Topic 8 – Motor Neuron Disorders Motor System Disorders ... · Topic 8 – Motor Neuron Disorders & Spinal Cord Injury ... Motor Neuron Disorders & Spinal Cord Injury 1. ... "Spinal

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Topic 8 – Motor Neuron Disorders & Spinal Cord Injury

1. Terminology

2. "Upper motor neuron" injury

3. Mechanisms of damage

4. Some disorders

Motor System Disorders -Terminology

• Muscle Strength• Paralysis / Paresis • hemi-, para- , or tetra (quad)-

plegia

• Muscle Bulk• atrophy – disuse or neurogenic


• Upper motor neurons• Originate in "higher" regions of

brain such as motor cortex• Corticospinal tract

• Lower motor neurons• Directly innervate skeletal

muscles

• Hypotonia - abnormally low resistance to stretch

• cerebellar disorders• LMN lesions• acute UMN lesions

• Hypertonia - abnormally strong resistance to stretch

• chronic UMN lesions• 2 types = spastic and rigid


• Spastic Hypertonia• resistance to passive movement

is velocity sensitive

• Rigidity • resistance to passive movement

remains constant regardless of velocity

• Decorticate / Decerebrate


Decerebrate Rigidity

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Source: Haines, Fundamental Neuroscience, Churchill-Livingstone, 2002

Decerebrate -upper brainstem or lower midbrain

Decorticate Rigidity

Source: Haines, Fundamental Neuroscience, Churchill-Livingstone, 2002

Decorticate -severe lesion superior to midbrain


1. Terminology



4. Some disorders

Overall muscle tone is determined by1. Intrinsic elastic properties of muscle

2. Neural input

Source: Kandel et al., Principles of Neural Science, McGraw Hill, 2000

- contraction in response to lengthening

- receptor is muscle spindle (Ia afferent fiber)

- descending pathways modify gain of reflex

Stretch reflex -

3

Hoffmann Reflex


- stimulate Ia afferents (and motor neurons)

- measure "M-wave" and "H-wave" using EMG

"Spinal shock" -• Complete absence of reflexes• Maybe from sudden withdrawal of

descending input

• Reflexes recover (weeks – months) and become oversensitive…

"Hyperactive" reflexes

Source: Latash, Neurophysiological Basis of Movement, Human Kinetics, 1998.

• ‘spasm-like' muscle bursts in response to mild stimuli

• loss of descending inhibition

tactile stim. foot

Increased resistance to stretch -• Velocity-dependent

hypertonia

Treatment -

- administration of baclofen to spinal cord

- GABA B receptor agonist

- inhibition of synapse between Ia fibers and motor neurons

Babinski’s Sign• stroking across plantar

surface of foot normally causes flexion of toes

• Upper motor neuron damage can reverse this response

Source: Lundy-Ekman, Neuroscience: Fundamentals for Rehabilitation, Saunders, 2002

Summary of "UMN" Injury Effects

Source: Latash, Neurophysiological Basis of Movement, Human Kinetics, 1998.

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1. Terminology



4. Some disorders

Primary Injury –mechanical damage to neuronal apparatus

Secondary Injury –occurs over hours post-injury

Glutamate - Excitotoxicity


NMDA Receptor - GLU binds to R and opens Na+ channels

- ↑ Na+, draws water into the cell = edema

- ↑ Ca++ , activates proteases, lipases that degrade components of cell, may initiate apoptosis

Neuroprotective strategies

- block glutamate receptors

- antioxidants

- block Na+ channels

Na+ Channel Blockers

Adapted from: Schwartz and Fehlings, J. Neurosurg., 2001, 94(Suppl 2):245-256.

Weeks Post-Injury

Riluzole

Control

BBB = measure of locomotor function

Na+ Channel Blockers

Adapted from: Schwartz and Fehlings, J. Neurosurg., 2001, 94(Suppl 2):245-256.

• effects on integrity of descending spinal tracts

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Na+ Channel Blockers – Tissue Loss

Source: Schwartz and Fehlings, J. Neurosurg., 2001, 94(Suppl 2):245-256.

Riluzole

Control

Wallerian Degeneration


Axotomy - transection of the axon by cutting or crushing

Can result in degeneration of pre- / post-synaptic cells and glia.

Wallerian Degeneration


Possible Therapies• Regeneration of damaged axons

• Remyelination – Schwann cell transplants

• Cell replacement – stem cells


1. Terminology



4. Some disorders

Poliomyelitis

• poliovirus• acute infection of ventral horn of spinal cord• Selectively destroys lower motor neurons –

denervates muscleSource: Lundy-Ekman, Neuroscience: Fundamentals for Rehabilitation, Saunders, 2002

Loss of lower motor neuron cell bodies

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Poliomyelitis Amyotrophic Lateral Sclerosis (ALS)

- degeneration of "upper" and "lower" motor neurons

- neurogenic atrophy of muscles

- correlated with mutation in chromosome 21

Multiple Sclerosis


Axonal Conduction Block• normally, voltage gated K+ channels

are present in the internodes and v-g Na+ channels are densely packed in region of node

• after demyelination, electrical properties of axon change

• Conduction slows or may become blocked

End of topic 8Topic 9 - Parietal Association Cortex

1. Sensory-to-motor transformations

2. Activity in parietal association cortex and the effects of damage

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Sensory to Motor TransformationSensory information (visual, somatosensationetc.) is integrated and used to generate an appropriate motor output.

Culham and Kanwisher, (2001) Cur. Opinion in Neurobiol. 11: 157-163

Superior parietal lobule (SPL)

Inferior parietal lobule (IPL)

Intraparietal sulcus (IPS)

Posterior Parietal Cortex (PPC) association area

Anterior Posterior

- PPC is neither purely sensory nor purely motor ("association cortex")

- important for integration of sensory information

- sends information to motor areas (e.g. premotor and M1)

- important for "sensory-to-motor" transformation

PPC association area Topic 9 - Parietal Association Cortex

1. Sensory-to-motor transformations

2. Activity in parietal association cortex and the effects of damage

Parietal Association Cortex

Source: MacKay, Neuro 101, Sefalotek Ltd., 1999

- integrates information from several sensory modalities (e.g. V1 and S1)

Superior parietal lobule (SPL)

Scott, Sergio & Kalaska (1997) J. Neurophysiol. 78: 2413-2426

Cells have "preferred postures"

Natural position

Elbow raised

- Provides info about how body segments are positioned

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Source: MacKay, Neuro 101, Sefalotek Ltd., 1999 Graziano et al. (2000) Science. 290: 1792.

Visual information is also important

General Take-Home Message!

PPC is involved in transforming sensory cues into info regarding- the locations of objects in the environment

- the location of our limbs in the environment

- relative location of body segments

helps provide a "reference frame" for the world around us.

Lesions of parietal association cortex produce complicated deficits…

Astereognosis- inability to recognize objects by touch alone

???

Personal neglect syndrome - lack of awareness of a body part

?

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Optic Ataxia"dorsal" and "ventral" streams

Dorsal stream

Ventral stream

Primary visual area (V1)

Parietal lobe

Temporal lobe

Optic Ataxia

From: Perenin & Vighetto (1988) Brain. 111: 643-674

Optic Ataxia The inability to accurately reach for visible objects

Ideomotor Apraxia

Dorsal stream

Ventral stream

Primary visual area (V1)

Parietal lobe

Temporal lobe

?

Loss of ability to perform previously learned motor tasks

Disorders in Action and Perception

Dorsal vs. Ventral Streams

Milner & Goodale, 1995

Dorsal vs. Ventral Streams

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•Visual control of motor output

•Absolute metrics

•Moment-to-moment computations

•‘Unconscious’

•Object identification

•Relational metrics

•Long term representation

•‘Conscious’

Goodale, MA & Humphrey, GK. (1998). Cognition

Ventral Stream Dorsal StreamWhy study lesions?

Disadvantages

• Lesions are rarely focal

Advantages

• Provides insight into normal functioning of the brain.

• Tells you which areas are necessary for which functions

PPC Functions

• Sensori-motor integration• Early, abstract planning of movements• Attention• Language

Neglect• Mostly found with right lesions in

the IPL.

• May be in the superior temporal cortex – site in monkeys that is associated with spatial awareness.

• Some subcortical damage: basal ganglia and thalamus.

Karnath, HO, Ferber, S, & Himmelbach, M. (2001). Nature

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• Lack of awareness of personal and extra-personal space contralateral to lesioned hemisphere, e.g.

• patient may believe the left side of body is someone else’s.

• patient eats only the food in the right half of plate.• patient may only dress or shave on side.

Neglect Neglect

• Attention Deficits

Yves Rossetti, INSERM 534, France

Neglect


Neglect


• Visuo-motor deficits.

Neglect

Mattingley et al., Brain, 1992

• Visuo-motor deficits.

Neglect


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Neglect

• Extinction• Anosognosia- The loss of recognition or awareness

of a disease.

• Most people with neglect are also unaware that they have the disorder.

Neglect

Balint’s syndrome

• Visuomotor and visuospatial disorders

• Bilateral damage to posterior parietal lobes

• Simultanagnosia – inability to interpret the visual field as a whole

• Ocular apraxia – deficit of visual scanning• Optic ataxia – inability to reach accurately under

visual guidance

Simultanagnosia

• Difficulty copying/drawing/writing because they can’t see the end of the pen and what is on the paper at the same time.

• Spatial disorientation: unable to discern spatial properties of objects e.g. distance and size.

• Difficulty describing complex scenes (eg. Boston cookie theft)

Simultanagnosia

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Ocular Apraxia

• Impaired visual scanning (moving the eyes voluntarily)

• Not an oculomotor deficit

• Reflexive movements are spared

• Eye movements toward auditory stimuli are spared

• Gaze restricted to narrow band, right of midline (similar to neglect)

Ocular Apraxia

Apraxic eye movementsNormal eye movements

Optic Ataxia

• Visuomotor deficits - errors in visually-guided movements

• No other perceptual or motor deficits

• Two types of optic ataxia patients

Unilateral Optic Ataxia Bilateral Optic AtaxiaOptic Ataxia

Unilateral Optic AtaxiaOptic Ataxia

Vighetto, 1980

Ataxic Hand

Healthy Hand

Healthy Field Ataxic Field

Unilateral Optic Ataxia

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Revol et al., 2003

Unilateral Optic AtaxiaBilateral Optic AtaxiaOptic Ataxia

Jeannerod, 1986. Neuropsychologia.

Bilateral Optic Ataxia

Milner et al., 1999; 2001; 2003

0 60 120 180 2400

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120

180

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60

120

180

240

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Optic Ataxia PatientControl

Immediate

0 60 120 180 2400

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120

180

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120

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Delayed

Bilateral Optic Ataxia

IT Functions

• Object perception, recognition, memory

• Face perception

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Visual Agnosia• Inability to recognize objects

from sight

• Deficient shape perception

• Famous case D.F.

• Can’t recognize or copy drawings of common objects (such as an apple or a key) but can draw from memory

• Can’t estimate size, distance of objects Milner & Goodale, 1995

Visual Agnosia

Prosopagnosia

• Inability to recognize faces by sight,• Even themselves• Can by recognize by voice

• Can recognize faces as faces and name parts

• Can discriminate faces (tell two faces apart)• Based on feature comparison not global

recognition

SummaryDissociation between ventral and dorsal streams

Inferior Temporal Damage

•Cannot recognize objects, faces

•Cannot judge relative distance, size

•Can make accurate visually guided action (taking shape into account)

•Aware of space

Parietal Damage

•Can recognize objects

•Can judge relative distance, size

•Cannot make accurate visual guided actions e.g. saccades, pointing, grasping

•Lack of attention of spaceMilner & Goodale, 1995

End of Topic 9

Topic 10 - Basal Ganglia

1. Motor circuit of BG

2. Disorders

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The Basal Ganglia- group of subcortical nuclei (4 main parts)

- influence movement by modulating activity in "upper motor neurons"

Source:http://cti.itc.virginia.edu/~psyc220

(partially cut-away to reveal underlying structures)

1. Striatum(caudate and putamen),

2. GlobusPallidus (external and internal segments),

3. Substantianigra (pars compacta and pars reticulata),

4. Subthalamicnucleus

Source: Purves et al. Neuroscience, Sinauer Associates Inc: Massachusetts, 2001.

Input to Basal Ganglia -From most of cerebral cortex (and other regions)--> to striatum - i.e caudate and putamen (main input areas)

Output from Basal GangliaTo motor areas via the thalamus--> from GlobusPallidus (int.) and

To eye mvtareas of brainstem--> from substantia nigra(pars reticulata)


Motor cortex

Caudate

Thalamus

Subthalamicnucleus

Substantia nigrapars reticulata

GP -intGP -ext

Putamen Superior colliculus

• Multiple loops between cortex and basal ganglia -

1. Motor - voluntary movements1. 2. Limbic - "emotional behaviour"2. 3. Executive - "cognitive processes"

BG Circuits

• Involved in initiation of voluntary movements

• motor circuit has a general somatotopic organization throughout projections

Motor Circuit


SMA – supplementary motor area; PMC – premotor cortex; MC – motor cortex GPe/GPi – globus pallidusexternal/internal segmentsSTN – subthalamic nucleusVLo/VApc/CM – thalamic nuclei

Tonic inhibitory outflow from BG -- During rest, BG continuously inhibit motor areas (tonic)

Motor cortex

Caudate

Thalamus

Subthalamicnucleus

Substantia nigrapars reticulata

GP -intGP -ext

Putamen Superior colliculus

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Tonic inhibitory outflow from BG -- During rest, BG continuously inhibit motor areas (tonic)

- This inhibition must be removed before movements can be initiated

- 2 main pathways ("Direct" and "Indirect" -from striatum to output nuclei) within the BG modulate tonic inhibitory output

"Direct" and "Indirect" pathways2 main groups of projection neurons in striatum

--> one group projects to GP(int) and SN pars reticulata

= direct pathway (decreases tonic inhibitory output from BG)

--> other group projects to GP(ext)

= indirect pathway (increases tonic inhibitory output from BG)

Direct Pathway

"Direct Pathway" disinhibits the thalamus which facilitates movement--> from striatum to GP(int)


inhibitory

excitatory

Tonic inhibitory

Excitatory inputs from cortex to cell "A"

Striatum cell

Globuspalliduscell

Thalamus cell

Motor cortex cell

To lower motor neurons


Disinhibitory circuit of direct pathway


"Indirect Pathway" further inhibits thalamus (inhibits movement)

Dopaminergic input from SN(pc) decreases inhibitory output from BG--> inhibits indirect & excites direct pathway

--> differential effects of DA (because of different R types)

Substantianigra pars compacta cells release dopamine (DA)

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Topic 10 - Basal Ganglia

1. Motor circuit of BG

2. Disorders

Hypokinesia- decrease in the amount and speed of movements

Hyperkinesia- unwanted movements

Normal

Source: Lundy-Ekman, Neuroscience: Fundamentals for Rehab. Saunders, 2002

Parkinson's Disease

PD

- Cell death in substantia nigra(unknown cause)

- Loss of dopamine

- Disrupts normal modulations of BG output


Parkinson's Disease

Parkinson Disease


• Loss of dopamine-producing cells in SNc

– - Akinesia – difficulty initiating movement voluntarily

– - Bradykinesia – once started, movements very slow

– - Resting tremor in distal limbs (4-6 Hz) from oscillator properties of pallidal cells

• Loss of acetylcholine-producing cells in pedunculopontine nucleus

– - Rigidity - unable to inhibit reticulospinal and vestibulospinal tracts

PD Treatments - Pallidotomy

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PD Treatments - STN lesion PD Treatments - L-DOPA (Dopamine precursor)

Increase DA levels

Source: http://web.sfn.org/content/Publications/BrainBriefings/

PD Treatments - Deep Brain Stimulation Huntington’s Disease


• - preferential loss of striatal neurons comprising the indirect pathway

• (neurons from striatum to external segment of GP)

• - hyperkinetic

(indirect pathway)

Huntington’s Disease

Normal

Huntington's Disease

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Hemiballism


• uncontrolled, involuntary flinging of limbs on side contralateral to lesion

• STN lesion - stroke

• ↓ output of Gpi

End of Topic 10

1. Theories of Function

2. Neuroanatomy

3. Basic circuitry and dysfunction

Topic 11 – Cerebellum

Cerebellum

Cerebellum - Introduction


Cerebellum - Introduction

• Approx 10% of total brain volume– But contains about half of brain's neurons!

• Can remove cerebellum without loss of perception or muscle weakness.

• Regulates movement indirectly by adjusting output of major descending motor systems

Cerebellum - Multiple Roles in Voluntary Movement

- Timing and spatial accuracy of movements

- Motor learning•– acquisition new motor skills

- "Comparator" •– compares sensory feedback with intended movement (receives a copy of the intended "motor plan" in the form of "efferencecopy").

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Cerebellum- basic connectivity

Premotor, motor, somatosensory, PPC


2. Neuroanatomy



Anatomy


• 2 hemispheres divided by vermis• 3 lobes – anterior, posterior, flocculonodular• Cerebellar cortex over white matter

Vermis

Anterior

Posterior

Cerebellar hemisphere

• Superior – output to cortex via thalamus

• Middle – input / output via pons

• Inferior – input / output with brain stem / spinal cord


AnatomyConnected to brain stem through 3 peduncles


Anatomy3 pairs of deep cerebellar nuclei

1. Fastigial

2. Interposed (globose and emboliform)

3. Dentate

Functional Organization


Spinocerebellum (vermis and intermediate)

Cerebrocerebellum(lateral hemisphere)

Vestibulocerebellum(flocculonodular lobe)

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Functional OrganizationMost output from cerebellar cortex goes through a deep nucleus - All connections are inhib. (GABA):

Cerebrocerebellum --> dentate

Spinocerebellum --> interposed, fastigial

Vestibulocerebellum --> lateral vestibular nucleus

To motor and premotor cortices

To lateral descending systems

To medial descending systems

To vestibular nuclei

Balance and eye movement

Motor execution

Motor planning


Somatotopic maps in cerebellum

Source: Purves et al. Neuroscience, Sinauer Associates Inc: Massachusetts, 2001; Grodd et al. (2001) Human Brain Mapping, 13: 55.

Different parts of cerebellar cortex are concerned with different parts of body.


2. Neuroanatomy



Stellate cell

Basket cell

Purkinje cell axon Climbing fiber

Golgi cell

Mossy fiber

Granule cell

Granule cell layer

Purkinje cell layer

Molecular layer

Purkinje cellParallel fiber

Purkinje cell

Source: Purves et al.Neuroscience, SinauerAssociates Inc: Massachusetts, 2001.

Cerebellar cortex

Basic circuitry -Parallel fiber

Purkinje cell

Granule cell

Mossy fiber

Climbing fiber

Deep cerebellar nucleus

To thalamus (motor cortex)

All output from cerebellar cortex (to deep nuclei) is via Purkinje cells- inhibitory (GABA)

Basic circuitry -Parallel fiber

Purkinje cell

Granule cell

Mossy fiber

Climbing fiber

Deep cerebellar nucleus

To thalamus (motor cortex)

Afferent input:

1. Mossy fibers - synapse directly with deep cerebellar nuclei

- synapse indirectly with Purkinje cells via granule cell parallel fibers

2. Climbing fibers- synapse directly with deep cerebellar nuclei and Purkinje cells

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Complex / Simple Spikes


• Mossy Fibers –result in simple spikes

• Climbing Fibers –result in complex spikes

(Intracellular recordings from Purkinje cells)

Interneurons modulate inhibitory activity of P-cells


- Golgi cells - stellate cells - basket cells

This "Basic circuit" is repeated throughout the cerebellum.

Purkinje Cells as "Relaxation Couplers"

Circuitry enables temporal control of output(i.e. Coordination) Source: MacKay, Neuro 101, Sefalotek Ltd., 1999 Source: Kandel et al., Principles of Neural Science, McGraw Hill, 2000

Source: Kandel et al., Principles of Neural Science, McGraw Hill, 2000 Source: Kandel et al., Principles of Neural Science, McGraw Hill, 2000

• lack of coordination among limb / body segments

Cerebellar Ataxia

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End of Topic 11

Topic 12 - Premotor Cortex

1. General

2. Medial regions

3. Lateral regions


- a set of interconnected areas in the frontal lobe (rostral to M1)

- divided into "lateral" and "medial" regions

Premotor CortexPremotor areas - Introduction

- Concerned with planning movements

- active during preparation of movement

- uses info from other regions to select movements appropriate to context of a required action

- extensive connections with M1 and direct projections to spinal cord


1. General

2. Medial regions

3. Lateral regions

Medial premotor areas- Supplementary motor area (SMA) - Cingulate motor areas (CMA)

Source: http://www.driesen.com/secondary_motor_cortex.htm

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Source: Parsons et al. (2005) Neuropsychologia 43: 199-215

SMA is involved in performing learned sequences of movements

Damage to SMA interferes with movement sequence production

Source: Getilucci et al. (2000) Neuropsychologia. 38: 1398-1404

Lesion

SMA and Basal Ganglia are highly interconnected

Patients with BG damage have trouble performing sequences of movements.

Source: Kandel et al., Principles of Neural Science, McGraw Hill, 2000 Source : http://www.med.tohoku.ac.jp/room/124/link04.html and Tanji (2001) Annu. Rev. Neurosci. 24: 631-651

SMA neuron activity during movement sequence

"Pre-SMA" is involved in learning motor sequences

Source: http://www.med.tohoku.ac.jp/room/124/english.html

Cingulate Motor Areas (CMA)

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Source: Lundy-Ekman, Neuroscience: Fundamentals for Rehabilitation, Saunders, 2002Source: Morecraft & Van Hoesen (1998) Brain Res. Bulletin. 45: 209-232

CMA may be involved in the "emotional" aspects of movements


1. General

2. Medial regions

3. Lateral regions


Dorsal premotor (PMd)

Ventral premotor (PMv)

Lateral Premotor Cortex


Medial areas - internally initiated movementsLateral areas - externally cued movements

Dorsal premotor area (PMd) - Involved in learning associations between a particular sensory input and a specific motor output. - Role in selection of action based on learned associations.

e.g. red = stop

Source: Petrides (1997) Neuropsychologia 35: 989-997

Subjects had to learn correct associations between different colour cues and hand postures.

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Patients with frontal lesions (incl. PMd) could not learn associations as well as controls.

Adapted from: Petrides (1997) Neuropsychologia 35: 989-997

PMv is involved in choosing hand shapes appropriate for a given task.

Ventral premotor area


Mirror Neurons in PMv- Respond when animal performs an action or views the same action being performed by another.

Source: Kandel et al., Principles of Neural Science, McGraw Hill, 2000Source: http://www.pbs.org/wgbh/nova/sciencenow/

End of Topic 12

Topic 13 - Cortical Networks

1. Subcortical White Matter

2. Cortical networks for movement

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Functional regions of the brain don't work independently of one another.

- Different regions work together in cortical networks.

Cortical Networks - Introduction

Source: http://www.umm.edu

Subcortical White Matter

All white matter consists of myelinated axons.

Subcortical White Matter3 categories of white matter fibers:

1. Projection 2. Association3. Commissural


Projection – between subcortical & cortical

thalamusPutamen

Projection fibers in internal capsule

thalamusPutamen

Caudate

Almost all projection fibers travel through the internal capsule.

internal capsule

Projection – between subcortical & cortical

http://retina.anatomy.upenn.edu

Internal capsule regions:

- Anterior limb

- Genu

- Posterior limb

Association – between cortical regions within one hemisphere


- Short association fibers ("U" shaped fibers)

- Long association fibers

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Commissural – between hemispheres

Connect homologous areas of the cerebral hemispheres.

Source: Lundy-Ekman, Neuroscience: Fundamentals for Rehabilitation, Saunders, 2002 http://retina.anatomy.upenn.edu

Commissural – between hemispheres

Corpus Callosum, body

Corpus Callosum, genu

Corpus Callosum, splenium

Posterior commissure

Anterior commissure

Corpus Callosum, rostrum

Topic 13 - Cortical Networks

1. Subcortical White Matter

2. Cortical networks for movement

Disruption of connections between homologous areas can lead to deficits in motor control.


"Alien Hand Syndrome"- Involuntary but seemingly purposeful unilateral limb movements - Sometimes observed after damage to corpus callosum and medial motor areas

Corpus Callosum, body

Corpus Callosotomy ("split brain")

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Source: Giovannetti et al. (2005) Neuropsychologia. 43: 75-88

leftright

6 months post-stroke: - left medial frontal lesion extending into corpus callosum

The "Dual Premotor systems" Hypothesis:

Source: Goldberg & Bloom (1990) Am. J. Phys. Med. Rehabil. 69: 228-238.

Lateral Premotor regions

- externally cued movements

Medial Premotor regions

- internally-generated movementsAlien Hand Syndrome may result from

imbalance between lateral and medial premotor systems


Medial areas - internally initiated movementsLateral areas - externally cued movements

(Slide from "Topic 12" lecture)

"Left hand apraxia" after CC lesion

- Can't pantomime object use from verbal command or visual presentation of object.

Lateralization of function (ie. localization of a function to the left or right side of brain) could be a factor in production of this deficit.

Evidence of Lateralization in Motor Areas

Left M1 Right M1

Amount of activity (pixels)

C = contralateral (I.e. hand on opposite side of body)

I = ipsilateral (I.e. hand on same side of body)

= left-handed

= right-handed

e.g. M1

Adapted from: Kim et al. (1993) Science. 261: 615-617.

Lateralization of function in M1 -

- Right M1 is mainly activated during movement of left hand

- Left M1 is activated during movement of either hand

(regardless of handedness)

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Other examples of lateralization in motor regions -

- Left-brain dominance for motor planning?

- Lateralization during performance of complex sequences in premotor and parietal regions?

Sources: Sabate et al. (2004) Neuropsychologia. 42: 1041-1049; Haaland et al. (2004) J. Cogn. Neurosci. 16: 621-636 Source: Lundy-Ekman, Neuroscience: Fundamentals for Rehabilitation, Saunders, 2002

Parieto-Frontal Connections

Importance of Parieto-Frontal Connections

• Premotor regions select behaviours and muscle synergies based on information supplied by posterior half of the brain

– this info is used by premotor regions to relate target to body position in order to act on it

premotor regions also integrate cognitive information (last lecture), rules for movement

Adapted from: Cavada (2001) NeuroImage. 14: S21-S26.

Regions within the Intraparietal Sulcus (IPS)

VIP = ventral intraparietal area

MIP = medial intraparietal area

AIP = anterior intraparietal area

LIP = lateral intraparietal area

Parietal lobe


Anterior Intraparietal region -

Source: Murata et al (2000) J. Neurophysiol. 83: 2580-2601.

AIP neuron activity varies depending on object grasped.- Neurons "prefer" some shapes to others.

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Some AIP neurons respond to purely visual info.



Examples of highly selective "object-type visual-dominant" AIP neurons during visual fixation of different objects.

PMv might use info about size, shape and orientation of objects from AIP to choose hand shapes appropriate for a given task.


Areas active in human brain during object manipulation.

Source: Binkofski et al. (1999) Exp. Brain Res. 128: 210-213 .

PMv

Anterior region of IPS

Human Anterior Intraparietal region also responds to pictures of "graspable" objects

(hammer, house, lion, face)

Source: Chao & Martin (2000) NeuroImage. 12: 478-484.Source: Kandel et al., Principles of Neural Science, McGraw Hill, 2000

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Scott, Sergio & Kalaska (1997) J. Neurophysiol. 78: 2413-2426 Scott, Sergio & Kalaska (1997) J. Neurophysiol. 78: 2413-2426

- MIP / area 5 provides info about how body segments are positioned (cells have "preferred postures")

- PMd might use info about current posture from MIP neurons to plan movements

The nervous system must also deal with ‘higher order’ relationships

PMd cells are active during the delay period when the rules are needed to make the appropriate

movement to a given cue (discussed last lecture)

Biomechanical / kinetic information provided in primary motor area

Complex force/emg profile

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Parietal (area 5) cells vs. MI

cells

Sergio, L. E. et al. J Neurophysiol 94: 2353-2378 2005

Reflects emg/force profiles

Doesn’t reflect emg/force profiles

Source: Gorbet et al. (2004) NeuroImage. 23: 1100- 1111.

Summary: What part of the brain is active for a simple movement?

Functional network active during a "simple" reaching movement -

"ventral stream"

BG

thalamus

Lateral premotor

Medial premotor

M1, S1 and PPC

Adapted from: Gorbet et al. (2004) NeuroImage. 23: 1100- 1111.

Take-Home Message

Many regions of the brain must work together in a network to generate even

"simple" motor outputs.

End of Topic 13

Topic 14 - Stroke

1. Blood supply to the brain

2. Types of stroke

3. Treatment of acute stroke

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Blood supply to the brain

- The brain has high metabolic rate and oxygen requirements:

Human brain is ~2% of total body weight but consumes ~20% of oxygen used by entire body

- "Autoregulation" helps maintain a constant supply of blood to brain tissues.

Source: Shulman et al. (2004) Trends Neurosci. 27: 489-495.

Energy is needed to maintain resting potential, synthesize, remove and recycle NT's etc…

- Most energy is obtained from glucose oxidation

- Brain requires a constant flow of blood rich in glucose and O2.

Anterior cerebral artery

Internal carotid artery

Basilar artery

Middle cerebral artery

Vertebral artery

Anterior cerebral artery

Posterior cerebral artery

To Middle cerebral artery Circle of Willis


Blood supply to the brain

Source: Haines et al., Fundamental Neuroscience, Churchill-Livingstone, 2002

AnteriorMiddle

Posterior

Territories supplied by anterior, middle andposterior cerebral arteries.

Topic 14 - Stroke


2. Types of stroke


Stroke- a.k.a. "cerebrovascular accident" or "brain attack"

- Sudden onset of neurologic deficits due to disruption of blood supply to brain.

36

STROKE - StatisticsDeaths• 4th leading cause of death in Canada• approx. 16,000 Canadians die each

year

Prevalence• 40,000-50,000 strokes in Canada each

year (500,000 in US)• approx every 10-12 minutes

STROKE

1) Ischemic - Blockage of a blood

vessel caused by a blood clot

2 major causes of a stroke:


Source: http://www.stjohn.org

Region of decreased blood flow

Interruption of blood supply (blood clot)

Ischemic Stroke


Lacunar Infarcts

2) Hemorrhagic- rupture of a blood vessel


STROKE 2 major causes of a stroke:


Hemorrhagic Stroke

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Watershed Lesions


Source: Lundy-Ekman, Neuroscience: Fundamentals for Rehabilitation, Saunders, 2002Source: Haines et al., Fundamental Neuroscience, Churchill-Livingstone, 2002

"Umbra" region (ischemic core)

"Penumbra" region (surrounding region)

Neural Effects1. Energy failure -

• Ischemia (deficiency in blood flow) results in hypoxia (deficiency in oxygen) and decreased glucose availability.

Source: Shulman et al. (2004) Trends Neurosci. 27: 489-495.


Na+/K+ pump requires ATP to maintain resting potential.

extracellularintracellular

Within 5 min of ischemia, extracellular glutamate ↑ ~8x.

Neural Effects

2) Excitotoxicity - excessive exposure to glutamate may kill neurons

Neural Effects

Transport of glutamate out of synaptic cleft

Astrocyte glutamine

glutamate

Source: MacKay, Neuro101, Sefalotek Ltd., 1999

Glutamate - Excitotoxicity


NMDA Receptor - ↑ Na+, draws water into the cell

- Changes in cell volume can lead to osmotic lysis(particularly in umbra region)

- ↑ Ca++ , activates proteases, lipases that degrade components of cell, may initiate apoptosis

38

Stroke outcome depends on regions effected -


Topic 14 - Stroke


2. Types of stroke


Treatment of acute stroke

Decreased blood flow in areas supplied by posterior cerebral artery.

Intracranial hemorrhaging.

Thrombolytics – dissolve clots– Tissue Plasminogen Activator (t-PA)– ~ 3 hour time window– 33% more likely to recover from stroke with

little or no disability– Risks include hemorrhage

Acute Treatment for Ischemic Stroke

TIME IS BRAIN!!!!

Acute Treatment

Neuroprotective strategies -

- Glutamate antagonists

- Ca++ and Na+ blockers

- Antioxidants (scavengers of free radicals)

May extend time window for thrombolytics.

Hypothermia as a Neuroprotective strategy?

Source: Kammersgaard et al. (2000) Stroke. 31: 2251-2256.

- Lowered body temperature by 1.3 degrees Celsius during acute phase of stroke

- Patients who were cooled were 2x more likely to survive 6 months post-stroke

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Hypothermia may decrease infarct volumeInfarct volume after thromboembolic stroke

Thrombolysis Hypothermia Thrombolysis and Hypothermia

Source: Kollmar et al. (2004) Exper. Neurol. 190: 204-212.

End of Topic 14 Topic 15 - Recovery from Stroke

Motor Recovery Post-Stroke - Spontaneous

Source: Duncan et al., Neuropharm., 39:835-841, 2000.

40

Recovery Post-StrokeAt least 3 separate but interactive

processes associated with recovery

1) Resolution of diaschisis, inflammation etc..

2) Behavioural compensation

3) Neuroplasticity





3) Neuroplasticity

- Loss of function in remote areas anatomically connected to region of lesion

Diaschisis

- Possibly from disruption of afferent excitatory input from lesioned area to other brain regions.

Diaschisis

Adapted from: Gold and Lauritzen (2002). Proc. Natl. Acad. Sci. 99: 7699-7704

Some initial improvement also likely corresponds to resolution of tissue inflammation.

- early stage inflammation starts a few hours after onset of ischemia

- microglia and leukocyte involvement

Motor Recovery Post-Stroke - Spontaneous

Source: Duncan et al., Neuropharm., 39:835-841, 2000.

41





3) Neuroplasticity

Behavioural compensation

e.g. - Use unaffected arm

- Learn to walk with a cane





3) Neuroplasticity

Mechanisms of NeuroplasticityImplicated in Stroke Recovery

1) Redundancy – alternate pathways take over lost function

2) Unmasking - activation of normally inhibited pathways

3) Long-term potentiation - increasing efficiency of synaptic connections and formation of new synapses.


Adapted from: Cramer et al. (1997). Stroke. 28: 2518-2527.

Cortical Activity During Index Finger Tapping


42

2) Unmasking – activation of normally inhibited pathways

Inhibitory interneuron prevents excitatory connections from whisker area from activating forelimb area.

Model of intracortical connections in M1 -

Adapted from: Jacobs & Donoghue (1991) Science. 251: 944-947.

Adjacent cortical regions expand when preexisting lateral excitatory connections are unmasked by decreased intracortical inhibition.

GABA antagonist

Adapted from: Jacobs & Donoghue (1991) Science. 251: 944-947.

Source: Qu et al. (1998) Brain Research. 813: 374-380.

Reduction in GABA Receptors throughout cortex after focal ischemic lesion.

Control7 days post-lesion

Site of ischemic lesion (somatosensory cortex)

Control subjects

Patients with ischemic lesion (left internal capsule)

Cortical activation during finger tapping with right hand

Source: Calautti et al. (2003) NeuroImage. 19: 1650-1654.

Redundancy and unmasking.

3) Long-term potentiation

- Increasing efficiency of synaptic connections.

- Formation of new synapses.

- A means of modifying neural circuitry

Increase in Ca2+ in post-synaptic cell is critical trigger for induction of LTP


3) Long-term potentiation

43

Source: Purves et al. Neuroscience, SinauerAssociates Inc: Massachusetts, 2001.

Ca2+ ions activate postsynaptic protein kinases

--> result is increased synaptic strength


LTP may arise from rapid insertion of AMPA receptors

Source: Luscher et al. (2000) Nature Neurosci. 3: 545

LTP may increase size and number of synaptic contacts

Source: Engert & Bonhoeffer (1999) Nature. 399: 66-70.

New dendritic spines begin to form approx 1 hour after induction of LTP

Long-term depression - weakening of a synaptic connection


End of Topic 15

44

Topic 16 - Rehabilitation After Stroke

1. Rehab techniques

2. Pharmacological approaches

Forced Use / Constraint-Induced Training

Patients practice using affected limb while other limb is restrained.

- ~6 hours/day for several weeks

- Can increase patient's ability to use affected limb.

Constraint-induced rehab training enhances cortical reorganization

The representation of the unconstrained limb increased.

Source: Kim et al. (2004) Yonsei Med. Journal. 45: 241-246.

- Induced lesion in part of hand representation area in M1.- Without post-stroke rehab digit representation in non-lesioned regions also diminished.

from Nudo, et al., Science, 272:1791-1794, 1996 from Nudo, et al., Science, 272:1791-1794, 1996

- Induced lesion in part of hand representation area in M1.- After rehab spared hand rep areas increased in size.

45

Rehabilitative Training

• Post-lesion training is important for optimizing plastic change.

• An absence of training can lead to a further reduction in representation of the affected limb.

Other approaches…

"Observation" therapy - patient observes someone else moving with intent to imitate movements

--> may involve "mirror neuron" system

"Mirror-box" therapy -movements of patient's unaffected arm appear to be made by patient's impaired limb.

Other approaches…

Source: Ramachandran & Rogers-Ramachandran (1996) Proc R Soc Lond B Biol Sci. 1369: 377-386.

Topic 16 - Rehabilitation After Stroke

1. Rehab techniques

2. Pharmacological approaches

Source: Walker-Batson et al. (1995) 26: 2254-2259.

Amphetamine Enhances Recovery ??

Source: Dam et al. (1996) Stroke. 27: 1211-1214.

Fluoxetine Enhances Recovery ??

46

Stem Cell Therapy

Stem cells are cells with the ability to divide indefinitely and, under the right conditions, give rise to many different cell types.

- potential to replace damaged tissues

http://stemcells.nih.gov/info/scireport(Photo Credit: Mr. J. Conaghan)

Human Blastocyst

Source: Sanai et al. (2004) Nature. 427: 740-744

Lateral ventricular walls of adult human brain contain stem cells.

"Activation" of these cells could allow the brain to heal itself.

Adapted from: Chu et al. (2004) Brain Res. 1016: 145-153.

• Acute treatment• Reperfusion and neuroprotection• Time window: hours• Target: ischemic core and penumbra• Limitations: time window, risks

• Recovery and Rehabilitation • Time window: days, weeks, months,

years• Target: the “rest” of the brain• Development of innovative rehabilitation

techniques and “stroke recovery drugs”

Summary - Stroke Management Strategies

End of Topic 16

(and lecture material!)

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