L4: Descending inputs

Why are inputs from higher centres (descending inputs) needed

• For goal-directed movements

  • move with purpose

• the spinal cord on its own produces feedforward→ which only predicts→ and can get this wrong

• note: these are not two separate components!→ it forms a heterachy!

Two places these inputs are from

1. Cortical motor areas (motor cortex

2. Brain stem (pre motor area)

How are these descending commands integrated with spinal circuits

1. project to the brain stem and spinal cord

2. connect to spinal interneurons

3. to motor neurons

Two types of descending pathways

1. Fast pathways→

   • instantaneous activation

   • control specific aspects of on going movements and motor neurone timing

2. Slow pathways→

   • More constant and longer lasting

   • Uses amines and neuropeptides

   • to modulate spinal and motor systems

Fast pathways are split via spatial differences

1. Medial

   • Proximal muscle

   • whole body movements

     • posture

2. Lateral

   • Distal muscles

   • movements of extremities

   • Fine movements

note: proximal distal rule from L2

1. Medical brain stem pathways

1. Vestibulospinal: postural control, maintaining equilibrium and has projections to limb extensor (antigravity) muscles

   • 2 pathways

2. Tectospinal: orientation (head and eye movements) to sound and objects

3. Reticulospinal: orientation and CPG activation

   • several brainstem tracts

1. Vestibulospinal system

• process information from the vestibular

  • found in the ear

  • Cupula in semi-circular canals:

    • filled with endolymph and modified hair cells in jelly-like substance

• posture and balance

• has projections to limb extensor (antigravity) muscles

1. How does this help control posture and balance

1. Move head (voluntary or involuntary)

2. deflects a couplet

3. sends a signal

4. get information of movement from the head

5. sent to motor system to matai the posture

6. e.g increase your base so you don not fall over

7. Very accurately and quickly dectects a change in signal

1. However, if we move the head voluntarily, the signal is still picked up. How is the reflex movement to maintain balance stopped in this case?

1. Feed-forward command to shut it down?→ but cannot be sure the prediction is correct

2. Solution: internal feedback (need to check this!)

   1. Send efferent copy of the signal back to the muscle

   2. calculates how much sensory input (re-afferent) is needed

   3. finds the correct signal

   4. adjusts posture as needed

its is not known has it does these calculations

2. Tectospinal system: strucuture

Coordinates head and eye movements (to sensory stimuli)

Has four bodies:

• 2 inferior colliculi→ integrate auditory, spatial and sensory data

• 2 superior colliculi→ direct behavioural responses to sensory stimuli

2. What does the superior colliculus do

1. Eye movements→ direct how we e.g scan faces in a particular way

2. Involuntary saccadic eye movements→ need to move constantly other wise the photoreceptors adapt

2. Why are these eye movements needed

Allows to orientate head and eye movements to sensory stimuli

• Linking the auditory and visual space around you

Example:

1. when hear or something catches your eye at night

2. superior colliculus will guide your eye, head or even trunk towards the stimulus (i.e can control the whole motor system to orientate)

3. so you can get more info as to what it is (can foveate)

4. and build up the sensory map around you

3. Reticulospinal pathway: what involved in

1. general body orientation

2. simple motor patterns

   • EVIDENCE: pathway activates spinal CPG circuits (see later with cat)

Where do reticulospinal neurons receive inputs from

1. motor cortex

2. cerebellum

Descending pathways activate spinal motor systems: Shik and Orlovsky experiment with cat

Procedure:

• electrical stimulation of midbrain of cat

• elicit locomotion

Results

• Low stimulation→ walking

• Increased→ trotting

• Further→ galloping

Conclusion:

• region stimulated→ Mesencephalic locomotor region (MLR)

What does the MLR do

• activates the reticulospinal system

  • → switch on movements

• THEREFORE: the descending systems allow the brain to modulate spinal locomotor networks (and their sensory inputs)

  • so that the output is appropriate for particular tasks

• analogous structures have been found in other vertebrate systems

Why is the CPG involved in this response?

1. The MLR just sends a continuous train of AP at at constant frequency

2. this cannot coordinate the cycle of flex/extensor movement

3. This signal is just to switch on CPG

4. CPG interprets this signal as a command to generate a motor output

   • e.g the freq of action potentials

5. (e.g walking or running)

6. THEREFORE: the coordination of the basic output id done by spinal cord CPG

Not only is there signal from brain-stem to spinal cord, but there is input from spinal cord→ brainstem Example of 2 way interaction (HETERARCHY)

→Brainstem motor centres send inputs to but also inputs from the spinal cord

note:

• another example of this (already seen in last lecture:

  • spinal CPG and sensory inputs

  • e.g golgi tendon organ reflex reversal (input to and from the spinal cord)

How was this (spinal cord→ brain stem) input found out?

Procedure:

1. evoke fictive locomotion in spinal cord

2. put barrier to stop connection to the brain

3. record from the neruon in the reticulospinal system

Result:

• Neurons also gets depolarised

Conclusion:

• two way interaction

• sends a signal BACK to brainstem

THEREFORE: evidence of heterarchy

2. LATERAL brain stem pathways

1. Rubrospinal

2. Corticospinal

1. Rubrospinal tract: where does it come from (hint at name)

• from the red nucleus

• which crosses over and goes to the lateral regions of the oppsite side of the spinal cord

• in lower vertebrates

1. Rubrospinal tract: controls what in mammals

1. reaching

2. limb movements

Inputs of the rubrospinal tract

1. Some direct inputs from motor neurons

   • esp. in primates

2. Motor cortex

3. Cerebellum

Rubrospinal tract in humans?

• replaced by the corticospinal tract

• Instead: the red nucleus mainly sends inputs to the cerebellum

  • not the spinal cord

2. Corticospinal pathway→two pathways

The most important descending pathway in mammals

1. Large lateral pathway (left) (80% of fibres)

   • crosses the brain stem

2. Smaller ventromedial pathway (right) (20% of fibres)

   • uncrossed

What do corticospinal lesions cause

(e.g from stroke)

1. Initially→ muscle weakness and loss of reflexes

2. With time→ subsequent spasticity

   • why: reflects changes in sensory processing over time due to loss of descending regulation

Comparative anatomy of corticospinal tract

Show how corticospinal tract has changed during evolution

1. Rodents→ tract terminates in dorsal (sensory) areas

2. Cat/dogs→ terminate in intermediate zone

3. monkey→ some direct connections to motor neurons appear

4. Humans→ inputs to motor neurons are widespread in humans

Therefore→ we emphasise the heteracrhy

• cortical areas are involved in direct execution of motor system

Descending pathways can also influence (what is this comparable to)

Development of spinal systems

(this is comparable to the effects of vision from L1→ where vision helps the development of the motor system and vise versa)

At what age do the direct projections from motor cortex to motor eurons begin to mature

• At 9 months

• About the same time that manipulative skills begin to develop

  • These manipulatve skills between children of 7-8 months can be compared to stroke patients who have lsot corticospinal inputs

Investigating descending regulation of inputs: receptive fields of nociceptive afferents and conclusion: EVIDENCE that inputs influence development

Procedure:

• Rats with spinal cord transected so just goes to dorsal

• either in

  • neonates (right)

  • (acute) adults (left)

Results:

• receptive fields of nocicepetic afferent are increased in neonates compared to (acute( adults

Conclusion:

• receptive fields are regulated during development by descending pathways

What was also found in this experiment (neonate vs adult)

Direction of limb movement in response to nociceptive stimuli also differs in normal adult rats vs rates subjected after birth

• Adult normal→ direction is away from nociceptive stimulus

• Adult transected→ direction inappropriate towards the nociceptive stimulus

• Neontatal transection→ prevents normal shaping of flexion withdrawal reflexes by descending inputs

Role of descending inputs in the development of spinal function is also shown in human cerebral palsy

Cerebral palsy→ defects descending systems

• which are associated with changes in the regulation of spinal reflexes

Dorsiflexion differences in normal adult vs infants and adults with cerebral palsy

Dorsiflexion: pushing the foot up

• Normal foot→ short-latency muscle response: causes reflex contraction of the tibialis anterior (extensor) muscles→ to oppose the movement

• Cerebral palsy→ Activate flexor and extensor muscles

What does this suggest: role for descending inputs in regulating the development of mature spinal function

Overall what do the fast pathways show us (in terms of hertarchy)

• Supraspinal ← → Sensory input

• Supraspinal ← → CPG

• Sensory input← → CPG

SLOW decesning pathways: what designates slow vs fast pathways

• the relative speed of onset of their effects and duration of action

• Largely reflected in synaptic transmission:

  • Ionotropic→ fast

  • Metabotropic→ slow

Characteristic of slow pathways

• does not affect directly

• create longer lasting modulatory responses

Slow pathways NTs and Neuropeptides

1. Predominantly→ Aminergic

   • 5-HT from Raphe nucleus

   • NA from locus coeruleus

2. Some use neuro peptides:

   • Substance P

   • galanin

   • thyrotophin-releasing hormone

   • NA

   • neuropeptide Y

Slow pathways showed evidence for co-localisation of transmitters

• loads of transmitters in one neuron

• if single neuron is stimulated→ can release more than one transmitter

• single neurons can co-localise and release multiple vescicles

How are these different NTs/Neuropeptides arranged in the neuron

From closest to terminus towards the axon:

1. Amino acids (glutamate)

2. Amines (larger vesicles)

3. Peptides (substance B)→ larger and even further from the active surface

Their release is dependent on the activity

• Low Ca2+ freq signal→ only release one closest (amino acids)

• As increase the freq signal→ the amino and peptides etc are also released too

THEREFORE: Dale’s principle is negatied (that single neuron contains a single transmitter)

• note: Dale never actually named it (was Eccles in honour of Dale )

• at one terminal→ can release different NTs

Eccles then changed the principle

• the same transmitters would be found at all branches of a neuron

• not that a neurone release only one transmitter

• HOWEVER: there have been some exceptions to this

Amines and peptides act via

• G-protein-coupled receptors

• intracellular pathways

• → Alter cellular and synaptic properties of spinal cord neurons

  • i.e locomotoer CPG or sensory inputs

This is Neuromodulation

Example of neuromodulation: 5-HT

• 5-HT converts a cell that is silent in response to a depolarising input

• positive current injected into the cell

• to one generating a high frequency train of action potentials

  • ‘plateau potential’

Descending modulatory pathways are activated when

During locomotion

• degree of activity increases as the demands of the task increase

1. At rest→ Raphe neurons fire tonically at low frequency

2. During locomotion→ high freq burst of APs develop (this is most effective in releasing amines and neuropeptides)

Modulatory effects of transmitters released by slow descending pathways on the activity in spinal CPGs have been studied using

Fictive locomotion:

Procedure:

• add NMDA to switch spinal cord on

• Add whatever transmitter you are interested in

Results:

1. 5-HT→ slows the locomotor activity in the lamprey locomotor CPG

   • (the network was activated by the glutamate receptor agonist NMDA applied to the isolated spinal cord)

2. substance P (neuropeptide)→ increase the freq of network activity and better coordinated

Therefore this shows:

• descending systems can use transmitter systems that act on the locomotor network to very the output of the locomotor CPG

How is this modulation happening?

• Modulatory transmitters and their receptors alter the properties of neurons in the spinal CPG to functionally recoonfigure the CPG:

  • Altering different tpyes of neurons

  • THEREFORE→ alters the motor output

How are a large number of spinal motor patterns from a single hard-wired network provided

1. larger number of transmitters in descending pathways

2. different types of receptors that they act on (over 30 5-HT receptors)

How do spinal cord injury show the role of descending inputs to the spinal cord

• injury→ paralysis and other dysfunction (spasticity, chronic pain etc)

• where the descending inputs have been lost

• therefore: shows how descending inputs are needed to activate and modulate locomotor activity

  • therefore: to treat spinal cord injury→ need to attempt to restore these inputs

Effective treatment→ making axons grow?

• neurons can regrow

• however→ they are inhibited (we do not know why)

• need to find inhibitory factors and switch them off

  • e.g Olfactory neurons re-grow when they are made from the nasal epithelium down a permissive pathway

  • cells that allow the axons to grow→ chiefing cells?

  • can transplant these in and see what happens

• some evidence for this but not been translated to effective treatment so far

What happens to the locomotor networks in the spinal cord below the lesion site

• not lost after injury

• but the lack the input needed for their activation and modulation

Therefore this suggested some therapeutic options:

• the role of drugs in activating (e.g glutamte) or modulating (5-HT) locomotor CPGs

• suggests that drugs that mimic effects of transmitters released naturally from descending neurons could help compensate for the effects of spinal injury

Results: using 5-HT or glutamte agonist as therapy

• in cats→ improve locomotor performance

  • sifure shows movement of the limbs and muscle activity in an intact animals

  • with receptor complete spinal lesion and in the same lesioned cat 2 min after applying noradrenergic agonist clonidine

  • RESULT→ dramatically improved the locomotor pattern

• BUT→pharmological approaches have had mixed success

There is considerable variability in drug effects depending on

1. extent of injury

2. time after injury→ Chlonidine is only effective soon after a spinal lesion (acute vs chronic lesions)

3. Reliable experimetntal effects may not be translated to the clinic

What else can be used as a treatment?

Electrical stimulation:

• stimulation to substitude for descending inputs

• BUT→ to generate actual locomotion some connection to the brain is needed

Therefore what does this suggest is needed for therapy

• combination of

  • regeneration with pharmalogical and electrical stimulation and locomotor traning tailored to the specific needs of individuals

Overall why is is so difficult to get these threapies to work

Heterachy network:

• cannot just dump in a load of stem cells/ NTs etc

• complex network that has to be re-wired

Summary of descending inputs

1. Descending pathways convey supraspinal signals to spinal CPGs to influence the development and function of spinal networks.

2. Ventromedial systems are principally concerned with control of proximal muscles.

3. Dorsolateral systems are principally concerned with control of distal muscles.

4. Slow pathways have global modulatory effects.