Upper NeuroMotor System.

System
A/Professor Peter G
G. Noakes
Noakes.
p
p.noakes@uq.edu.au
@ q
Rm 422 MacGregor
Text references:
Kandel, Schwartz and Jessell. Principals of Neural Science
pp 548-559 Ch 36 Muscles, 4th Edition is Best. (KSJ – 3rd
Ed; KSJ-4th Ed)
B
Bear, C
Connors and
dPPardiso
di - Neuroscience
N i E
Exploring
l i the
th
(B) 3rd Ed.
Human Physiology
y y L. Sherwood ((S 7th Ed).
gy by )
Overview of the NeuroMotor System
 Cerebellum
• 10% Brain vol. 50% of CNS neurons
Already covered in BIOM2011 - 2010 – S1
 Cerebellum
• 10%% Brain vol. 50%
% of CNS neurons
•
* Functions as a COMPARATOR
= intended movt with performance of movt , & makes adjustments

• Function achieved by 3 Mechanisms

1) Internal feedback (corollary discharge)
2)) External feed back (reference)
( )
3) Input to lower motor neurons
1 & 2 allow for comparisons, & 3 for correction.
• Gross appearance.

* Cortex 3 functional subdivisions

Functions as a COMPARATOR

1) Internal feedback (corollary

discharge)

2) External feed back (reference)

3) Input to lower motor neurons

1 & 2 allow for comparisons

comparisons, & 3
for correction
 •Cortex 3 functional subdivisions
i) Cerebrocerebellum (lateral hemisphere)
Function initiation, planning of movts, and timing of movts
Input - cortical afferents
Output - Dentate Nucleus to Motor and Pre-motor
Pre motor cortices.

ii) Spinocerecellum (2 parts)

a) Vermis
Function control of axial and proximal muscle, ongoing execution of movt.
Input auditory, visual & vestibular
Output
p Fastigalg Nucleus.

b) Intermediate part of hemisphere

Function control of distal muscles, ongoing execution of movt.
Input Spinal afferents (distal parts)
Output Interposed Nucleus
Outputs via the Reticular Formation - to motor execution in the spinal cord.

iii) Vestibulocerebellum
Function axial control & Vestibular reflexes (balance and eye movements).
Input Vestibular apparatus
Output Lateral Vestibular N.
 Vestibulocerebellum
Receives input from
Vestibular apparatus
And projects directly
To Vestibular Nuclei
(lat and medial)

Lesions
Seen on the same
(ipsilateral) side

KSJ 4th Ed Fig 42-10

 CerebroCerebellum and SpinoCerebellum
KSJ 4th Ed Fig 42-12 Lesion will affect motor performance on the
same) side of the body
 Vestibulocerebellum
Receives input from
Vestibular apparatus
And projects directly
To Lateral Vestibular
Nucleus then to Motor
neurons – antigravity
muscle (extensors)

Lesions to
V tib l
Vestibulocerebellim
b lli
Seen on the same
(ipsilateral) side

SpinoCerebellum –
((Vermis)) to Fastigal
g N.
then to brain Stem
(e.g. Medullar Ret
formation)
Lesions ipsilateral
KSJ 4th Ed Fig 42-10
 CerebroCerebellum and Lateral SpinoCerebellum
p
Lesion will affect motor performance on the
Ipsilateral of the body – even though their projections
From their respective
p Deepp Cerebellar Nuclei are
Contralateral (to Motor Cortex and Red N respectively)
KSJ 4th Ed Fig 42-12
* How Cerebellum inputs modulate output from the Cerebellum
(Excitatory Output of Cerebellum can be
modulated by inhibitory inter-neurons).
 * How Cerebellum inputs modulate output from the Cerebellum
(Excitatory Output of Cerebellum can be
modulated by inhibitory inter-neurons)
inter neurons).

kSJ 3rd Ed 41-4

41 4
 •Cerebellar Dysfunction
•Does NOT
•Alter sensory thresholds. Or the strength of muscle contraction.

•DOES
DOES
•Disrupt spatial accuracy and temporal coordination of movement.
•Imparies balance
•Reduces muscle tone
•Motor learning and cognitive functions.

•CLINICALLY THESE DISTRUBANCES ARE SEEN AS

1) Hypotonia - a diminished resistance to passive limb displacements
displacements.

2) Ataxia or lack of coordination.

- delay in initiating responses
- errors in the range of movement

3) Tremor. Most marked at the end of a movement, when the patient

attempts to stop the movement by using antagonist muscles.
 Left

right

KSJ 3rd Ed, 41-16

 Upper NeuroMotor System.
System
A/Professor Peter G
G. Noakes
Noakes.
p
p.noakes@uq.edu.au
@ q
Rm 422 MacGregor
Text references:
Kandel, Schwartz and Jessell. Principals of Neural Science
pp 548-559 Ch 36 Muscles, 4th Edition is Best. (KSJ – 3rd
Ed; KSJ-4th Ed)
B
Bear, C
Connors and
dPPardiso
di - Neuroscience
N i E
Exploring
l i the
th
(B) 3rd Ed.
Human Physiology
y y L. Sherwood ((S 7th Ed).
gy by )
Overview of the NeuroMotor System
 BASAL GANGLIA.
GANGLIA
* Inter connection g
group
p of 5 Nuclei located in forebrain

1) Caudate (CN)
2)) Putamen
u a e ((Pt))
1+ 2 = Striatum (S)

3) Globus Pallidus (GPe

(GPe, GPi)

4) Substantia Nigra (Pars Reticulata [SNr]+ Pars Compactor [SNc])

5) Sub-Thalamic N. [STN]

* Inputs from all Cerebral Cortex - project back to frontal lobes of Cerebral
cortex (Pre-frontal, Pre-motor and Motor cortices). There is no direct
connection to lower MNs . Hence the motor functions of the basal ganglia
are therefore mediated in part by motor areas of the frontal cortex
cortex.
 Gross – internal feed back circuit
loop of the basal ganglia

Input via the Striatum – Output

via the Ventral Thalamic Nucleus

KSJ – 3rd Ed
 • Function motor control and cognitive function

1) Old idea:
id Pl
Planning
i and
d execution
ti off complex
l motor
t strategies
t t i ((old
ld id
idea))

2) Current idea 1: do not generate movements BUT inhibit motor

mechanisms that interfere with the desired movement and Dis-inhibit.

3)) Current idea 2: Specification

p of movement on the bais of the memory
y
of the movement or memory of the outcomes.

Revealed by clinical observations e

e.g.
g Parkinsons'
Parkinsons and Huntingtons
Huntingtons' disease
•Neuronal connections of 5 Nuclei + Neuro transmitters and Receptors
 • Parkinson's neuro degenerative
g disease
• - example of diminished movement.
Signs
i) tremors at rest,
ii) postural reflex impairment ,

iii) increase in muscle tone with ratchet - like - characteristics,

iv) difficulty in initiating movt & paucity of spontaneous movts

v)) slowness
l iin th
the execution
ti off movtt
Treatment - L-DOPA

• Neural pathway affected by Parkinson's

((degeneration
g of the nigirostriatal
g p
pathway)
y)
(Diagram)
 * Mechanism to go with the diagram
i) DA input inhibits cholinergic Ins

ii) Loss Dis-inhibits

Dis inhibits these Ins

iii) Consequently inhibition of Caudate and Putamen (Striatum) is Reduced

iv) Thus stronger inhibition of GPe

v) Inhibition of GPe leads to a Reduction in inhibitory out put from GPe

vi) Results in Dis-inhibition of Sub-thalamic N (activation of the indirect circuit).

vii) This causes the Subthalamic N to excite the GPi and SNr more strongly

viii)) GPi and SNr inhibits the ventral thalamus more strongly.
gy

viii) Causes a reduction in excitation of the motor cortex (from thalamus)

All this leads to a poverty of MOVT.

Possible causes of Parkinson’s disease.
*) Disease off the aged

*) Neurotoxins - eg drug addicts exposed to meperidine derivative (MPTP = 1-methyl-4-phenyl-

1,2,3,6-tetrahydropyridine)
y py ) - develop
p Parkinson’s - with loss of the Dopa
p ppathway
y ((SNc to
Striatium). MPTP animal model.

*) Drugs that block DA receptors 1 and 2 in the Striatum ( i.e. antagonists to DAR1 or 2).

*) Drugs that interfere with the synthesis of dopamine (eg. α-methyl dopa)

Genetic factors - inherited forms of PD (familial PD)

Many Candidate genes have been identified -

1) Genes whose proteins are linked to the the ubiqutin-proteosome system the major pathway
for p
protein degradation
g ((turn over;; mis-processing
p g ((eg
g mis foldings)
g )

PARK2 (early onset PD- recessive) - encodes for Parkin - a Key enzyme in
q p
ubiqutin-proteosome system.
y PARK5 - encodes ubiqutin
q terminal hydrolase
y
L1. which also functions the ubiqutin-proteosome system Disturbances to the
the ubiqutin-proteosome system. Seen in both genetic and Sporadic PD).
 What is Huntington
Huntington’ss Disease?
• First described
Fi d ib d b
by G
George HHuntington
i iin 18
1872
2
• It is an autosomal dominant disorder and affects 8 in 100 000
people
• The Huntingtin gene (Htt) is located on chromosome 4 and it is
the mutated version (mHtt) of the gene that is responsible for
the disease
• Polyglutamine disease: Involves triplet repeat: CAG
• Only 1-3%
1 3% of the disease is sporadic
• Adult onset –90% = 30-40 years old – symptomatic
• Juvenile onset – 10% = symptoms before 20 yrs
• Terminal disease: death occurring 10-25 years
after onset.
Huntingtin is a cytoplasmic protein. Mutations to this protein leads to mitochondria
d f
dysfunction
ti and d activation
ti ti off programmed d cellll d
death
th via
i caspases ((proteases
t
Capases 9,8 and 3).

(Greater than 40 CAG repeats - greater than 40 - unstable and can increase from
generation to generation - 126 plus with age). Onset dependant on the number of
CAG repeats .

Mutated huntingtin protein - sticky - found in intracellular (cytoplasmic inclusion

bodies - suggests failure to be degradated by the ubiqutin-proteosome system)

Mutant huntingtin protein - translocates to the nucleus to induce programmed

neuronal cell death by Apopotic mechanisms.

What does Huntingtin protein normally do - function still to be

worked out.
Found in cytoplasm and in the nucleus - it is associated with microtubles and
synaptic vesicles.
 Programmed cell death
Common - Features
Ti
Triggers att membrane
b (Receptors)
(R t )
Eventual activation of Caspase 3 (cysteine-dependent aspartate directed proteases – degrades
polypeptides)
Cl
Cleavage off DNA (200 Kb segments t – endo-nuclease)
d l )

E. Coulson DEVB3001
Huntingdon's disease = Degeneration of intrastriatal and
cortical cholinergic neurons and
GABA- ergic neurons. An example of excessive movement.
Signs
Si

i) chorea (dance) uncontrolled movts of

limbs and facial muscles

ii) dementia (reason goes)

iii) death (progressive)

Huntington’s Disease Circuits:
Dashed Arrows shows the
Change in the size of the
arrows when the GABAergic
neurons are lost within the
Striatum (Caudate and
Putamen) is lost “ X “.
 Mechanism

To go with the diagram

i) Motor impairment due to atrophy of CN and Putamen

ii) Dis-inhibition of the GPe

iii) This leads to stronger inhibition of the STN by the GPe

iv) Thus excitation of GPi and SNr by the STN is reduced

v) This leads to reduced inhibition of Ventral thalamus by GPe and SNr

vi) Hence the Ventral thalamus excitatory drive to cortex is higher

(i over excitation
(ie i i off cortex).
)

All this lead to over-exuberance of movement.

 T t
Treatment
t

1) ffetal
t l grafting
fti off Striatal
St i t l tissue
ti
(now underway)

2) inhibition of Caspase I an enzyme

proteases associated with cell death & inflammatory
cascades
Huntington’s disease : Evidence that blocking
CD88 slows
l d
down neurall d
degeneration
ti iin a
Toxin Induced Animal Model of HD

Admistration of 3-NP
3 NP to the striatum to induce
death of cells within the striatum – followed by
Treatment with CD88 anatgonists PMX205
and or PMX53, Vs control treatment PBS
(S li ) or Nothing
(Saline) N thi (3 (3-NP)
NP)

(Woodruff et al 2006 FASEB J Vol 20

Histopathology
PBS
Histopathology
3-NP

PBS
Histopathology
3-NP + PMX205

PBS

3-NP
CD88 antagonist PMX205 and PMX53 reduces the lesion size and reduces
inflammation and cell death in the 3-NP HD toxin model compared to controls.
Reduced numbers of Apoptotic cells (brown) in 3-NP model treated with PMX205
Vs controls (PBS and 3-NP)
3 NP)

Reduced numbers of GFAP stained astrocytes (black ) in 3-NP model treated with
PMX205 Vs Control (PBS and 3-NP)
Overview of the NeuroMotor System
MOTOR AREAS OF THE CEREBRAL CORTEX.

Lateral view of the cerebral

hemisphere showing the location
of the motor areas.

SMA (Get Set) = Supplementary

Motor Area
PMA (Ready) = Pre-Motor Area
PMA (GO) = Primary Motor Cortex.
 MOTOR AREAS OF THE CEREBRAL CORTEX.

1) Primary Motor Cortex (M1) . {GO!} = Controls Simple Features of Movement,

Pre-centrall G
P Gyrus
Somatopic representation of the body (body map)

C ll b
Cell bodies
di llocated
t d iin llamina
i V - Betz
B t Cells
C ll

Controls movts on opposite side of body

Excitatory connections to α, γ MNs and Ins

Descending tract = CORTICOSPINAL tract tract.

(Lateral Cortical spinal Tract, and Ventral Cortical spinal tract)
Cortex – location of the cell bodies of projection cortiospinal neurons to spinal cord
 2) Pre-Motor Area (PMA). GET SET

30% project to spinal cord (corticopsinal tract) also makes

connections to brain stem Nuclei. Vestibular, and Reticular Formation

e.g. - reticulospinal neurons to axial – proximal muscle (Indirect)

Function - setting up the motor programs for learned sequences,

- coordination of bilateral MOVTS

- active when told to dream movt
– send axons to distal muscles (Direct).
- reticulospinal neurons to axial – proximal muscle (Indirect)

Inputs Sensory cortex and Visual feedback

Neural activity before M1
Lesion - impaired ability to execute purposeful MOVTS

y Motor Area ((SMA)) {{Ready

3)Supplementary
) y
Connections with speech centers
 a) READY – waiting – activity on PMA
Neuron a low level

b) SET – the instruction light goes “on”

At the indicated arrow – increase in PMA
Neuronal activity.

c)) GO – shortlyy after the movement

is initiated, the PMA neuron activity
ceases, *.

Fig 14.9 Bear et al 3rd Ed.

Different areas of cortex are activated during simple, complex and imagined
Sequences
q of finger
g movements.

A: Simple finger flexion B: Sequential finger movts

C: Mental rehearsal of finger movts

KSJ 4th Ed, Fig 38-17

Looking at Words Listening to Words

Speaking Words Thinking Words

 Speech Centres – KSJ 4th Ed Ch 59
Language disorders = aphasias
Type of Aphasia Speech Comprehension Repetition Region Affected

Broca’s Non-fluent Largely preserved Impaired Left Posterior

Effortful for simple
p words & frontal cortex
sentences

Wernicke’ss
Wernicke Fluent, Imparied Impaired Left Posterior, superior
Abundant & middle temporal
Well articulated cortex
melodic

Conduction Fluent with Intact or largely Impaired Left superior temporal

some
so eaarticulatory
cu a o y p
preserved
ese ed Sup
Supramarginal
a a g a gygyri
defects
 Locomotion- Setting Motor
Activity patterns
Via sensory and Upper Motor
Neuron Inputs
2) Crossed Extensor coupled with Withdrawal Reflex. (S Fig 13-24)

* Locomotion (walking)
Avoiding injury (protective)
* Polysynaptic Activation and
Inhibition via Ins
Both sides of Body
(Ipsilateral & Contralateral)
F
Forms the
h b basis
i off llocomotor
circuits for
alternating flexion and extension.
Figure 14-7 Rhythmic patterns during locomotion. A, The experimental tracings are electromyograms (EMGs)-extracellular recordings of the electrical activity of muscles-
from the extensor and flexor muscles of the left hind limb of a walking cat. The pink bars indicate that the foot is lifted; purple bars indicate that the foot is planted. B, The
walk, trot, pace, and gallop not only represent different patterns and frequencies of planting and lifting for a single leg but also different patterns of coordination among
the legs. LF, left front; LH, left hind; RF, right front; RH, right hind. (Data from Pearson K: The control of walking. Sci Am 2:72-86, 1976.)

Downloaded from: StudentConsult (on 29 August 2005 04:23 AM)

© 2005 Elsevier
* Half centre model of Rhythmic Activity (basis of a locomotor generators)
 * Half centre model of Rhythmic Activity (basis of a locomotor generators)
Red inputs to See KSJ Fig 37
37-4
4
These Ins – from
Afferents
And can also be from upper Motor centres – e.g. brain stem
The clinical Motor Lesion

1) Lower Motor Neurons

Weakness or Paralysis
Muscle tone reduced or absent
Muscle mass is lost
Myostatic reflexes reduced or absent
Causes
P li
Poliomyelitis
liti ((viral
i l iinfection
f ti off CNS)
Motor Neuron Disease
Spinal cord injury at segmental level
N
Nerve T
Trauma (compression,
( i d
deymelination)
li ti )
Muscle disorders (MG, Dystrophies)
The clinical Motor Lesion (Cont'd)
2) Upper Motor neurons

Weakness or paralysis
Muscle tone increases (except acutely)
Myotatic reflexes increases (except acutely)
Muscle mass is maintained
Babinski's sign (upper plantar reflexes)

Causes

Stroke

Cord lesion
 Vestibular p
parts of
NeuroMotor System.
A/Professor Peter G
G. Noakes
Noakes.
p
p.noakes@uq.edu.au
@ q
Rm 422 MacGregor
Text references:
Kandel, Schwartz and Jessell. Principals of Neural Science
pp 548-559 Ch 36 Muscles, 4th Edition is Best. (KSJ – 3rd
Ed; KSJ-4th Ed)
B
Bear, C
Connors and
dPPardiso
di - Neuroscience
N i E
Exploring
l i the
th
(B) 3rd Ed.
Human Physiology
y y L. Sherwood ((S 7th Ed).
gy by )
Vestibular System
Role of Brain Stems Motor Centers on Motor Neuron output
-reflex control of Posture.

TEXT references; Schwartz Kandel and Jessell CHAPTER 39 (3rd edition).

Posture adjustments needed for:

1) Balance
2) Stabilize
3) Alignment of head and body WRT gravity
4) Protective
3) Falling forward while walking up steps
 1) Vestibular N l i (Vestibulo-spinal
V tib l Nuclei. (V tib l i lT Tract)
t)

Receive Vestibular Afferent inputs - signal position of Head WRT Gravity

i) Lateral = maintaining stance

ii & iii) Medial & Superior - coordination of eye with head movts

iv) Inferior - integrates afferents and cerebellum to higher centers

 Vestibular System
y
• Coordination of head, neck and eyes
during movement

Semi
Circular
canals

All mediated by the Vestibular Apparatus (Vestibular Labyrinth)

The Otolith organs (Saccule and Utricle) detect changes of head angle + linear
Acceleration of the head.
Macular – sensory epithelium
epithelium, Saccule (vertical)
(vertical), Utricle (horizontal) orientation
orientation.

Endolymph

Gelatinous
cap

Hair cell

Supporting
cells

Vestibular
Nerve axons to CNS
 The Otolith Organs – Saccule and Utricle

Macula – sensory epithelium

* Sickle orientated vertically and Utricular orientated horizontally

* Otoliths – CaCO3 crystals – over gelatin cap – needed for tilt sensitivity
(in that they have a higher density than surrounding endolymph fluid
fluid.

* When head move – causes Gelatin cap to move in same direction

Which causes hair cells to deflect. Direction of hair cell movement is
selective – all with respect to the tallest hair cell –the Kinocilium

* Bending
g hair cells towards the Kinocilium – depolarizing
p g signal
g
whereas hair cells away from Kinocilium – inhibitory signal

* There exist a mirror image of the Saccule and Utricle on the opposite side
of the head. Thus when a given head movement excites hair cells on one
side, it tend to inhibits hair cells in the corresponding location on the other side
(of the head)
 Direction of
Depolarization

* Bending hair cells towards the Kinocilium – depolarizing signal

whereas hair cells away from Kinocilium – inhibitory signal

The Semi-circular canals –
Detect turning
g movements of the
Head (Angular acceleration).

Mediated by hair cells in a gelatin

Cap (Cupula) with a bulge along the
canal – (ampula).

All hair cells dominated by a

Kinocila hair cells – as a group either
Get excited or inhibited together.

Cupular surrounded by endolymph

(different fluid density)

When you move you head endolymph

Moves within the canals – causing the
Cupula to bend and thus bending the
Clia (hair cells within it).

On each side of the head there are

3 semi-circular canals to help
Sense all possible head rotations
Semi-circular canal – pairs – located on each side of the head and in the same
orientation and responds to rotation about the same axis

However while rotation excites hair cells in one canal, it inhibits the hair cells of its
contra lateral partner (below). Vestibular axons fire (APs) all the time – so rates can be
d i up or d
drive down.
 Central Vestibular Pathways
f Balance,
for B l and
d coordinated
di t d hhead-neck
d k and
d eye movements
t

(e.g. VestibuloCerebellum)

Maintain Head and neck aligned

Posture (e.g. With respect
p to g
gravity
y
balance)
 Vestibulo-Ocular Reflex (VOR)

•Keep your eyes in a particular direction

during movement (e.g. Turn head but
keep
eyes fixed in an object).

•VOR
VOR senses rotations
t ti in
i the
th head
h d and
d it
then sets a set of commands to bring
about compensatory movements of the
eyes in the opposite direction
direction.

•It is triggered by the vestibular apparatus

rather than by the visual system (i.e.
(i e can
Work in dark or when eyes are closed.

Shown is half of the VOR circuit

In action when head turns to the Left but
Eyes turn on opposite direction (right).
Damage to Vestibular system
Antibiotics such as strepomycin (Kills hair cells – also deafness)

Viral infections

Trouble – fixating
g on visual targets,
g , cannot stabilize an imageg
dizzy spells, balance – falls (e.g. walking and standing difficult)