W11 Pain and Motor Control and disease

Question 1

Loss of pain

Answer 1

Loss of pain sensation due to nerve damage is a feature of diabetes mellites adn leprosy. Absence of pain means a person is unaware of minor injury. Unless carefully managed, these injuries become infeted; in the case of leprosy: can lead to loss of fingers, toes or entire limbs.

Question 2

What is pain?

Answer 2

Differs from the classical senses (vision, hearing, touch, taste, smell) because it’s both discriminative sensation and a graded motivation.
It’s a leading clinical complaint that can present mystifying symptoms, such as allodynia, referral, placebo-effect, after-sensations, emotional variability and hyperpathia.
It can attain intolerable intensity, can disappear in the heart of a battle

Question 3

Specificity Theory

Answer 3

Ambiguity about pain is reflected in ow we think about its repesentation in the brain.

Specificity theory: holds that pain is a distinct sensation, detected and transmitted by specific receptors and pathways to distinct pain areas of th ebrain.

Question 4

Convergence thoery

Answer 4

Suggests that pain is an integrated, plastic state represented by a pattern of convergent somatosensory activity within a distributed network.

Question 5

What are afferent neurons with free nerve ending?

Answer 5

Nociceptors.
Classified according to activating stimlus, fiber-tpe and conduction velocity.

Question 6

Lightly myelinated A[delta] fibers

Answer 6

fast ~20m/s: mechano sensitive and mechanothermal sensitive

Question 7

Unmyelinated C fibers

Answer 7

slow ~2m/s = Polymodal: mechanical thermal and chemical

Question 8

What neuron responses specificially to pain

Answer 8

Nociceptors respond specifically to pain and are a subset of afferents with free nerve endings.

Thus, there are a distinct set of A[delta] and C fibers, nociceptors, specifically associated with pain detection.

Question 9

Fast pain

Answer 9

Fast, first pain: sharp and immediate, can be mimicked by direct stimulation of A[delta] fiber nociceptors.

Question 10

Slow pain

Answer 10

Slow or ‘second’; more delayed, diffuse and longer lasting; mimicked by stimulation of C fiber nociceptors.

Question 11

Molecular pain receptors

Answer 11

Specific molecular receptors associated with nociceptive nerve ending are activated by heat.

The capsaicin receptor (TRPV1) is activated in nociceptive A[delta] and C fibres at 45°C and by capsaicin, a vanilloid which is the active component in chilis. Related receptors are activated in A fibres alone at even higher thresholds (52°C)

Question 12

Central pain pathways

Answer 12

Pathways carrying nociceptive information, not the brain are complex. Two components:

1- Sensory discriminative: signals location intensity and type of stimulus.

2- Affective motivational: signal unpleasantness and enables autonomic activation, classic flight or fight response.

Discriminative pathway is easiest to define and involves a tract we have already met: the spinothalamic tract, also called the anterolateral system.

Question 13

What does Spinothalamic prokections preserve?

Answer 13

Topology. Measurement of activity in the somatosensory cortex indicate that this region does indeed respond to painful stimuli and that rsponse correlates to intensity of pain. That this is spatially mapped, shown ecperimentally.

Question 14

Comparison (MRI) of cortical activation by painful (C fibre) or innocuous mechanical (vibration 1 [beta] fiber)

Answer 14

stimuli to skin demonstrates that painful stimuli activate the same region of the somatosensory cortex as the non-painful mechanical stimulation applied to the same region of skin (yellow arrows in A).

Question 15

Affective-motivational pathways

Answer 15

Shares some pths with the anterolateral system.

Little or no topographic mapping: neurons in parabrachial nucleus an respond to painful stimuli from anywhere on the body’s surface.

Nmber of points of input to the emotional limbic and homeostatic hyopthalamus.
Strong Correlation or painful experience with activity in cingualte cortex.

Question 16

Summary of the specificity theory

Answer 16

There are receptors, both celullar and molecular, that respond specifically to pain (a subset of A [delta] & C fibres; TRPV1). There are specific pathways that convey pain messages. There are regions of the CNS that are specifically and distinctly activated in response to pain.

Question 17

Limitation - specificity theory

Answer 17

Pain perceived is not always proportional to intensity of stimulus. Modulation by other stimuli (e.g. acupuncture). Perception of pain in severed limbs (phantom limbs). Referral of pain from viscera to skin. Placebo effect.

Question 18

Hyperalgesia

Answer 18

increased response to a painful stimulus. Hypersensitivity of damaged skin to a normallly tolerable painful stimulus. (e.g. light skin rpick)

Question 19

Allodynia

Answer 19

Painful response to a normally innocuous stimulus. Painful sensitiivity of sunburnt to skin to gentel mechanical stimuli

Question 20

What is the inflammatory response - peripheral effects

Answer 20

Peripherally, tissue damage relase a soup of inflammatory substances which affect nerve function, recruit mast cells and neutrophils and increase local lood flow.

Prostaglandins lower the threshold for axon potential generation. Some painfkiller (analgesics) e.g. aspirin act on Cycloocygenase, an enzyme important in prostaglandin biosyntheisis.

Question 21

Central sensitisation

Answer 21

result from the acitivity dependent local release of sustances like prostaglandins from nociceptive dorsal horn neurons.

This can lower the thresholds fro action potentials generation for neurons relaying nociceptive inforamtion, also giving rise to hyperalgesia.

Consequence: relay neurons also become sensitive to nervy non-nociceptive inputs, normally innocuous stimuli can be perceied as painful: allodynia

Question 22

Hyperpathia

Answer 22

is a variant of hyperalgesia and allodynia, but its underling causes are different and so the symptoms are also slightly different.
It resutls when there is fibre/axonal loss/damage, that results in a raissing of the detection threshold.
The result however is that when the detectio threshold is exceeded the subsequent excitability I much greater and patients report explosive pain.

Question 23

Phantom Limb Pain

Answer 23

Phantom limbs are experienced after amputation. Patients have the illusion that the limb is still present. Indicates that central representation of the body is not passive, ie that it persists in the absence of peripheral input. Surprisingly, children born without limbs can also have phantoms, suggesting that central maps may be partly pre-formed.

Question 24

Referred Pain

Answer 24

Phenomenon not easily expalined in term of the specificity theory.
Pain due to damage in the viscera is often perceived as coming from a specific location in the sin according to what organ is affect: reffered pain.
This aids clinical diagnosis of organ dysfunction.

Question 25

Central Modulation of Pain

Answer 25

It is clear that our perception of pain varries according to its context. Henry Beecher, WWII: soldiers with severe battle wounds often experienced little/no pain. Similarly the mere suggestion that pain will be relieved can result in pain relief: placebo affect. Indicates that mechanisms exist, voluntary or involuntary, to overcome even severe pain.

Question 26

Physiological basis of pain modulation

Answer 26

Discorved when experiements stimulating certain regions of the midbrain produced pain relief. Stimulation of the periqueductal gray activates brainstem nuclie that modulate the activity of dorsal horn neurons (descending inputs activate enkephalin, realising interneurons inhibit nociceptive fibers)

Question 27

Enkephalins

Answer 27

Member of a famly of endogenous opiod peptides that also include endorphins and dynorphins. If activated, realise interneurons which presynaptically inhibt nociceptive fiber

Question 28

Where could modulatio also occur?

Answer 28

Locally. Rubbing an injury often relieve the pain. This is thought to be due to local inhibition by mechanoreceptors (A [beta]fibres) of nociceptive (C fibre) inputs in the spinal cord

Question 29

Gate or Senosry interaction theory of pain - Melzack & Wall, 1965

Answer 29

Suggested pain perception to be the result of integration of convergent sensory information. The existence of such circuits is provocative, and certainly challenges the simple assumption of a ‘straight-through’ pain input that underlies specificity theory.

Question 30

Motor Control hierarchy

Answer 30

Simple reflexes involve local circuit control of spinal motor neurons by spinal sensory neurons. All movements produced by the skeletal musculature are initiated by these lower motor neurons.

Question 31

1870 Fritsch & Hitzig - Electrical stimulation of part of the cortex

Answer 31

Elicits contraction of contralateral body muscle. Region became known as the motor cortex and more specifically the primary motor cortex. The neurons found in the brain that onntorl motor function: upper motor neurons

Question 32

Motor cortex - Somatotopically maps

Answer 32

The correlation of the site of stimulation with the location of muscle contraction and the topographic map is similar to that of the somatosensory system.

Question 33

Similarities and diffferences of both sensory/motor maps

Answer 33

Similarities: Lower body is represented medially, upper body laterally. Proportions reflect density of innervation and behavioral significance. Differences: the ears do not move but they do a lot of sensing

Question 34

Axial muscles

Answer 34

Trunk movement

Question 35

Proximal muscles

Answer 35

Shoulder, elbow, pelvis, knee movement

Question 36

Distal muscles

Answer 36

Hands, feet, digits (finger/toes) movements

Question 37

Somatic motor system basics

Answer 37

Control of lower motor neurons in the ventral horn of the spinal cord which innervate striated muscle to control movement. Specifically: Axial muscles, Proximal muscles, Distal muscles. Innervation is via a specialized synapse called the Neuro Muscular Junction (NMJ)

Question 38

What are the low motor neurons rules and definitions?

Answer 38

Each muscle fibre receives input from a single lower motor neuron. Each lower motor neuron innervates the fibres of just one muscle.

Question 39

Motor unit

Answer 39

Motor neuron and all the muscle fibres it innervates

Question 40

Motor neuron pool

Answer 40

All the motor neurons that innervate a single muscle

Question 41

How are Motor pools organized in the spinal cord

Answer 41

Spatially organised. All motor neuron innervating a particular muscle: the motor pool for that muscle are groued in rod-shaped clusters within the spinal cord extending over several vertebral segments.

Question 42

How is the motor pool organised

Answer 42

Somatotopic organization. The medio-lateral position of a motor pool reflects whether it’s MNs innverate a proximal or distal msucle. Therefore, motor pools are organised somatotopically both medio-laterally and rostro-caudally. There’s 3 dimensional representation (map) of the body’s musclature iwthin the spinal cord.

Question 43

Motor cortex reflect in Somatotopy

Answer 43

Location of the upper motor neurons that innervate lwoer motore neurons in the spinal cord. Local spina lcord imputs and lower motor neurons receie direct input from the upper motor neurons.

Question 44

Corticospinal tract (CST) - upper motor neurons projection

Answer 44

Upper motor neurons project axons to lower motor neurons via the descending tracts of the spinal cord Key for voluntary movement is the corticospinal tract (CST) one of the lateral pathways of the spinal cord. The axons of the CST origniate in layer V of the motor cortex.

Question 45

Pyramidal cells

Answer 45

Cells of the motor cortex project axons in the corticosponal tract. 90% of cortex, including the motor cortex, is a six layered structure. Main inputs to the cortex are to stellate cells in layer IV. Main outputs are from layers III, V and VI. Axons of corticospinal tract derive from large Pyramidal cells* in Layer V

Question 46

Projection - axons of the corticospinal

Answer 46

The axons of the corticospinal tract cross midline in the pyramidal decussation in medulla. Project laterally in the spinal cord to synapse on laterally located lower motor neuron circuits that control distal muscles (esp. at limb levels). The CST is one of the lateral pathways.

Question 47

Motor ortex upper motor neurons

Answer 47

Primarily concerned with fine voluntary control of more distal structures

Question 48

Brainstem upper motor neurons

Answer 48

Prokect to medial motor pools primarily concerned with postural movement

Question 49

Axons from the brainstem prokect ipsilaterall in several tracts

Answer 49

Vestibulospinal Reticulospinal Prokect medially in spinal cord. Synapse on medially located lower motor neuron circuits that control axial muscles. Ventromedial pathways.

Question 50

Doing great love

Question 51

Tectospinal tract

Answer 51

orienting response (inputs from visual system via superior colliculus).

Question 52

Vestibulospinal tract

Answer 52

head balance and turning (inputs from vestibular system)

Question 53

Reticulospinal tracts

Answer 53

Control antigravity refleces

Question 54

Upper motor neurons of the motor cortex

Answer 54

Initiate complex voluntary movements Project mainly contralaterally via the corticospinal tract primarily to muscles involved in precise limb movements, particularly those of the hands in humans – one of the lateral pathways of the spinal cord

Question 55

Upper motor neurons of the brainstem

Answer 55

More concerned with the maintenance of posture and balance. Located in several nuclei including = Reticular formation and Vestibular nucleus (vestibular co-ordination and superior colliculus (visual co-ordination) Project mainly ipsilaterally to lower motor neurons controlling axial muscles concerned with maintianing posture - the ventromedial pathways of the spinal cord.

Question 56

What is the intergration of postural control with voluntary movement

Answer 56

Volunteer will lift level in response to auditory stimulus (tone), recording frm different msucles reveals that the first to contract are those in the leg. The anticipatory echanism pre-adujest body posture to compensate for the forces that will generate when the lever is lifted.

Question 57

What is the indirect cortical control of lower MNs?

Answer 57

Feedforward mechanism makes sense when realise that upper MNs in the cortex influence spinal cord circuits by two routes: Area 6/PMA Area 4

Question 58

Area 6/PMA

Answer 58

Anticipation of movement activates an indirect projection to exial muscles via reticular formation.

Question 59

Area 4

Answer 59

acitvation of voluntary movement direct to spinal cord via corticospinal tract.

Question 60

Neuropathology

Answer 60

Can effect both upper and lower motor neurons

Question 61

Mirror Therapy - Phantom limb pain, anticipation

Answer 61

Patient feels imaginary movement of removed limb as normal movement through mirror image of normal limb. Mirror neurons identified (in somatosensory and motor cortex) which fire both when a person acts and when they observe the action in another. Can be accompanied by emotional responses appropriate for the action in a specific context. Thus, reduces pain associated with limb amputation or during stroke recovery. Part of our ability to empathise and understand the behaviour of others.

Question 62

Lower motor neuron disease is characterised by ...

Answer 62

Muscle paresis (weakness) or paralysis. Loss of muscle tone due to loss of stretch reflexes. Ultimately, leads to severe muscle atrophy. Patients usually die from lung dysfunction

Question 63

Upper motor neuron disease characterised by

Answer 63

Muscle weakness. Spasticity due to increased muscle tone (due to failure of modulation of stretch reflex). Hyperactive reflexes. Loss of fine voluntary movement. Patients usually die from loss of input to the bulbar muscles (tongue and pharynx) via the corticobulbar tract

Question 64

ALS

Answer 64

ALS is one of several neurodegenerative disease. The cause of deeneration is not well understood.E

Question 65

Excitoxicity

Answer 65

Excitoxicity is one possibility, where overstimulation, typically by glutamate, leads to neuronal cell death A ‘vicious cycle’ of glutamate release can occur, particularly in hypoxic conditions, e.g. after cardiac arrest, stroke or brain trauma. The only drug to have any effect is a blocker of glutamate release (Riluzole) but this only delays the disease by a couple of months. About 10% of cases have a clear genetic (inherited) basis.

Question 66

Results -mutation of gene encoding Superoxide dismutase (SOD1) (ASL)

Answer 66

One of these results from mutations in the gene encoding Superoxide dismutase (SOD1), a key enzyme that ‘mops up’ the free radicals that accumulate in metabolically active cells. Other genes, however, appear to affect a variety of cellular processes and there is clearly much more to be learned.

Question 67

Basal Ganglia and cerebullum

Answer 67

These structures influence movement indirectly by regulating the function of upper motor neurons, no direct connection s to lower motor neurons. Neurodegenerative diseases affect both of these systems.

Question 68

Key components in the initation of movement

Answer 68

Motor cortex (AF4): Telencephalon. Basal Ganglia: (Forebrain): Caudate, Putamen, Globus Pallidus and Subthelamic nucleus. Ventral lateral nucleus of thalamus: Diencephalon. Substantia nigra: Midbrain

Question 69

Motor Loop

Answer 69

The motor cortex connects to the basal ganglia, which in turn feedback to the premotor area (Area 6) via the ventrolateral complex of the thalamus (VLo) to control the initiation of movement. 2 pathways: direct/indirect

Question 70

What is the role of the Basal Ganglia in the initiation of movement: direct pathway?

Answer 70

1- With no initiating cortical inputs, the Globus pallidus internal segment GPi tonically (producing continuous stimulation or inhibition) inhibits the VLo. 2- Input from many cortical regions converges on the striatum. 3- When activated by this input, the striatum inhibits the inhibitory activity of the GPi, releasing the VLo to activate Area 6 and initiate movement.

Question 71

Direct pathway

Answer 71

Direct pathway is modulated by a complex indirect pathway which involves the substantia nigra (SN) and GP external segment (GPe)

Question 72

Substantia nigra

Answer 72

The substantia nigra has a complex role and act via the striatum (CP) to maintain the balance between inhibition and activation of the VLo. Excitatory input from the SN stimulates VLo activation, by activating the inhibition of the GPi through the direct pathway. In the indirect pathway, the GPe inhibits the GPi. But the GPe is inhibited by the CP -> VLo inhibition However, inhibitory input from the SN decreases CP inhibition of the GPe, -> GPi inhibition, thus allowing activation of the VLo.

Question 73

Parkinson's disease

Answer 73

‘……involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported, with a propensity to bend the trunk forward, and to pass from walking to a running pace, the senses and intellects being uninjured.’

Question 74

Motor symptoms - Parkinson's

Answer 74

Hypokinesia - paucity/insufficiency of movement Bradykinesia - very slow movements Akinesia - no movements Increased muscle tone - rigidity Resting Tremor - @4-5Hz- ‘pill rolling’ Shuffling gait and flexed posture, impaired balance Mask-like expression.

Question 75

Non motor symptoms - Parkinson

Answer 75

mood-disorder, loss of sense of smell. Caused by loss of dopamine (DA) first example of a brain disorder resulting from deficiency of a single neurotransmitter.

Question 76

What causes the dopamine loss in parkinsons

Answer 76

Due to loss of dopaminergic neurons in the substantia nigra. 80% of the brain’s dopamine is found in the basal ganglia, specifically the substantia nigra (SN). Loss of dopamine in PD patients is due to loss of dopaminergic (DA-ergic) neurons in the substantia nigra. Degeneration of these neurons is marked by the presence of Lewy bodies – intracellular protein aggregates.

Question 77

What is an effective but temmprary theory? L-DOPA

Answer 77

Oleh Horyenkiewicz: intravenous L-dihydrocyphenylalanine (L-DOPA- a dopamine precursor) provided a dramatic though brief reversal of symptoms in PD patients. The gradual increases in oral L-DOPA provide significant and longer benefits.

Question 78

Limitations of L-DOPA

Answer 78

However, beneficial effects of L-DOPA only last for ~ 5 yrs. Works by boosting capacity of surviving DA-ergic neurons in substantia nigra (SN) to make dopamine (DA). However, does not stop the degeneration of SN neurons. Eventually there are insufficient SN neurons left to make DA. Also has side effects: increase in motor response fluctuations and drug related dyskinesias (erratic movements).

Question 79

Hypokinesis

Answer 79

reduced movement: L-DOPA reverse this effect, but only as long as some DA-ergic neurons survive.

Question 80

Surgery - PD cases

Answer 80

surgical removal of the GPi can be effective in reversing the Parkinsonian effects. More recently deep brain stimulation is used to inhibit GPi hyperactivity.

Question 81

Effects of loss of DA on the basal ganglia in parkinson

Answer 81

Reduced dopaminergic input from substantia nigra to striatum leads to both: Increased activity of indirect activity and Decrease activity of the direct pathway. This means less inhibition of the GPi and so it’s inhibiotyr activity is increased. This leads to decreased activity of the VLo and so less motor cortex activation.

Question 82

Huntington's disease

Answer 82

Rare, hereditary, progressive, fatal. 3-7 people per 100000 with European ancestry, less in other ethnic groups.

Question 83

Huntington - symptoms

Answer 83

Early hyperkinesia or dyskinesia, chorea (involuntary jerking or twitching movements. Later: Akinesia and dystonia (muscle spasms), dementia, personality disorders (psychosis).

Question 84

Huntington - Cause

Answer 84

autosomal dominant genetic disease resulting in neuronal degeneration: - initially in the indirect pathway components of the striatum, - subsequently in the direct pathway components & in the GPe.

Question 85

How do Huntington disease arise?

Answer 85

Basal Ganglia Early on: degeneration in the striatum reduce (X), the indirect path inputs to the GPe, this increase the inhibition of the GPi with the results that the VLo is dis-inhibited and there is inappropriate initiation fo movement: Hyperkinesis, chorea. Later: the striatal diret path & GPe neuron also degenerate, releasing the GPi to over-inhibit the VLo: Akinesia (lack of movement)

Question 86

Genetic element - PD

Answer 86

Most cases of PD are sporadic/idiopathic (specific to an individual cause unknown), but the disease is common (1% in >60s), only 10-15% are inherited. Mutations in multiple genes ‘predispose’ you to getting PD: some are rare but with high ‘penetrance’, others are common but have low penetrance PD genes encode proteins involved either in protein degradation pathways or in mitochondrial function

Question 87

Genetic element - Huntington D

Answer 87

HD is rarely sporadic (mainly inherited), but rare. Only mutations in HTT (encoding ‘Huntingtin’ protein) cause HD, but if you have the specific mutation, you are certain to get the disease at some point (onset varies). Mutant HTT protein contains extended stretches of poly-glutamine (polyQ) which contributes to aggregation of proteins in ‘inclusion bodies’ in affected neurons.

Question 88

Spinal motor neurons

Answer 88

Lower motor neurons

Question 89

Brainstem and cortex

Answer 89

Upper neurons

Question 90

Motor neuron disease -

Answer 90

Motor neuron disease can affect either upper or lower motor neurons.

Question 91

Basal ganglia

Answer 91

Funnel to collect information from the prefrontal and motor cortices, the filter decides which information to act upon, balancing the different input. Sensory imputs from sensory cortex. Substantial nigra: inputs from emotional and decision-making areas that evaluate risk vs reward.

Question 92

Cerebellum and motor learning

Answer 92

It modulates the upper motor neurons, with no direct connection to the spinal cord. Requires for the learned execution of planned voluntary, multijoin movements.

Question 93

Muscle Memory

Answer 93

Motor learning, involves the cerebellum comparing what is intended with what actually happens.

Question 94

Cerebellum - Motor cortex - Loop formation

Answer 94

Cerebellum receives input from many areas, it projects back to the motor cortax via thalamus (VLc) but has no direct output to spinal cord. Primary function: detect/correct difference between intended movement and actual movement = motor errors.

Question 95

Cerebellar ataxia

Answer 95

Codition characterised by poorly integrate movement. Lesions to the cerebellum.

Question 96

Dyssunergia

Answer 96

Even simple tasks require co-ordination of multiple muscle and joints in sequence. Ataxia: lost of that ability: dyssynergia