CENTRAL NERVOUS SYSTEM PHYSIOLOGY

ORGANIZATION:

• Central Nervous System
• Brain
• Spinal Cord
• Peripheral Nervous System
• Cranial nerves & Spinal Nerves & Receptors
• Somatic: sensory neurons for skin, muscle, joints
• Autonomic: involuntary innervation of various organ systems
• Sympathetic
• Parasympathetic
• Enteric

CELL TYPES: 

2 Primary cell types

• Neuron: basic functional cell of CNS; cell body (perikaryon), dendrites, axon
• Neuroglial (glial)

NEURON

A single axon emerges from the cell body at the axon hillock.  The axon may branch to form collateral nerves at a point distal to the neuron cell body.  Axon diameters range from 0.2 to 20 nm.  Most axons in the brain are only a few millimeters long.  Axons that run from the spinal cord may be as long as 1 meter.  

NEURON CELL BODIES: vary in size and shape; classified as follows:

• Unipolar - found only in lower invertebrates
• Bipolar - found in retina, ear, olfactory mucosa
• Pseudounipolar - have one cytoplasmic process that exits the cell and divides into 2 branches - 1 serving as dendrite and one serving as axon. Present in dorsal root ganglia and cranial ganglion cells, enabling sensory impulses to travel from dendrite directly to the axon without passing through the cell body.
• Multipolar - have multiple dendritic processes but only one axon and constitute the majority of CNS neurons.

GREY MATTER VS. WHITE MATTER

• Grey matter: composed of neuron cell bodies
• White matter: composed on myelinated axons

GANGLIA: regions of concentrated cell bodies within the PNS to form cranial, spinal and autonomic ganglia.

NEURON CLASSIFICATION BASED ON FUNCTION:

1. Motor neurons - multipolar and innervate and control effector tissues such as muscle and glands
2. Sensory neurons - pseudounipolar and receive exteroceptive, interoceptive, or proprioceptive input
3. Interneurons - pseudounipolar and connect adjacent neurons

NEUROGLIAL (GLIAL) CELLS

Glial cells are smaller, outnumber neuronal cells, and lack dendritic and axonal processes.  Do not participate in neuronal signaling, but are essential for neuronal function.

Role: maintenance of proper ionic environment, modulation of nerve cell electrical conduction, control of reuptake of neurotransmitters, and repair after neuronal injury.

TYPES OF GLIAL CELLS:

1. Astrocytes: predominant glial cell.  Provide structural neuronal support, group and pair neurons and nerve terminals, regulate the metabolic environment, are active in repair after neuronal injury. Have multiple processes that radiate from cell, producing a star-shaped appearance.  Some of these processes (astrocytic feet) terminate on the surfaces of blood vessels within the CNS (perivascular feet).  The contact of the cerebral endothelium by astrocytes has been proposed to be essential in the development of the blood-brain barrier.  2 distinct types:
• Fibrous astrocytes: found in white matter
• Protoplasmic astrocytes: concentrated in grey matter
2. Oligodendrocytes: have fewer branches than astrocytes.  Form the myelin sheath of axons in the brain and spinal cord (CNS) and are capable of myelinating more than one axon.  However, are incapable of division and fail to regenerate after injury.
• The velocity of nerve impulse conduction in an unmyelinated axon increases with the square root of the diameter of the axon.  A doubling of impulse conduction requires that the axon be doubled in size.  Myelin is essential to increase the velocity of impulse conduction and minimize the size of the axon.
• Schwann cells: modified glial cells which form myelin the the peripheral nervous system.  Only myelinates one axon (unlike oligodendrocytes).  Forms successive layers of plasma membrane. The thickness is variable in different axons. The junction between adjacent schwann cells is devoid of myelin at 1 mm intervals along the length of the axon - this area is called Node of Ranvier, and is the site of electrical impulse propagation.  Impulses in myelinated axons travel from one node to another (saltatory conduction), bypasing the area between the nodes and increasing velocity of conduction.
• Wallerian degeneration results in distal degeneration of the axon after peripheral nerve injury.
• Proximal degeneration may also occur
• Within 1 week of initial injury, Schwann cells proliferate to form a tube into the area of degeneration, forming a scaffold to direct axon regeneration.  Myelin regeneration precedes axon regeneration, with myelin eventually reaching its previous thickness.
3. Microglial cells: smallest of neuroglial cells and are scattered throughout the CNS.  Transported throughout the CNS to sites of injury or degeneration, where they proliferate and develop into large macrophages that phagocytize neuronal debris.
4. Ependymal cells: line roof of third and fourth ventricles of brain and central spinal canal.  Form cuboidal epithelium (choroid plexus), which secretes CSF.

*Most neoplasms of CNS arise from glial cells - particularly astrocytes.

BLOOD BRAIN BARRIER: 

effectively isolates brain and spinal cord extracellular compartment from the intravascular compartment.

BBB = Vessel --> Astrocytes --> Neuron

The endothelial cells of the CNS form tight junctions between adjacent cells, preventing the transport of polar substances from the intravascular to the cerebral extracellular fluid compartment.  CNS endothelial cells lack transport mechanisms, so little intracellular transport takes place.

A number of midline brain structures receive neurosecretory products from the blood and, therefore, lack a BBB.  These structures, the circumventricular organs, include the area postrema, pituitary gland, pineal gland, choroid plexus, and portions of the hypothalamus.

The BBB is incompletely developed in the newborn. The high vascular content of bile pigments in jaundiced newborns may enter the basal ganglia, producing kernicterus (bilirubin-induced neurological damage, possibly irreversible).

BBB disruption can be caused by traumatic head injury, subarachnoid or intracerebral hemorrhage, or cerebral ischemia.  The development of mass lesions may also produce BBB disruption.  Osmotically active substances may penetrate the brain or spinal cord after BBB disruption.  Intentional intracarotid injection of a hyperosmolar solution shrinks the endothelial cells, opens tight junctions, and disrupts the BBB. This technique allows the delivery of chemotherapeutic drugs through the BBB for the treatment of neural malignancy.

ANATOMY OF THE CENTRAL NERVOUS SYSTEM

Cerebral Structures

Meninges

Cerebrospinal Fluid

Spinal Cord

CEREBRAL STRUCTURES

1. Cerebral hemispheres: most intricately developed and largest regions of the brain; contain:
1. Cerebral cortex: gray matter; forms outer 3-mm layer of cerebral hemispheres.  Controls perception, memory, higher cognitive functions (concentration, reasoning, thinking). The surface is convoluted to increase the surface area of cerebral hemispheres.  
1. Elevated convolutions called gyri, separated by shallow grooves called  sulci and by deeper grooves called fissures.
2. The medial longitudinal fissure divides cerebral hemispheres into right and left halves.
3. The lateral fissure of Sylvius and central sulcus of Rolando divide each hemisphere into four lobes, each named for the cranial bones that overlie each area.
1. Frontal lobe: motor control (separated by central sulcus); voluntary muscle activity is controlled by motor cortex located in precentral gyrus, or the Brodmann areas.
1. dopamine-sensitive neurons
2. attention, short memory tasks, planning & drive
3. higher mental functions (moral, suppress unacceptable social responses)
4. ego, superego, id
2. Parietal lobe: senses of pain and touch (separated by central sulcus); limb position, sensory perception of grasped objects controlled by somatic sensory cortex located in postcentral gyrus of parietal lobe.
1. visuospatial processing; integrates sensory information
2. 2 hemispheres: left - math & language; right - spatial relationships
3. Temporal lobe: Auditory cortex, separated from frontal and pariental lobes by sylvian fissure.
1. Contains hippocampus (part of limbic) --> long term memory
2. Semantics in both speech and vision
4. Occipital lobe: lies posterior to parietooccipital sulcus; visual cortex lies within walls of calcarine fissure on medial brain surface.
1. dreams
2. lesions --> visual hallucinations

1. Corpus Callosum: lies deep in longitudinal fissure and contains commissural fibers that interconnect the cerebral hemispheres (white matter).  These fibers arise from neurons in one hemisphere and synapse with neurons in the corresponding area of the adjacent hemisphere.
2. Hippocampus: memory formation and learning.
1. medial temporal lobe
2. limbic system
3. long/short term memory
4. emotion/behavior
3. Amygdala: functions in regulation of emotional behavior, response to pain, appetite and forming response to stressors.
4. Basal Ganglia: involed in control of movement; crude motor movements; white matter below cerebral cortex
1. Diencephalon: located midline between 2 cerebral hemispheres and brain stem; "between brain"
1. Thalamus: oval-shaped; integrates and transmits sensory information to various cortical areas of the cerebral hemispheres via separate thalamic nuclei. (sensory relay center); processes all sensory information going to cerebral cortex and all motor info coming from cerebral cortex to SC.
2. Hypothalamus: composed of several nuclei, including mammillary bodies.  The master neurohumoral organ.  Master control center of ANS.  Controls heart, glands, smooth muscle.
1. Pre-optic portion: body temperature
2. Supraoptic nuclei: thirst/excretion of H2O in urine; osmlolality of body fluids
3. Lateral hypothalamus: hunger
4. Ventromedial nuclei: satiety
5. Control of body weight (all of the above vegetative functions of the brain)
6. Paraventricular portion: cell bodies of neurons; oxytocin: uterine contractions and milk ejection; ADH
7. Stimulation of anterior pituitary to secrete endocrine hormones via hypophysial portal blood.
2. Brainstem: contains the reticular activating system, which functions to maintain consciousness, arousal and alertness.
1. Midbrain
2. Pons: anterior to cerebellum, separated by 4th ventricle, connecting medulla and midbrain.
1. Contains ascending and descending fiber tracts and the nuclei of the trigeminal nerve (V) and facial nerve (VII)
2. relay station from cerebral hemispheres to cerebellum; tracts cross here
3. Regulation of breathing (along with medulla)
3. Medulla oblongata: extends from pons to foramen magnum where it becomes continuous with spinal cord.
1. contains respiratory and cardiovascular control centers (autonomic functions)
2. Ascending and descending fiber tracts
3. Vestibulocochlear nerve (VIII), Glossopharyngeal nerve (IX), vagus nerve (X), spinal accessory nerve (XI), hypoglossal nerve (XII).
4. sound localizations
5. sneeze, cough
6. sucking reflex
7. Chemoreceptor trigger zone (N/V)

• Cerebellum: convoluted in appearance, lies below occipital lobe and posterior to pons and medulla.  Outer layer of grey matter and inner core of white matter with several nuclei embedded within (similar to cerebral cortex).  Can be divided into 3 functional areas:

1. Flucculonodular lobe (archeocerebellum): maintenance of equilibrium
2. Paleocerebellum (anterior lobe and part of vermis): regulates muscle tone
3. Neocerebellum (posterior lobe plus most of vermis): largest subdivision of cerebellum and is essential in coordinating voluntary muscle activity.
• Cerebellum integrates information received from other areas of the CNS and the peripheral nervous system.  Information from the cerebellum is transmitted to the cerebral cortex and to lower motor neurons involved in the maintenance of muscle tone, equilibrium, and voluntary muscle 
• coordination, posture

ANOTHER CLASSIFICATION SYSTEM
Forebrain/Prosencephalon: cerebrum, thalamus, hypothalamus, limbic

• At 4 weeks development, prosencephalon separates into:
• Diencephalon: prethalamus, hypothalamus, subthalamus, epithalamus, pretectum
• Telencephalon: cerebrum, cerebral cortex, white matter, basal ganglia

Hindbrain: cerebellum, pons, medulla

• General motor control
• maintaining body equilibrium via vestibular apparatus

Midbrain/Mesencephalon: smallest section: thalamus, hypothalamus, hippocampus, basal ganglia, pineal gland, corpus callosum

• pineal gland: melatonin; sleep/wake cycle

Limbic System: amygdala, hippocampus, hypothalamus, thalamus, fornix, parahippocampal gyrus

• Border system
• emotional behavior, motivational drive

HOMUNCULUS

MENINGES

The brain and spinal cord enveloped by 3 meningeal layers: dura mater, arachnoid mater, pia mater.

1. Dura mater: thickest of meningeal layers, overlies cerebral hemispheres and brainstem.  Functionally separated into and outer periosteal layer (adherent to inner cranium) and an inner meningeal layer.  
1. Dura forms a fold, the falx cerebri, that functionally separates the cerebral hemispheres.  A similar fold, the tentorium cerebelli, seperates the occipital lobe and the cerebellum.  
2. The dura of the spinal cord is continuous with the meningeal layer of the cranial dura mater and the perineurium of the peripheral nerves.  
3. Innervation of the dura mater is provided by the first three cervical roots and the trigeminal nerve. During awake craniotomy, the patient may complain of pain "behind the eye" when traction is applied to the dura. 
4. The subdural space (a potential space between dura and arachnoid) - unintentional injection of local anesthetic into subdural space produces patchy, asymmetric block.  Injury to blood vessel in subdural space can create subdural hematoma possibly requiring surgery.
5. The epidural space is located outside the dura but inside the spinal canal.  Contains venous plexus and epidural fat that provides protection of the neural structures.  This distance from the skin to the epidural space may be a little as 3 cm or as large as 8 cm.
2. Arachnoid mater: thin, avascular membrane joining the dura mater.  
1. Subarachnoid space: lies between arachnoid mater and pia mater. In the spinal cord, the subarachnoid space extends to S2-S3 and is filled with CSF.  Also, the vasculature that overlies the CNS is located within this space.  Injury to the vascular structures may produce subarachnoid hemorrhage and hematoma.
3. Pia mater: thin, avascular membrane adherent to brain and spinal cord.

CEREBROSPINAL FLUID

Contained within the ventricles of the brain, cisterns surrounding brain and subarachnoid space of brain and spinal cord

• Total volume of cranial and spinal CSF approximately 150 ml.
• Specific gravity 1.002 - 1.009; pH 7.32
• CSF bathes brain and spinal cord, cushioning delicate structures and controls and maintains extracellular milieu for neurons and glial cells
• Entire CSF volume is replaced every 3-4 hours.
• Normal CSF pressure is 5-15 mmHg

CSF secreted by ependymal cells of chroid plexus within ventricular system at rate of 30 ml/hr.

• Although isotonic with plasma, it is not a plasma filtrate.
• Concentrations of K, Ca, HCO3, and glucose are lower than plasma concentrations
• Concentrations of Na, Cl, and Mg are higher than plasma concentrations

Pathway of CSF: Lateral ventricles --> foramen of Monro --> third ventricle  --> aqueduct of Sylvius in midbrain --> fourth ventricle --> Foramen of Magendie and paired lateral foramina of Luschka --> subarachnoid space --> arachnoid villi & arachnoid granulations in the arachnoid membrane

BRAIN BLOOD SUPPLY

The brain represents 2% of total body weight in humans but it receives 15-20% of the resting cardiac output. 

Blood supply to the brain is carried by 2 pairs of arteries: the internal carotid arteries and vertebral arteries; the IC anastomose at the base of the brain to form the circle of Willis . The R and L vertebral arteries form a single basilar artery at the base of the brain that feeds the circle of Willis posteriorly.

Blood in the circle of Willis (Circulus Arteriosus) is then redistributed to the anterior, middle and posterior cerebral arteries. The anastomosis between arteries created by the anterior communicating artery and the posterior communicating artery is responsible for creating collateral circulation (safety mechanism) - if one of the major vessels becomes occluded within the circle or proximal to it, the circle will still provide a continuous blood supply to the brain to decrease neurological damage (must maintain blood pressure at leat 50% of normal).

Smaller arteries arise from the circle of Willia and from the major cerebral arteries.  The form four groups which include the anteromedial, anterolateral, posteromedial, and posterolateral.

INTERNAL CAROTID

Divides into two main branches:

1. MCA: supplies blood to frontoparietal somatosensory cortex
2. ACA: supplies blood to frontal lobes and medial aspects of parietal and occipital lobes
3. Before divide, IC gives rise to ophthalmic artery, anterior choroidal artery, posterior communicating artery

VERTEBRAL ARTERY

Run along the medulla and fuse at the pontomedullary junction to form midline basilar artery (vertebro-basilar artery).  Before forming the basilar artery, each vertebral artery gives rise to the posterior spinal artery, anterior spinal artery, posterior inferior cerebellar artery (PICA) and branches to the medulla.

BASILAR ARTERY

At the ponto-midbrain junction, the basilar artery divides into the two posterior cerebral arteries.  Before this divide, it gives rise to the numerous paramedian, short and long circumferential penetrators and two other branches known as the anterior inferior cerebellar artery and the superior cerebellar artery.

VENOUS DRAINAGE

Primary course of venous drainage is through cerebral veins that empty into the dural venous sinuses and ultimately into the internal jugular vein. 

Cerebral veins are divided into 2 groups, superficial and deep. 

• Superficial veins: usually lie on surface of cerebral hemispheres and empty themselves into superior sagittal sinus.
• Deep veins:  drain internal structures and ultimately drain into straight sinus

Cerebral veins are thin walled and valveless.  Interconnected by several functional anastomoses both within a group and between superficial and deep groups.  The numberous connections assist the spread of thrombus or infection between these vessels.

Perfusion to Ischemic and Non-ischemic Regions of the Brain
Cerebral Steal (Luxury Perfusion)
In ischemic brain regions, blood vessels are maximally dilated.  In non-ischemic brain regions, blood vessels have tone.  When a vasodilator (Nitroprusside) is administered, or when patient is hyPOventilated so that CO2 accumulates, vessels in non-ischemic brain dilate, flow to non-ischemic brain increases, and flow to ischemic brain decreases.

Inverse Steal (Robin Hood, Reverse Steal)
When the patient with an ichemic region of the brain is hyperventilated and PaCO2 falls, blood vessels in non-ischemic brain constrict and blood is diverted to ischemic brain.  Hyperventilation improves blood flow to ischemic brain. Rob from the rich and give to the poor.
***KNOW (Valley tips):

• Stump pressure measures the pressure transmitted through the circle of Willis back to the carotid artery for which endarterectomy is proposed.  A good stump pressure indicates that the brain will be perfused adequately during the procedure.  Recent studies indicate that stump pressures > 40 mmHg are as reliable as EEG monitoring (the gold standard) in predicting cerebral ischemia during cross-clamp application in CEA and are more cost-effective (Barash, Miller).

SPINAL CORD

Extends from the medulla at the foramen magnum to the filum terminale, a threadike connective tissue structure that attaches to the first segment of the coccyx.

• 31 pairs of spinal nerves carry motor and sensory information:
• 8 cervical
• 12 thoracic
• 5 lumbar
• 5 sacral
• 1 coccygeal
• The first pair of cervical nerves exits the spinal cord between the base of the skull and the first cervical vertebra (atlas), and the remaining 30 pairs exist between adjacent vertebrae.
• All exiting spinal nerves are covered with pia mater
• Spinal cord is 25 cm shorter than vertebral canal in adults, so lumbar and sacral nerves have long roots (cauda equina).

The spinal cord is divided into dorsal, lateral and ventral regions by the entering dorsal sensory root fibers and the outgoing ventral motor root fibers.  Neuron cell bodies and unmyelinated fibers lie in the H-shaped central gray region of the cord, surrounded by fiber tracts that form the white matter.  Although it does not have a uniform appearance, this general arrangement continues throughout the entire spinal cord.

SPINAL GRAY MATTER:

The spinal gray matter is divided into the ventral and dorsal gray commissures.

• Ventral projections of gray matter are called gray horns or columns
• Posterior/Dorsal projections are called posterior gray horns or columns. 
• Intermediolateral gray horns or columns found between T1 and L2

The gray matter has been subdivided into 10 (I through X) laminae of Rexed:

• Rexed laminae I through VI are located in the dorsal (posterior) horn and contain cell bodies that receive sensory information from the periphery.
• Projections from the laminae form afferent tracts
• A large number of interneurons are found in laminae V, VI and X.
• Laminae VII, VIII, and IX make up ventral (anterior) horn and contain motor neurons and interneurons involved in motor functions.  

The gray matter is enlarged in two areas of the spinal cord, C5-C7 and L3-S2.  

• The cervical enlargement contains neuron cell bodies that innervate the upper extremities
• The lumbosacral enlargement contains neuron cell bodies that innervate the lower extremities.

SPINAL WHITE MATTER

The tracts or fascicles that make up the white matter are highly organized.  The dorsal white matter is composed almost exclusively of ascending sensory fiber tracts.  The lateral and ventral white matter contains descending motor tracts.  

Commonly, fiber tracts at some level int he spinal cord or brain decussate (cross over to the other side).

As in the brain, spinal cord fiber tracts can be projection tracts connecting the spinal cord and brain, or they can be association tracts (intersegmental, fasciculi proprii) tracts that originate and terminate entirely within the spinal cord.  The association tracts play an important role in spinal reflexes.

SPINAL NERVES

Shortly after leaving the spinal cord, the meningeal coverings of the peripheral nerves merge with the connective tissue layers that cover the peripheral nerve.  The outermost covering of the peripheral nerve is called the epineurium.  The bundles or fascicles of axons in each nerve are covered by the perineurium, and each axon in a fascicle is surrounded by the endoneurium.

Peripheral nerves may be classified according to their diameter.  Generally, the larger the diameter, the faster the conduction velocity.  The degree of myelination also affects the conduction velocity.  Classification of nerves:

• A-alpha
• A-beta
• A-gamma
• A- delta
• B fibers
• C fibers

BLOOD SUPPLY OF SPINAL CORD:

Arterial blood is delivered to spinal cord via:

• one anterior spinal artery (75%) - traverses length of spinal cord
• two posterior spinal arteries (25%)
• radicular: small segmental spinal arteries - arise from intercostal and lumbar arteries; augment anterior and posterior spinal artery blood flow.  Enter each side of cord via intervertebral foramen and give rise to anterior and posterior radicular arteries
• 8 radicular branches: 1 cervical, 2 thoracic, 1 upper lumbar
• the largest is the artery of Adamkiewicz (great redicular artery/GRA; radicularis magna)
• enters the vertebral canal from L side in majority of patients (not bilateral) in lower thoracic region and upper lumbar region.
• It may be the major source of blood in the lower 2/3 of the spinal cord - interruptions in flow through this vessel can lead to paraplegia

Spinal Cord Ischemia During Reconstruction of the Aorta
Spinal cord ischemia occurs in 1-11% of operations involving repair of distal descending thoracic aorta.  2 posterior arteries (supply only 25% of blood to cord) are formed from anastomoses of posterior branch of vertebral artery and ascending branch of bifurcation of the second posterior radicular artery.  The anterior spinal artery, (supplies blood to anterolateral 75% of the cord) is formed thorughout by a series of radicular arteries.  The mid-thoracic region, supplied by the anterior spinal artery, usually receives only one afferent vessel, which arises from a L or R intercostal vessel.  The afferent arteries to the posterior spinal cord from T2 to T8 are also poor in collateralization.  The blood supply to the thoracolumbar cord (from T8 to the conus terminalis) is derived from the artery of Adamkiewicz.  In 75% of cases the artery of Adamkiewicz joins the anterior spinal artery between T8 and T12, and in 10% of cases it joins between L1 and L2.  Although other radicular arteries supply this third section, much of the blood flow in the anterior spinal artery is dependent on the artery of Adamkiewicz.  Because the flow in the spinal arteries is dependent on collateralization by vessels such as the artery of Adamkiewicz, the blood supply to the spinal cord can be severely compromised when a single high aorta-occluding clam is applied.  Spinal cord ischemia leading to paraplegia may result.

***KNOW (Valley tips):

• afferent nerves (sensory) enter the spinal cord on the dorsal (posterior) side; efferent nerves (motor) exit the spinal cord on the ventral (anterior) side
• The spinal nerve root is connected to the paravertebral sympathetic ganglia by communicating channels called the white and gray rami communications.
• White rami carry myelinated sympathetic preganglionic neurons and gray rami carry unmyelinated sympathetic postganglionic neurons (type C fibers)
• Motor nerves to skeletal muscle arise from the anterior horn of the spinal cord
• Preganglionic sympathetic nerves arise from the intermediolateral horn of the spinal cord.
• The two divisions of the peripheral nervous system are the somatic and autonomic.