Selective ablation of nociceptive neurons for elimination ...contents.kocw.net/KOCW/document/2014/gacheon/chohwiyoung/9.pdf · • Spinal cord 16 years after injury. Three spinal

CH 11. 척수손상에

의한 통증 중재 - 1

Hwi-young Cho, PT, Ph.D

Gachon University. College of Healthscience. Depart of Physical Therapy.

(Pre) Korea University. College of Medicine. Depart of Physiology.

(Pre) Part-time instructor at Department of Physical therapy in Korea &

Sahmyook Univ. Graduate school

Course schedule

• Anatomy & Physiology

• Neuroscience

• Pathophysiology

• Symptoms following SCI

• Target strategies for SCI

Spinal Cord Injury (SCI)

• An SCI occurs when the spinal cord is damaged

as a result of trauma, disease, or congenital

defects

• Spinal cord = bridge from periphery to the Brain

• Nervous system

http://www.surgicalneurologyint.com/article.asp?issn=2152-7806;year=2011;volume=2;issue=1;spage=156;epage=156;aulast=Ogungbo

http://www.meditouch.co.il/en/Spinal-Cord-Injury





• Spinal cord 16 years after injury. Three spinal segments are telescoped into the space of one. The center of the scar is connective tissue which is invaded by regenerating fibers from the dorsal roots.

• Cervical spinal cord above a complete transverse traumatic lesion showing ascending degeneration in the dorsal (posterior) columns and spinal cerebellar and spinothalamic tracts.

Left: Dorsal view of spinal cord

with fracture-dislocation at

the T12-L1 junction which

crushed the lumbar cord.

Top Right: Longitudinal

section showing site of direct

cord trauma and rostral and

caudal hemorrhagic

extension.

Bottom Right: Twelve

transverse sections through

the cervical and thoracic

cord. The third rows from

the left show almost

complete hemorrhagic

necrosis. Hemorrhages can

be seen in the grey matter in

other blocks for several

centimeters.

Christopher Reeve

• 1995 (age 42), suffered from

a fall off a horse

• Was totally paralyzed

(tetraplegia) from a

complete C1/C2 injury

• Died October 2004 from a

pressure sore

http://www.IMDB.com

http://www.imdb.com/gallery/mptv/1337/5422_0123.jpg.html?seq=2

Demographics (1)

• 82% male

• 50% between 15-24 y/o

• 80% < 40 y/o

Demographics (2)

• Incidence (new cases/year)

• USA : 11,000

• Worldwide : 3,000,000

• Prevalence

• USA : 700,000

• Korea : 150,000

• Advanced medical technology

• Survival rate ↑

• SCI pt. = lifelong

Accumulate SCI pt

Increased Life Expectancy with Spinal Cord

Injury due to Improved Patient Management

World War II: 3 months

1958: 3 years

1966: 20 years

1980: 21 years

Current: 27 +

Cause of Death: In the past-renal failure; Current-

cardiac failure, pneumonia, pulmonary emboli

and septicemia.

Therefore, we can turn our attention to therapeutic

opportunities to increase function after SCI.

Falls

21%

Sports

8%

Other:

8%

Vehicular

Accidents

41%

Violence

22%

SPINAL CORD INJURIES

Source: National Spinal Cord Injury Statistical Center

Car Crashes: 83%

Motorcycle incidents: 10%

Bicycle accidents: 3%

Diving: 55% Snow skiing: 8%

Surfing: 6%

Gunshot: 92% Personal Contact: 6%

SCI can occur from these causes..

• Trauma : automobile crashes, falls, gunshots, diving

accidents etc..

• Tumor : meningiomas, ependymomas, astrocytomas

• Ischemia : occlusion of spinal blood vessels, including

dissecting aortic aneurysms, emboli, arteriosclerosis

• Developmental disorders : spina bifida, meningomyolcoele

• Neurodegenerative diseases : Friedreich's ataxia,

spinocerebellar ataxia

• Demyelinative diseases : Multiple Sclerosis

• Vascular malformations : arteriovenous malformation

(AVM), dural arteriovenous fistula (AVF), spinal

hemangioma, cavernous angioma and aneurysm

Quality of Life Issues Targeted by Patients

of Spinal Cord Injury

1. Bowel and bladder control

2. Pain management

3. Hand use if limited

4. Improved locomotor function

Restorative treatments will be incremental; thus, both basic

and clinical measures need to be refined to be able to

detect the interventions that are successful.

Live & Lifelong Needs of SCI

• Medical doctor

• Physical therapist

• Occupational therapist

• Psychosocial

• Financial

• Vocational

• Social Functioning

The recent trend of Rehab

• Physical therapy

• Occupational therapy

• Human engineering (=Ergonomics)

• National institute

• Private research company

Virtual Reality

http://master.design.zhdk.ch/projekte/a-physiotherapeutic-

video-game-for-children

Assistive Robotic Manipulator (Netherland)

WAM Arm (USA, Barrett Tech Inc.)

The Latest Trends for SCI Tx

• Cell Therapy approach

Stem cells

Embryonic stem cell

Fetal stem cell

Neural stem cell

Induced pluripotent cell

Et al..

USA 캘리포니아주의 CIRM (3조원)

역분화 줄기세포연구: Harvard, MIT

배아줄기세포 임상연구: UC Irvine, Geron Inc

EU 8개국 11개 연구기관 공동참여

영국 UK Stem Cell Initiative (약 2조원)

Japan Milenium Project로 세포치료 선정 (200억원)

고베시 재생의료 클러스터 조성

Kyoto Univ. 역분화 연구 지원 (연간 550억원)

Pharmaceutical

Industry

Pifzer: 스웨덴 연구팀과 공동연구 협약

Roche: 미국 DCI사와 줄기세포 약물스크리닝 개발

AstraZeneca, GSK, Roche: SC4SM 컨소시엄 구축

GSK: 하버드 줄기세포 연구소에 5년간 최소 2500

만 달러 투자

생명공학 정책 연구센터 BT 기술동향 보고서, 2008

NYU

impactor

Animal

preparation

Cord

exposure

Impact

loading

Intracerebral

Intravenous (tail vein) Intra-arterial Intra-thecal

(A) (B) (C) (D)

Caudal Rostral

(E)

F3.BDNF

characteristics

Neural Mature

Marker

Neural

Immature

Marker

: Mature

potency

Immortalization

Inflammation Gliosis Apoptosis Endogenous neurogenesis

NSC

My Suggestion!

• Additional PT & OT intervention with Stem

cell therapy.

Physical rehab may boost the recovery of physical

functions following stem cell therapy.

• Limitation

• Required the suitable Subjects involving Stem cell

therapy.

Anatomy & Physiology

Spinal architecture

&

Spinal cord

http://www.17daydiets.com/search/spinal-nerves

http://www.merckmanuals.com/home/brain_spinal_cord_and_nerve_disorders/biology_of_the_nervous_system/spinal_cord.html

http://www.merckmanuals.com/home/brain_spinal_cord_and_nerve_disorders/spinal_cord_disorders/overview_of_spinal_cord_disorders.html

In vertebrates

1st defense

• The Brain = bony skull (Cranium)

• The spinal cord = vertebral column

2nd defense

• Meninges

1. The Dura matter

• Thick

• Veins

2. The Arachnoid membrane

• Loosely tied to the Pia

3. The Pia matter

• Adheres to CNS

• Arteries

3rd defense

• Extracellular fluids : cushion

Final : BBB

http://apbrwww5.apsu.edu/thompsonj/Anatomy%20&%20Physiology/2010/2010%20Exam%20Reviews/Exam%204%2

0Review/CH%2012%20Gross%20Anatomy%20of%20the%20Spinal%20Cord.htm

2nd defense

1st defense

3 Meningeal layers

2nd defense

http://www.pennmedicine.org/encyclopedia/em_DisplayImage.aspx?gcid=19088&ptid=2

http://apbrwww5.apsu.edu/thompsonj/Anatomy%20&%20Physiology/2010/2010%20Exam%20Reviews/Exam%204%20Review/CH%2012%20Gross%20Anatomy%20of%20the%20Spinal%20Cord.htm

http://apbrwww5.apsu.edu/thompsonj/Anatomy%20&%20Physiology/2010/2010%20Exam%20Reviews/Exam%2

04%20Review/CH%2012%20Gross%20Anatomy%20of%20the%20Spinal%20Cord.htm

3rd defense

• Extracellular fluids

• Cranium = 1.4 L (fluid = ICF + ECF)

• The cell = 1L

• Extracellular fluids

• The blood = 100 – 150 ml

• The cerebrospinal fluids & interstitial fluids = 250 – 300 ml

• Form the extracellular environment for neurons.

Extracellular fluids in CNS

• The cerebrospinal fluids & interstitial fluids

1. The cerebrospinal fluids (CSF)

• In the ventricles & between the pia & arachnoid space

• A salty solution that is continuously secreted by the chroid

plexus(vnetricle).

2. Interstitial fluids

• Inside the pia mater

The cerebrospinal fluids (CSF)

• Flow sequence

• Ventricle → subarachnoid space → flows around

the neural tissues → absorbed back into the blood

by villi on arachnoid membrane

• Purpose

1. Physical protection

2. Chemical protection

1. Physical protection

• Buoyancy

• ↓ the weight of brain nearly 30 fold

• Less pressure on blood vessels & nerves

• Protective padding

• Tofu in an empty jar VS Tofu in a jar completely

filled with water

Cerebral Ventricles

http://www.lookfordiagnosis.com/mesh_info.php?term=Cerebral+Ventricles&lang=1

http://apbrwww5.apsu.edu/thompsonj/Anatomy%20&%20Physiology/2010/2010%20Exam%20Reviews/Exam%204%20Revie

w/CH%2012%20Cerebrospinal%20Fluid.htm

Cerebrospinal

circulation

http://www.mananatomy.com/body-systems/nervous-system/ventricular-system-brain

2. Chemical protection

• Closely regulation

• Choroid plexus

• Composition

• K, Ca, HCO, glucose level : ↓

• H : ↑

• Na : similar to the blood

• Very little protein & no blood cells

Choroid plexus (맥락막총)

http://searchpp.com/choroid-

plexus/classconnection.s3.amazonaws.com*183*flashcards*799622*png*choroid-

plexus.png/imgarcade.com*1*choroidplexus/

http://www.corpshumain.ca/en/Cerveau3_en.php

Final defense : BBB

• Blood brain barrier

• Between the interstitial fluid & the blood

• Protection from pathogens such as bacteria

• Brain capillary

• Selective permeability : hormones, ions and NTs

• Tight junction

Cerebrospinal fluid Clear

50-200 mm H2O pressure

0-10 WBC 0 RBC

< 45 mg/100 ml protein glucose 2/3 blood level 50-80 mg/100 ml

Dural sac ends at vert. S1-S2

Spinal tap done at L3-L4

http://slvshade.tistory.com/168

http://slvshade.tistory.com/168

Blood supply

• Paired spinal arteries

• branch off the vertebral, cervical, thoracic, and lumbar arteries

• Travel through the intervertebral foramina, split into anterior and posterior arteries

http://www.frca.co.uk/article.aspx?articleid=100360

http://www.frca.co.uk/article.aspx

?articleid=100360

Anatomy Review

• Cervical Spine

• 7 vertebrae

• very flexible

• C1: also known as the atlas

• C2: also known as the axis

• Thoracic Spine

• 12 vertebrae

• ribs connected to spine

• provides rigid framework of thorax

Anatomy Review

• Lumbar Spine

• 5 vertebrae

• largest vertebral bodies

• carries most of the body’s weight

• Sacrum

• 5 fused vertebrae

• common to spine and pelvis

• Coccyx

• 4 fused vertebrae

• “tailbone”

Anatomy Review

Vertebral body •posterior portion forms part of

vertebral foramen

•increases in size from cervical to

sacral

•spinous process

•transverse process

Vertebral foramen •opening for spinal cord

Intervertebral disk •shock absorber (fibrocartilage) http://biology.stackexchange.com/questions/20427/difference-between-

intervertebral-and-vertebral-foramina

http://en.wikipedia.org/wiki/Nervous_system#mediaviewer/File:NSdiagram.svg

Autonomic Nerve System

http://wiki.bethanycrane.com/somaticautonomicnervoussystems

http://howmed.net/wp-content/uploads/2010/09/functions-of-autonomic-nervous-system.bmp

http://howmed.net/wp-content/uploads/2010/09/functions-of-ans-cont..bmp

Origin from CNS & location of autonomic

ganglia

Sympathetic

• Origin : thoracic &

lumbar

• Ganglia : close to spinal

cord

• Pre : short

• Post : long

Parasympathetic

• Origin : brain stem,

cervical & sacral region

• Ganglia : near target

organ

• Pre : long

• Post : short

• 75% : vagus n. (Ⅹ)

• Stability

Vagus nerve

http://www.netterimages.com/image/4620.htm

Redistribution of Blood Flow During Exercise

Changes in Oxygen Delivery to Muscle During Exercise

1.25 ℓ

1.25 ℓ 1 ℓ 1 ℓ

1.25 ℓ 0.25 ℓ 1 ℓ 0.75 ℓ

Spinal Cord & Spinal Nerves

• Spinal nerves begin as

roots

1. Dorsal or posterior root is

incoming sensory fibers

• dorsal root ganglion =

cell bodies of sensory

nerves

2. Ventral or anterior root is

outgoing motor fibers

Posterior

Root

(Sensory)

Anterior

Root

(Motor)

Direction of

Information flow in neurons

• Sensory/Afferent neurons

; conduct impulses into

CNS

• Motor/Efferent neurons

; carry impulses out of CNS

• Association/ Interneurons

; integrate NS activity

• Located entirely inside

CNS http://en.wikipedia.org/wiki/Afferent_nerve_fiber#mediaviewer/File:A

fferent_(PSF).png

Neuroscience

Neuron

Spinal cord

Copyright © 2005 Pearson

Education, Inc., publishing as

Benjamin Cummings.

Organization of the Nervous System

Structures of a neuron

1) Cell body ( = perikaryon or soma)

2) Dendrites (the receiving end) :

3) Axon (the outgoing end) :

* Axon hillock

4) Presynaptic terminals

http://www.enchantedlearning.com/subjects/anatomy/brain/Neuron.shtml

Neurons and Synapses

Types of Neurons

Sensory Motor Interneurons

Neuron

- Electrically excitable

- Receive information

- Generation & propagation of action potential

- Neurotransmitter release : communicate with other neuron

http://www.wpclipart.com/medical/anatomy/cells/neuron/neuron.png.html

How neurons communicate

• Neurons communicate by means of an electrical signal

called the Action Potential

• Action Potentials are based on movements of ions be-

tween the outside and inside of the cell

• When an Action Potential occurs, a molecular message is

sent to neighboring neurons

Action potentials Synaptic potentials

Voltage Gated Na+ CH

http://www.slideshare.net/schwartzcm/ch-8-neurons-9-11


3 : Threshold -45 mV = voltage-

gated Na+ CH open

5 : voltage-gated

Na+ CH

inactivated gate

close & voltage K+

CH open http://www.slideshare.net/schwartzcm/ch-8-neurons-9-11





Synapse

• Synapse (place)

• Neural communication

• Electrical current & chemical transfer (method)

• Dz & disorder in order to synaptic

communication

• Disrupt neural function (nerve-muscle signaling)

Structure of the synapse

1. Presynaptic terminal

The end of the axon

A projection specialized for the release of chemicals

Contain vehicle : neurotransmitters(NT)

NT : transmit information

2. Postsynaptic terminal

The membrane region of the receiving cell

3. Synaptic cleft

The space between the two terminals

Synapse

• Two basic forms;

• Electrical synapse; rapid and stereotyped

• Chemical synapse;

http://pixshark.com/che

mical-synapses.htm

Electrical synapse

http://en.wikipedia.org/wiki/Electrical_synapse#mediaviewer/File:Gap_cell_junction-en.svg

Chemical synapse

http://pixshark.com/chemical-synapses.htm

Neurotransmitters produce diverse postsynaptic

responses

• Transmitters (information transport)

• 3 styles of receptor-channel coupling

• Ionotropic

• Metabotropic

• Activating a cascade of intracellular events

• Amino acid neurotransmitters produce fast PSPs

• Amine and peptides are slower neuromodulators

Glutamate-gated channel; excitatory

http://webvision.med.utah.edu/imageswv/GLU5.jpeg

GABA- and glycine-gated channels;

inhibitory

• GABAA; ionotopic, Cl-

• GABAB; metabotropic, K+

• Glycine; ionotropic, Cl-

http://sites.sinauer.com/psychopharm2e/webbox18.04.html

Neurotransmission

• Fast excitatory transmission

Na channel open in postsynaptic neuron

• Fast inhibitory transmission

Cl channel open in postsynaptic neuron

• Slow inhibitory transmission

K channel open in postsynaptic neuron

• Slow excitatory transmission

K channel block in postsynaptic neuron

Locks and Keys

• Neurotransmitter molecules

have specific shapes

• positive ions (NA+ ) depolarize

the neuron

• Negative ions (CL-)

hyperpolarize

When NT binds to receptor,

ions enter

• Receptor molecules have

binding sites

http://pharmacymagazine.blogspot.kr/

Some Drugs work on receptors

• Some drugs are shaped

like neurotransmitters

• Antagonists : fit the

receptor but poorly and

block the NT

• Agonists : fit

receptor well and

act like the NT

• e.g. nicotine.

http://pharmacymagazine.blogspot.kr/

https://courses.washington.edu/psy222/psy222drugsaddiction.html

Methylprednisolone - trials

1. No neurological difference one year post injury

Insufficient dose

2. Small but significant improvements in motor scores at one year

Lack of standardised assessment of functional outcome, rather than basic motor scores

3. Greatest benefit within the first 3hours

• Remains only an option in SCI

• complications

• increased incidence of infection

• Gastrointestinal problems

• Pulmonary issues

• Long-term effects

• Mixed evidence

Alternatives

• Naloxone • opiate antagonist

• No clinical benefit

• Tirilazad • 21-aminosteriod

• No benefit

• No true placebo group

• GM-1 • Ganglioside

• Two randomised trials

• Improvement in smaller trial not detected in larger one

• Remains an option

• Other agents with no benefit • Thyrotropin-releasing hormone

• Gacyclidine (NMDA-receptor antagonist)

• Nimodipine (calcium channel antagonist)

• 4AP • K+ channel antagonist

• Stabilises axonal membranes during acute injury only

• Riluzole • Sodium channel antagonist

• Improved outcome in animal models

• Approved for treatment of amyotrophic lateral sclerosis

• Attenuation of inflammatory response • COX-2, NSAIDS, tetracycline,

erythropoeitin

• Improved functional recovery

Integration of neural information transfer


Spatial summation


Temporal

summation



Glia (Neuroglia); Supporting cells

• Within the CNS ; astrocytes, ependymal cells and microglia

• In the PNS ; Schwann cells


Glial cell

• Function

• Support network for neurons

• Transmit information (Parpura, 2000)

• Ailments : Alzheimer`s Dz, Multiple sclerosis

• Categorize

• Macroglial cells

• Astocytes

• Oligodendrocytes

• Schwann cells

• Microglia cells


Spinal tracts

https://www.boundless.com/physiology/textbooks/boundless-anatomy-and-physiology-textbook/peripheral-nervous-system-pns-13/distribution-of-spinal-nerves-133/sensory-and-motor-tracts-720-6504/

Tracts of the Spinal Cord

• Function of tracts

1. Highway for sensory & motor information

2. Sensory tracts ascend

3. Motor tracts descend

• Naming of tracts

• Indicates position & direction of signal

• Example = anterior spinothalamic tract

• Impulses travel from spinal cord towards brain (thalamus)

• Found in anterior part of spinal cord

Location of Tracts inside Cord

Motor tracts Sensory tracts

pyramidal tract (corticospinal) spinothalamic tract

extrapyramidal tract posterior column

spinocerebellar

Function of Spinal Tracts

two-point discrimination,

pressure and vibration

pain, temperature,

deep pressure


Function of Spinal Tracts

voluntary movements,

posture & muscle

tone, equilibrium


1. Ascending Tracts

• Carry sensory signals up to the supraspinal region

• Typically uses 3 neurons

• 1st order neuron - detects stimulus and carries it to spinal

cord

• 2nd order neuron - within s.c.; continues to the thalamus

(the sensory relay station)

• 3rd order neuron - carries signal from thalamus to

sensory region of cerebral cortex

• Carries sensations related to

discriminative touch, vibration,

and proprioception

• 1st order neuron - detects stimulus

• Fasciculus gracilis

• Carries sensation from below T6

• Fasciculus cuneatus

• Carries sensation from T6 or higher

• 2nd order neuron synapses with 1st in

medulla and decussates

• 3rd order neuron synapses with 2nd in

thalamus and carries signal to cerebral

cortex (postcentral gyrus)

• System is contralateral

1-1. Dorsal Column Ascending Pathway

http://www.corpshumain.ca/en/Touche_en.php

1-2. Spinothalamic Pathway

• Carries sensations of pain, pressure, temperature, light touch, tickle and itch

• Located in the anterior and lateral columns

• Decussation of the second order neuron occurs in spinal cord

• Third order neurons arise in thalamus and continue to cerebral cortex of the postcentral gyrus

http://www.corpshumain.ca/en/Touche_en.php

1-3. Spinocerebellar Pathway

• 1st order neurons originate in muscles and tendons

• 2nd order neurons ascend in ipsilateral lateral column

• Terminate in cerebellum (a large motor control are of the brain)

• Transmit proprioceptive signals from limbs and trunk

2. Descending (Motor) Pathways

• Brain → spinal cord

• Pyramidal tracts (Direct pathways)

• Corticospinal tract

• Corticobulbar tract

• Extrapyramidal tracts (Indirect pathways)

• Vestibulospinal tract

• Tectospinal tract

• Reticulospinal tract

• Rubrospinal tract

• Motor pathways involve two neurons

• Upper motor neuron (UMN)

• Lower motor neuron (LMN)

2-1. Pyramidal Tracts

• Originate from the pyramidal cells of the primary motor

cortex. These nerve tracts decussate.

2-1-1. Corticobulbar tract • Originate : primary motor cortex of the cerebrum.

• Destination : motor nuclei of cranial nerves in the brain stem.

• Provide conscious control over skeletal muscles of the eye, jaw

and face, as well as some muscles of the neck and throat.

2-1.2. Corticospinal tracts • Origination : primary motor cortex of the cerebrum.

• Destination : the ventral horns of gray matter in the spinal cord.

• Provide voluntary motor control of skeletal muscles throughout

the body.

2-1. The

Direct

(Pyramidal)

System

http://www.profelis.org/webpages-

cn/lectures/neuroanatomy_3.html

2-2. Extra-Pyramidal tracts

Originate from centers in the cerebrum, diencephalon and

brain stem not from pyramidal cells (extra-pyramidal).

2-2-1. Vestibulospinal tracts – do not decussate • Neurons respond to information from the vestibulocochlear nerve

about the position and movements of the head.

• The tract carries motor commands that alter muscle tone and position

the head, neck and limbs to maintain balance and posture.

2-2-2. Reticulospinal tract (reticular formation)

• Controls limb movements important to maintain posture and balance

2-2. Extra-Pyramidal tracts

Originate from centers in the cerebrum, diencephalon and

brain stem not from pyramidal cells (extra-pyramidal).

2-2-3. Tectospinal tracts – Cross over in the brain stem • Neurons originate in the superior and inferior colliculi in the tectum of

the midbrain. The colliculi receive visual (superior) and auditory

(inferior) sensations.

• Neurons of these tracts direct reflexive changes in the position of the

head, neck and upper limbs in response to bright lights, sudden

movements or loud noises.

2-2-4. Rubrospinal tracts • Originate in ‘red nucleus’ of midbrain; control flexor

2-2. Indirect

(Extrapyramidal)

System

http://www.profelis.org/webpages-cn/lectures/neuroanatomy_3.html

Example Motor and Sensory Pathways

To thalamus and cerebral cortex (sensory)

Brain

Stem

Spinal

Cord

Pain - Temp Proprioception

(conscious)

Spinothalmic

tract

Example Motor Pathway

(corticospinal tract)

LMN

Motor Cortex

Corticospinal

tract

Posterior

column

Documents

Selective ablation of nociceptive neurons for elimination ...contents.kocw.net/KOCW/document/2014/gacheon/chohwiyoung/9.pdf · • Spinal cord 16 years after injury. Three spinal