Motor Neuron Diseases (MNDs) and Amyotrophic Lateral Sclerosis

• Motor neuron diseases (MNDs) are hereditary or sporadic disorders affecting upper motor neurons (UMNs), lower motor neurons (LMNs), or both.
• Amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, is the most common and lethal neurological condition of MNDs in adults.
• "Pure" ALS involves the degeneration and loss of motor neurons in the spinal cord, brainstem, and brain, leading to UMN and LMN symptoms.
• Sporadic ALS causes include poliomyelitis and its variants; less common causes: immune-mediated, endocrine, traumatic, and paraneoplastic infections.
• Hereditary causes of ALS include spinal muscular atrophy (SMA), familial ALS, and X-linked bulbospinal muscular atrophy (Kennedy disease).
• ALS is increasingly viewed as a multisystem disorder, affecting other neural networks and systems beyond motor neurons.

Motor System Anatomy and Physiology

• The primary function of the motor system, centered in the brain and spinal cord, is to regulate posture and balance, facilitate movement, enable communication.
• Reflexive movements are involuntary and mediated by the brainstem and spinal cord, without conscious input.
• Voluntary movements are consciously initiated to achieve specific objectives.
• Voluntary movements involve UMNs and LMNs; initiation occurs in the cerebral cortex's premotor area.
• Axons of UMNs form descending tracts to LMNs, stimulating skeletal muscle contraction.
• Precise movement execution involves the cerebral cortex in conjunction with the basal nuclei and cerebellum for planning, coordinating, and refining motor activities.
• The motor system has upper motor neurons (UMNs) from corticospinal/corticobulbar tracts and lower motor neurons (LMNs) from spinal cord's anterior horn cells.

Upper Motor Neurons (UMNs)

• Motor impulses originate in the upper motor neurons (UMNs) within the motor cortex.
• UMNs are part of descending pathways carrying signals from the cerebrum and subcortical brainstem to spinal cord anterior horn cells.
• Axons travel through the corona radiata and internal capsule, then the brainstem, and most fibers cross over at the medullary pyramids.
• UMNs are located rostral to LMNs in the spinal cord or brainstem, with descending axonal projections.
• The corticospinal tract originates in the motor cortex, traverses the internal capsule/brainstem, and synapses with LMNs in spinal cord.
• The corticobulbar tract projects to brainstem nuclei for cranial nerve function, innervating striated muscles.
• UMNs voluntarily regulate LMNs, facilitating purposeful movement initiation.
• Upper motor neuron (UMN) activity governs posture and gross limb movements automatically, often without conscious effort.
• Medial UMN activity starts before conscious awareness; involuntary responses originate in the brainstem: medial UMNs transmit signals to LMNs.
• Medial UMNs establish synaptic connections with LMNs for musculature of the neck, trunk, and limbs (less specific muscle groups).

Motor Pathways

• Motor pathways are descending neural circuits conveying action potentials from the cerebrum to the brainstem or spinal cord.
• Direct (pyramidal) pathways regulate muscle tone/speed/precision of voluntary skills, especially fine motor control.
• Indirect (extrapyramidal) pathways regulate broader motor functions: posture, and body coordination, often involving the cerebellum.
• Direct pathways exist only in mammals, positioned over indirect pathways, and enable fine facial/distal limb control control.
• Indirect pathways originating from the basal ganglia and cerebellum support direct pathways by refining movement.

Pyramidal System (Direct Pathways)

• Direct motor pathways, known as the pyramidal system, transmit action potentials from upper motor neurons in the cerebral cortex to lower motor neurons in the brainstem or spinal cord.
• The system consists of the corticospinal and corticobulbar tracts, both originating from the sensorimotor cortex near the central sulcus.
• About 55% of axonal fibers come from the frontal lobe, 35% from the parietal lobe along the postcentral gyrus, and 10% from other regions.
• The corticospinal tract receives contributions from Betz's cells, large pyramidal neurons in layer V of area 4, accounting for about 5% of fibers
• The pyramidal tracts show somatotopic organization, are vital for motor control, and also modulate sensory processing.
• The portion of the pyramidal tract starting from the frontal lobe is responsible for performing motor functions.
• Fibers starting in the parietal lobe modulate ascending sensory pathways; tracts have collaterals synapsing at the thalamus, brainstem, and spinal cord.
• Direct pathways to spinal cord motor neurons are critical for precisely controlling distal musculature, important for coordinated movements
• Direct pathways enhance the speed and precision of voluntary movements like independent finger movement.

Corticospinal Tract

• The corticospinal tract starts at the sensorimotor cortex and other cortical regions, with primary motor and premotor areas in the frontal lobes, and somatic sensory areas in the parietal lobes.
• Upper motor neuron axons descend through the internal capsules and cerebral peduncles of the midbrain before the pyramids of the medulla oblongata.
• At the medulla's inferior angle, 75-85% of corticospinal fibers decussate at the pyramidal decussation, then go to the spinal cord's lateral corticospinal tract.
• The remaining 15-25% descend uncrossed in the anterior corticospinal tract, decussating near their destination to synapse with LMNs.
• The anterior corticospinal tract mostly controls musculature of neck and upper limbs, and the lateral tract provides motor control to the entire body.
• A small percentage remain uncrossed in the lateral corticospinal tract, supporting ipsilateral trunk/proximal limb control for maintaining upright posture.
• Most corticospinal fibers synapse w/ interneurons in the spinal cord's gray matter.
• The interneurons are connected with lower neurons (LMNs) for facilitating precise motor control with distal limb muscles.
• Selective motor control is the ability to activate specific muscles independently of others
• Absence of selective motor control results in unified movements/actions.

Corticobulbar Tract

• The origin of corticobulbar fibers is the sensorimotor cortex, specifically in the area that represents the face.
• The fibers pass through the posterior limb of the internal capsule and the middle portion of the crus cerebri before going to the brainstem's target nuclei.
• Target nuclei in the brainstem somatic and brachial efferent nuclei.
• The corticobulbar tract directly control movements in the head and neck.

Extrapyramidal System (Indirect Pathways)

• Neurons from the cerebrum and cerebellum synapse in brainstem nuclei before synapsing with LMNs, rather than directly synapsing with them.
• These pathways are triggered by neurons in various brainstem nuclei, do not use the pyramidal/corticobulbar tracts, and are extrapyramidal.
• The extrapyramidal system is an older set of subcortical circuits and pathways than the corticospinal system.
• Its structures encompasses the corpus striatum: caudate nucleus, putamen, globus pallidus, subthalamic nucleus, substantia nigra, red nucleus, and brainstem reticular formation.
• Key extrapyramidal tracts include the rubrospinal, vestibulospinal, reticulospinal, and tectospinal tracts.
• The indirect pathways have extensive connections/feedback loops for motor function coordination and modulation.
• Cortical and subcortical components are interconnected, either directly, reciprocally, or via fiber loops.
• Most of these interconnections are apart of the extrapyramidal system, traversing the basal ganglia.

Reticulospinal Tract

• The reticulospinal tract begins in the reticular formation within the brainstem.
• Neurons facilitate the activation of bilateral LMNs for controlling muscles that are responsible for postural stability and large-scale limb movements.
• Reticulospinal neurons synapse with LMNs at various spinal cord levels, giving primary input to propriospinal interneurons.
• This promotes coordinated contraction of multiple muscle groups across joints, initiating anticipatory movements and coordinating synergies.
• Tracts contribute to voluntary movements like reaching and grasping.
• These neurons synapse with LMNs controlling wrist and finger flexors, but not extensors, initiate gross motor actions that engage fingers and thumbs.
• Modulating reticulospinal neurons depends on input from the cerebral cortex, cerebellum, and sensory pathways to the reticular formation.

Medial Vsestibulospinal Tract

• The medial vestibular nuclei receive sensory input about head movement/position from the vestibular apparatus in the inner ear.
• Originates from medial vestibular nucleus, projecting bilaterally to cervical/thoracic spinal cord, modulates activity of lower motor neurons.
• It controls neck and upper back muscles.

Lateral Vestibulospinal Tract

• The lateral vestibular nuclei process gravitational information from the vestibular apparatus, and facilitates ipsilateral lower motor neurons for extensor muscle activity and inhibits flexor muscles.
• During upright posture, vestibulospinal tracts are continuously active, maintaining center of gravity/responding to minor forces dynamically.

Rubrospinal Tract

• The rubrospinal tract originates from neurons within the red nucleus, located at the diencephalon/midbrain interface.
• After decussating in the mindbrain, it descends through the spinal cord's lateral column, receiving input from cortex/cerebellum.
• Related to cerebellar activity, lesions in the nucleus lead to intention tremors similar to cerebellar impairments.
• The tract parallels the corticospinal tract, terminating in the lateral gray matter of the spinal cord, and involved in action potentials transmission.
• Its primary function is fine motor control, particularly in the upper extremities' distal muscles.
• Damage to the rubrospinal tract disrupts forearm and hand movements with limited impact on broader coordination.

Tectospinal Tract

• The tectospinal tract arises from the superior colliculus; facilitates head movements that are relfexive in response to stimuli, like sudden motion.
• It enables rapid orientation of the head toward environmental stimuli.

Central Nervous System

Primary Motor Cortex

• The primary motor cortex, located anterior to the central sulcus within the precentral gyrus, controls voluntary movements precisely primarily.
• Corticospinal and corticobrainstem cell bodies arrange somatotopically, forming an inverted homunculus mirroring the somatosensory cortex.
• It is important to highlight that, in this motor homunculus, movements, rather than individual muscles, are represented.
• Anterior regions - premotor area: located in the lateral hemisphere, for muscles across joints; supplementary motor area: on the superior/medial hemisphere, requiring both hands.
• Supplementary motor area cells activate before movements, enabling coordinated execution.
• Most lateral corticospinal and corticobrainstem neurons start from the motor, premotor, and supplementary motor cortices contralateral to the lower motor neurons target .
• However, both tracts do possess ipsilateral projections; muscles for posture/trunk stabilization use both primary cortices (medial corticospinal tract).

Brainstem

• The brainsstem is made of the medulla oblongata, pons and midbrain and a stalk-like structure at the posterior fossa of the skull.
• It connects the narrow spinal cord/expanded forebrain, integrating pathways/functions; conduit for tracts, reflex centers and contains nuclei of III-XII nerves.

Midbrain

• The midbrain is about 0.8 inches long, it connects the pons, cerebellum and the forebrain.
• Its posterior surface has four rounded eminences (colliculi); the trochlear nerves emerge below the inferior colliculi in the midline.
• The oculomotor nerve begins from a groove on the crus cerebri's medial side advancing forward, passing through cavernous sinus wall.

Pons

• The Pons is front of towards the cerebellumm, a connection between the midbrain
• Around 1” long, from the bridge -appearance: links the cerebellar hemispheres bilaterally.
• It has trigeminal nerve coming from each side containing a smaller root of motor component and lateral root with sensory component; nerves 6, 7, and 8. traverse it.

Medulla Oblongata

• The medulla oblongata connects the spinal cord and the pons
• The first cervical spinal nerve roots origin mark the junction between the cord and medulla, around the foramen magnum.
• Inferior half, reveals the great motor decussation; CNs 9, 10 and spinal the 11th nerve all course reticularly there exiting as well.
• The substance gelatinosa continuous through nuclei of cord and trigeminal nerves, in addition the CN 12 nerves traverse reticularly/laterally.

Spinal Cord

• The spinal cord is cylindrical crucial CNS structure beginning superiorly the foramen magnum where it extends into the brain's medulla oblongata.

• Ends borderL1, occupying cord 2/3 of the spinal canal in length.

• The spinal cord surrounded by the protective dura mater, arachnoid mater, and pia mater, addiditonal cerebrospinal spinal cord fluid.

• The spinal cord has gray matter with an H shape and white matter.

• The cord has anterior/posterior gray columns (horns) and commissure in the middle (central canal).

• A smaller one appears at lumbar segment.

Upper Motor Neurons to the Spinal Cord

• Upper Motor Neurons are responsible for sending most of the motor signs to spinal from brain and cord.
• Neurons project mostly and cortically to alpha/gamma motor neuron to the cord.
• That project to the cord are put in classes in on position at synapse at each level. Medial tracts work to and with limbs for posture.
• Axons extend and synapse with muscle.
• That cannot active individual stimulation or preciseness. The cord has background to the spinal activity and coordination.

Lower Motor Neurons

• Lower neurons extend out from the cord (anterior segments) that communicate to limbs through nerves.
• This is the final pathway to the muscle through tracts.
• Nerve fiber that transmits the message from the spinal to the muscles.

Lower Motor Neuron Cell Body Pools in the Spinal Cord

• Cell bodies at cord from exit point to motor axon pool.
• There fibers are in order with the pool set up.
• With that, pools located medially do things for more medial fibers and laterally move more laterally.

Myotomes

• Myotome refer and single fibers corresponding. Spinal nerve of movement
• The movements range from flexing elbows and wrist extensions. The flexion middle finger is another movements

Alpha and Gamma Motor Neurons

• Motor neurons range between into 2 types: alpha and Gamma motor neutrons. Both bodies located at ventrical side of the cord.
• They axon to skin and out spinal nerve through their respected areas and muscles.
• Alpha neurons are larger and have thick skin, and their axons skin to fibers, and extend approach skin. In contrast y neurons are medium skin and project the muscle skin at side spinal.

Alpha-Gamma Coactivation

• Activating and making actions as a motor neutron at most point.
• Making action as a center fiber neutron as muscle extended.
• Mechanism protect to the sensitive of the muscule from actions extended to neuron.
• Also trigger same sides a muscle as the side. With that, it makes easy a action to move more.

Motor Units

• Fiber to action at each neuromuscular junctions to each of the action are attached to muscle to contracted .

• Are put is categories as moving and fast moving.

• Speed to what muscle moves after a stimulus. fiber located at small and slow with action action more on neurons alpha.

• A single for alpha motor neuron, are unit fibers.

• Average number of muscle fibers

Spinal Region Motor Function

• Movements for somatosensory including to the activating action.
• Neural interacts and the coordination movement. Is cord of the most crucial to movement coordination.
• Reciprocal inhibition (spinal to preventing a agonist musucle.

Reciprocal Inhibition

• (spinal ) action to musicles The process and into actions grouping . Signals from muscles activating neurons to control fibers. Muscle the minimums to from.
• For instance, muscles stops to action after stretching at quadracipes

Body schema

Golgi Tendon Organs in Movement

• The roles and movements are detecting tension. Information transmits to the cord (spinal) a neutrons activity where muscles move. These organ functions are in with other spinal, join and the decending pathways. In addion integrates/facilitate for coordinated movement. Control to walks : stepping with spinal. Coordination action to hip, knees and leg on SPG for for flexing muscles, but is not effective for other actions.

Spinal Reflexes

• Movement from the autonomic and the external stimulus/reflex. and the response and afferent.

Skeletal Muscles

• All have fundamental at their core to and excital to their properties and stretching.
• A cell membrane and tubes stretching them.
• Calcium are store calcium, When the released binds or depolarization membrane that stretches a fibers starting action. Fiber myofilaments at action and length for units. Sarcomeres building the for contracting at proteins.
• At the end Mlines, in addition Z line to the actin overstretching.

Amyotrophic Lateral Sclerosis (ALS) Etiology

• ALS has unknown etiology; 90% of cases are sporadic, 5-10% are familial (FALS).
• ALS from genetic, environmental, and molecular factors causing progressive motor neuron degeneration.
• Oxidative stress plays a significant role in ALS, where superoxide dismutases (SODs) mitigate oxygen free radicals.
• Mutations in the SOD1 gene, encoding CuZnSOD, accounts for about 20% of familial ALS cases.
• Resulting mutations from gain of toxic function, potentially leading to motor neuron death (not clear).
• Excessive glutamate activity contributes to motor neuron degeneration.
• Elevated glutamate levels are in patients cerebrospinal fluid, plasma, and postmortem tissues.
• Reduced excitatory amino acid transporter 2 (EAAT2) suggests this is a key factor due to toxicity in ALS.
• Histopathological aspect is clumping of neurofilament proteins into spheroids in motor neurons.
• Association with axonal dysfunction.
• Disruptions in mitochondrial function and protein misfolding occurs.
• TDP-43 proteinopathy links ALS to frontotemporal lobar degeneration. Exogenous toxins include heavy metals (lead, selenium, mercury); interactions with susceptibility with may environmental exposure.

Autoimmune Mechanisms

• Factors targeting motor neurons/calcium channels suggesting immune-mediated component/motor injury in autoimmune processes.
• Deficiencies in factors such as ciliary neurotrophic factor (CNTF) and nerve growth factors may contribute.
• Physical activity, trauma, and repetitive brain injuries are debated as risk factors.
• Viral infections and chronic microglial inflammation: contributors to motor neuron degeneration; evidence is anecdotal.
• ALS comes with from complex factor including among genetic, environmental, and molecular factors.

Epidemiology

• ALS is rare but serious.
• Overall prevalence rate between 5 and 7 per 100, 000 population
• 4 to 12 is the number of cases per 100,000, and 30,000 people in the USA have ALS.
• Average age onset 58-63 years old
• 5% -10% of cases family
• 5%- 10% inherited primarily and
• 20%-20% hereditary to mutations are on Sord1 code.

Pathophysiology

• Main characteristic of ALS is the gradual loss/degradation of motor neurons in the brainstem, motor cortex, and spinal cord
• Studies have revealed that non-motor areas are also impacted
• Identification of C9orf72 gene, which is linked to ALS-frontotemporal dementia
• ALS affects system but also the cerebellum, frontotemporal, oculomotor, autonomic, nerves
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Motor neuron diseases (MNDs) are disorders affecting upper and lower motor neurons. Amyotrophic lateral sclerosis (ALS), the most common MND, involves motor neuron degeneration. ALS can be sporadic, due to causes like poliomyelitis, or hereditary, including spinal muscular atrophy (SMA).