE)

- cholinergic: medial septal nucleus, pedunculopontine tegmental (PPT)

- serotonergic: median raphe nucleus (dorsal raphe-serotonin)

Neuroscience: OBJECTIVES (page 108 of 117)







- GABAergic: reticular thalamic nucleus

- glutamatergic: thalamocortical



coma: pathologic unconsciousness

- coma: condition of unconsciousness from which a patient cannot be aroused

- stupor: condition in which patient arouses but quickly falls back to unconsciousness

- anatomy of coma involves dysfunction of one of:

- bilateral cerebrum

- thalamus (diencephalic)

- ascending reticular activating system (ARAS)

- etiology of coma

- metabolic derangement: (66%)

- drug overdose

- GABAA: barbituates, alcohol (enhance an inhibitory neurotransmitter)

- anticholinergic: opiates (reduces cholinergic drive on thalamic and cortical neurons)

- endogenous metabolic abnormalities

- encephalopathy following hypoxia (due to organ failure)

- electrolyte or glucose disturbances

- brainstem lesion

- types

- supratentorial: (20%)

- mass lesion

- hemorrhage, infarction, tumor

- subtentorial: (14%)

- ischemic

- mass lesion

- etiology: coma results from injury to the ARAS

- locked-in syndrome: lesion of the ventral pons that bilaterally cuts off corticospinal, corticobulbar tracts

- spares ARAS, as that travels in the tegmentum

- EEG: normal with sleep-wake cycles (lack of damage to ARAS)

- importance: false anesthesia

localizing coma pathology

- motor posturing

- decorticate rigidity

- posturing

- flexion of arms

- extension of legs

- plantar flexion of feet

- lesion: localized above red nucleus

- decerebrate rigidity

- posturing

- extension of arms

- extension of legs

- plantar flexion of feet

- lesion: localized between mid-collicular level and CN VIII

- doll’s eyes: fixed direction of the pupils (eyes stay forward despite turning the head)

- coursebook scenarios

- A: scenario: subarachnoid hematoma diffusely affecting thalamus and hypothalamus

- posturing: decorticate

- pupils: constricted but reactive

- calorics: normal movement, loss of snap back

- eyes: doll’s eyes

- B: scenario: compression and death to deeper structures, pushing on midbrain

- posturing: decorticate/decerebrate

- pupils: fixed

- calorics: unilateral loss of adduction (damage to CN III removing medial rectus)

Neuroscience: OBJECTIVES (page 109 of 117)







- eyes: no doll’s eyes

- C: scenario: lesion localized at junction of superior, inferior colliculus

- posturing: decerebrate

- pupils: fixed

- calorics: unilateral loss of adduction (damage to CN III removing medial rectus)

- eyes: no doll’s eyes

- D: scenario: lesion extends into medulla

- posturing: no extreme posturing (mechanism unknown)

- pupils: fixed

- calorics: absent

- eyes: no doll’s eyes

syndromes associated with coma

- central herniation syndrome

- diffuse mass effect with rostral to caudal deterioration

- stages

- diencephalic

- midbrain-upper pons

- lower pontine-upper medullary

- medullary

- uncal herniation syndrome

- etiology: supratentorial pressure

- uncus and medial temporal lobe structures herniate into tentorial notch

- Kernohan’s notch: compression of contralateral cerebral peduncle against tentorial notch

- Duret hemorrhages: damage to basilar artery penetration branches

- twisting, compression, or stretching of the brain stem

- resulting damage can leave certain brain stem areas ischemic

- stages

- early third nerve stage

- contralateral hemiparesis

- pupillary asymmetry

- late third nerve stage

- dysconjugate gaze

- pupillary reflex loss

- may develop ipsilateral hemiparesis

- midbrain-upper pons

- bilateral pupillary loss

- quadriplegia



brain death

- brain death: lack of any cortical or brain stem function

- diagnosis

- proximate cause known, irreversible

- comatose

- absent brainstem reflexes

- absent pain response

- complete apnea (lack of breathing)

- clinical diagnosis from exam

- lack of hypothermia

- lack of medications that could depress brain stem reflexes (curare, barbiturates, anesthetics)

- confirmatory lab tests

- no cerebral blood flow

- EEG without cerebral activity

- absent somatosensory evoked potentials

- testing for respiratory drive

- disconnect ventilator

- deliver 100% O2 to the distal trachea (through intubation)

Neuroscience: OBJECTIVES (page 110 of 117)







- function: respiratory drive should kick in if any is left

- maintains oxygenation

- allows CO2 buildup

- testing brainstem reflexes

- pupillary: in on II, out on III

- normal: direct, consensual response of the pupil

- brain dead: neither pupil reacts to light, pupils in midposition

- corneal: in on V, out on VII

- normal: bilateral contraction of orbicularis oculi upon contact with eyeball

- brain dead: absent bilaterally

- vestibul-ocular: in on VIII, out on III/VI/VOR

- normal: characteristic eye movements upon caloric irrigation of ear

- brain dead: no movements of either eye

- pharyngeal: in on IX, out on X

- normal: gag reflex

- brain dead: no gag reflex



persistent vegetative state

- persistent vegetative state: complete unawareness of self and environment with persistence of vegetative functions

- characteristics

- no evidence of awareness of self or environment

- no evidence of purposeful behavior

- presence of sleep-wake cycles

- bowel and bladder incontinence, but other autonomic function persists

- variable preservation of cranial nerve, spinal cord reflexes

- diagnosis

- persistent vegetative state: criteria met for 1 month

- permanent persistent vegetative state non-traumatic: criteria met for 3 months

traumatic: criteria met for 12 months

- etiology

- acute traumatic injury

- acute non-traumatic injury

- degenerative and metabolic disorders

- severe developmental malformations

- pathology: frequently results from damage to the cortex with relative preservation of hypothalamus, brain stem

- legal precedents

- Karen Ann Quinlan, 1976: guardians can withdraw ventilatory support

- Nancy Cruzan, 1990: guardians can withdraw water and feeding tube

- Terri Schiavo, 2005: guardians can still withdraw water and feeding tube

spouse in Florida is still the guardian

the Republican-controlled United States Congress can:

- make a law regarding treatment of a single person if it might be politically useful

- threaten violence against judges who do not decide their way

- interfere in what should be a very private, family matter



TABLE: Summary of Pathologies of Perception

coma brain death persistent locked-in syndrome

vegetative state

wakefulness – – + +

attention – – – +

memory – – – +

cognition – – – +

EEG abnormal silent abnormal normal

(wide range) (slow)

respiration variable absent normal usually normal

Neuroscience: OBJECTIVES (page 111 of 117)







(may be depressed)

sleep-wake cycle – – + +









Epilepsy

anatomic and physiologic correlates

- seizure

- definition: phenomenon of abnormal synchronization of cortical neurons

- prevalence: 8% at some point during life

- symptoms: alteration in:

- awareness

- perception

- motor control

- epilepsy

- definition: chronic recurrent seizures resulting from an inherent problem with brain hyperexcitability

- prevalence: epilepsy: 1%

intractible epilepsy: 0.5%

- onset: varies with age

- age of onset: prevalence declines with age

- adult onset: may be more severe due to reduced plasticity of the brain

- etiology: varies with age

- early: perinatal injury, metabolic defect, congenital malformation

- late: brain tumor, vascular disease



classification

- significance of classification: differences in

- pathophysiology

- treatment

- prognosis



- classification by cause

- non-recurrent seizure

- drug-related (cocaine, alcohol withdrawal)

- syncopal

- metabolic

- low glucose

- low calcium

- hepatic or renal failure

- toxic

- poison

- infectious

- febrile

- recurrent (epilepsy)

- symptomatic: secondary

- idiopathic: primary

- classification by localization

- partial (focal): begin in a single area of the brain

- simple partial: consciousness unaffected, symptoms refer to cortex involved

- complex partial: consciousness impaired, amnesia

- 2° generalized: consciousness impaired, bilateral cerebral involvement

- generalized: begin bilaterally

- tonic

Neuroscience: OBJECTIVES (page 112 of 117)







- tonic-clonic

- clonic: repetitive motion with 2 phases (fast, slow)

- absence: staring/unresponsive

- myoclonic: fast jerks with intervals

- atonic: sudden loss of body tone (requires wearing a helmet)



study of epilepsy and seizures

- methods

- electroencephalography (EEG)

- video electroencephalography

- metabolic and genetic studies

- neuroimaging

- magnetic resonance imaging (MRI)

- functional MRI

- positron emission tomography

- neuropsychology

- animal models

- EEG findings

- partial seizures: associated with underlying regions of abnormal cortical excitability

- intrerictal (between seizure or ictus) spike or sharp wave localized to a region of scalp

- during seizure: more sustained abnormal rhythm consisting of rhythmic slow and spike activity

- absence seizures: associated with spike wave activity

- thalamocortical pathways in seizure are identical to those mediating sleep-wake cycles

- generators of sleep spindle activity lead to absence seizures

- untreated: few spindles, replaced by spike wave activity

- treated: normal spindle activity

treatment

- seizure onset: imbalance of synaptic inhibition and excitation

- treatment of generalized seizures

- etiology: imbalance of thalamocortical circuitry

- treatment: ethosuximide: reduces low threshold Ca2+ currents

- treatment of partial seizures

- etiology: imbalance of a specific cortical area

- treatment: decrease ability of neurons to fire high rate action potentials (phenytoin, carbamazepine)

increase inhibition by GABA enhancement (phenobarbital, diazepam)









DRUG SUMMARY

- atropine: anticholinergic drug used in sedation

- tricyclics: anticholinergic antidepressant used in sedation, anti-depression

- neostigmine: anticholinesterase inhibitor that enhances arousal

- benzodiazepine: GABA-ergic drug used in sleep disorders

- naltrexone: opiate blocker that can reduce palatability of food without reducing hunger drive

- Aricept: anticholinesterase inhibitor

- yohimbine: α2-NE receptor antagonist that can mimic a panic attack

- clonidine: α2-NE receptor agonist that reduces panic attack (and firing of LC neurons)

- reserpine: antihypertensive agent now known to deplete monoamines and cause depression

- reboxetine (mesylate): selective norepinephrine reuptake inhibitors (SNRIs)

- chlorpromazine (Thorazine): first neuroleptic (antipsychotic drug), works as a dopamine antagonist

- phenytoin, carbamazepine: anti-seizure medications that decrease high rate firing of action potentials

- phenobarbital, diazepam: anti-seizure medications that enhance GABA

Neuroscience: OBJECTIVES (page 113 of 117)









SELF-LEARNING: Brain Tumors

overview: tumors of brain parenchymal cells

- tumor growth: generally, the more primitive the cell type, the faster the growth

- cell types giving rise to most brain tissue tumors

- astrocytes

- oligodendroglia

- ependymal cells

- neurons

- grading system

- four level (I – IV) grading scale

- highest grades: highest malignant changes

- evidence of malignancy

- increased cellularity

- pleomorphism of cells (including bizarre and giant forms)

- hyperchromasia of nuclei

- presence of immature cells

- vascular proliferation

- in fast-growing tumors (e.g. glioblastoma multiform), can actually decrease nutrition of tumor

- addition of numerous small vessels increases resistance to flow

- necrosis

- typing: highest malignancy seen in astrocytomas

- three level grading scale

- same structure as four level

- combines two levels into one

- maturation scale

- stresses resemblance of neoplastic cells to normal cells at various stages of maturity

- example: astrocytotic series of increasing malignancy (decreasing maturity)

- astrocytoma

- anaplastic astroctyoma

- glioblastoma multiforme

- incidence (parenchymal tumors)

- glioblastoma multiform: 55%

- astrocytoma: 20%

- ependymoma: 6%

- medulloblastoma: 6%

- oligodendroma: 5%

- other: 8%



glial tumors

astrocytoma

- incidence: primarily found in adults

leading primary brain tumor in children

- localization: anywhere in the CNS

- adults: most frequently seen in anterior half of cerebrum

- children: most frequently seen in posterior fossa, hypothalamus

- course: grade I-II (astrocytoma): several years

grade III (anaplastic astrocytoma): < 1 year

grade IV (glioblastoma multiform): < 1 year

- malignance: all forms can be relatively malignant

- virtually always invasive

- display uncontrolled growth

- histology: fibrillary astrocytoma

Neuroscience: OBJECTIVES (page 114 of 117)







- growth: slow (grade I)

- appearance: normal astrocytes with uniform, oval, vesicular nuclei and fibrillar cell processes

- pathology: only pathology is increased cellularity

protoplasmic astrocytoma

- growth: slow

- appearance: cystic degeneration of the cytoplasm, with decreased prominence of processes

cystic cerebellar astrocytoma

- growth: slow

- appearance: elongated, neoplastic astrocytes (pilloid)

- pathology: such localization permits easy excision, as opposed to other pilloid astrocytomas

pilloid astrocytomas

- growth: slow (but can manifest signs of higher malignancy)

- appearance: Rosenthal fibers (worm-like eosinophilic bundles)

oval granular eosinophilic bodies

anaplastic astrocytoma

- growth: rapid (grade III)

- appearance: bizarre, dark, irregular nuclei

evidence of vascular proliferation

glioblastoma

- growth: rapid (grade IV)

- appearance: similar signs to anaplastic astrocytoma

pseudopalisading: presence of necrotic tissue (due to outgrowing blood supply)



ependymoma

- incidence: primarily found in children and adolescents

- 6% of all neuroectodermal tumors

- most common glioma in the spinal cord and filum terminale

- localization: anywhere in the ventricular system of central canal

- frequently found in the fourth ventricle (may result in non-communicating hydrocephalus)

- histology: tapering shape: “ice cream cone,” “tadpole,” “carrot cells”

true rosettes: arrangement of cells in miniature ventricles

pseudorosettes: nuclear free cell arrangement around blood vessels



choroid plexus papilloma

- malignance: generally benign

related to ependymoma

- histology: choroid plexus tumor



colloid cyst

- localization: ventricular

- pathology: can cause death with obstruction of the ventricles

- sudden increase in intracranial pressure

- due to presence on stalk, can intermittently cause obstruction

- histology: resembles bronchial mucosa (formerly thought to be related to ependymoma, choroid plexus



oligodendroma

- incidence: 5% of neuroectodermal tumors

primarily found in middle-aged adults

- pathology: mean 5-year survival

- histology: uniform appearance (“fried egg,” “fish eye”)

appearance depends on fixation, and may not be seen immediately in frozen tissue

distinct cell membranes

compartmentalized by blood vessels (“chicken wire”)

tendency to calcify



neuronal tumors

Neuroscience: OBJECTIVES (page 115 of 117)







medulloblastoma

- incidence: highest during first decade of life

additional peak in young adulthood

- tend to be more laterally placed

- have an overall better prognosis

- localization: posterior fossa (midline of the cerebellum)

- origin: migrating neuroblasts that have arrested in the roof of the 4 th ventricle

- accounts for the midline migration of many

cells of the external granular layer of the immature cerebellum

- due to inward migration, layer disappears by second year of life

- explains high incidence during first decade of life

- prognosis: poor

- cells have a tendency to migrate up and down the CSF pathway

- can be improved by heavy, total neuraxis irradiation

- histology: highly cellular sheets that resemble the normal granular cerebellar cortex



meningeal tumors

meningioma

- etiology: tumor growing from the dura mater impinging on neural tissue

- 18% of all intracranial neoplasms

- 25% of all intraspinal neoplasms

- incidence: most common tumor in adults

peaks at 45 years

females 2X more likely to be symptomatic

- localization: most common in parasaggital region

- symptoms: intracranial:

- headaches

- seizures

intraspinal:

- weakness

- sensation deficits

- treatment: surgical excision

- grow slowly, rarely malignant

- will readily recur if not completely removed

- histology: meningothelial whorle









SELF-LEARNING: Integrative Disorders

hydrocephalus

- etiology: increased levels of CSF causing stretching of brain structures

- communicating: difficulty in CSF reabsorption in subarachnoid space

- non-communicating: obstruction in ventricular system, inability to enter subarachnoid space

- symptoms: headaches: meningeal stretching

incoordination: CN VI stretching, cerebellar distortion

incontinence: frontal lobe distortion/stretching

dementia: frontal lobe distortion/stretching



epidural hematoma

- etiology: tearing of middle meningeal artery (frequently due to trauma)

- symptoms: pupillary defects

loss of consciousness

numerous high level defects

Neuroscience: OBJECTIVES (page 116 of 117)







- progression: generalized brain edema

uncal herniation

brain stem destruction

- diagnosis: lens-shaped MRI (high pressure)



subdural hematoma

- etiology: tearing of subarachnoid veins

- frequently due to trauma

- common in elderly patients, even with no history of head trauma

- symptoms: similar to epidural, but with slower progression

- diagnosis: quarter moon-shaped MRI (lower pressure)



subacute combined degeneration

- etiology: demyelination of dorsal column system, LCST

- thiamine/B12 problem

- can also affect myelin of optic nerves, hippocampus

- symptoms: incoordination and balance

UMN symptoms

memory problems

vision problems



Meniere’s disease (hydrops)

- etiology: underlying cause unknown

- pathology: blockage of the endolymphatic duct drainage system, causing dilated membranous labyrinth

- symptoms: early: low tone sensorineural hearing loss

middle: reduced hearing at all frequencies, but especially low or high



benign paroxymal positional vertigo (BPPV)

- etiology: head injury

stroke of the anterior inferior cerebellar artery

- pathology detachment and translocation of utricle/saccule ear stones to the semicircular canals

- symptoms: vestibular symptoms (vertigo, unexplained feelings of falling)

precipitated by changes in head position with respect to gravity (e.g. shaving under chin)

- incidence: older people (degenerating vestibular system)



diabetic aneurism

- symptoms: spares pupil

- autonomic fibers lie peripherally

- diabetes affects central axons



saccular (berry) aneurism

- origin: posterior communicating artery: 40%

middle cerebral artery: 34%

anterior cerebral artery: 30%

posterior cerebral artery: 4%

- incidence: more commonly found in adults

- more common in women (3:2 margin)

- all ethnic groups affected

first degree relatives (esp. siblings) have a 4X greater risk

recurrence risk: 6X more likely

associated with smoking

- pathology: 35-40% of saccular aneurisms rupture at some time



lateral medullary (Wallenberg) syndrome (or PICA syndrome)

- etiology: blowout of the posterior inferior cerebellar artery

- affects medulla at the level of the inferior olive

Neuroscience: OBJECTIVES (page 117 of 117)







- symptoms: ipsilateral loss of pain and temperature from the face (CN V)

contralateral loss of pain and temperature from the body (ALS)

ipsilateral Horner’s syndrome (descending hypothalamics)

contralateral deviation of the uvula (nucleus ambiguus)





TABLE: Clinically Irrelevant Chromosomes to Memorize and Soon Forget

disorder implicated gene implicated chromosome

Parkinson’s disease --- chromosome 8

Huntington’s disorder IT15 chromosome 4

acoustic neuroma NF2 chromosome 22

Alzheimer’s disease amyloid precursor protein chromosome 21

- early onset presenilin 1 chromosome 14

presenilin 2 chromsome 1

- late onset apolipoprotein E chromosome 19