Introduction To Nervous System & Meninges PDF

I N R OD U C T ION TO N SY ST E ERVOU S M & M E N I N GES. DR. LSK School Of Nursing FHS 201 1 Your Nervous System is the mo...

I N R OD U C T ION TO N SY ST E ERVOU S M & M E N I N GES. DR. LSK School Of Nursing FHS 201 1 Your Nervous System is the most complicated and fragile system… It tells all your other systems what to do… 2  Objectives By the end of the topic students should be able to:  Cell communication-membrane potential, impulse conduction  List all the bones covering the nervous system State the basic functions of the nervous system (NS) Outline and explain the divisions and structures of the NS Describe the developmental and microscopic anatomy of the NS Explain the organization of neurons and how they connect/communicate List all the part of Central and Peripheral NS State the functions of the different parts/structures in the CNS & PNS 3 Introduction to skull and brain.  RECAP:Sk ull Part of Axial Skeleton Cranial bones = cranium – Enclose and protect brain – Attachment for head + neck muscles Facial bones =framework of face – Form cavities for sense organs – Opening for air + food passage – Hold teeth  Cranial and Facial Bones Cranial - 8 Facial – 14 – Frontal – Mandible – Occipital – Maxilla (2) – Sphenoid – Zygomatic (2) – Ethmoid – Nasal (2) – Parietal – Lacrimal (2) (2) – Palatine (2) – Temporal – Vomer (2) – Inf. Nasal Conchae(2)  Bones of Skull Flat bones: thin, flattened, some curve Sutures: immovable joints joining bones Calvaria = Skullcap =Vault – Superior, Lateral, Posterior part of skull Floor = Base – Inferior part of skull 85 openings in skull  Cranial Fossae Created by bony ridges Supports, encircles brain 3 Fossae – Anterior – Middle – Posterior All the bones visible from this view are the cranial bones!!  Skull through Life Ossifies late in 2nd month of development Frontal + Mandible start as 2 halves- then fuse Growth of Skull – ½ adult size by age 9 months – ¾ adult size by 2 years – 100% adult size by 8-9 years – Face enlarges between ages 6-13 years  Fetal Skull Skull bones separated by unossified membranes = Fontanels – Allow compression of skull during delivery – Allows rapid growth of brain Mostly replaced by bone after 1st year Tabulate the differences between fetus and adult skull  Basic functions of NS coordinating or control center for all body activities orientation of the body to internal and external environments assimilation of experiences requisite to memory, learning, and intelligence 11 Divisions of the NS 12 13  Structures of the NS Central NS: – composed of brain and spinal cord – contains gray and white matter – covered by bone and meninges Peripheral NS: – composed of nerves, ganglia and nerve plexuses Autonomic NS: – Sympathetic and parasympathetic Meninges (meninx): – fibrous membranes covering the CNS – include: Dura mater, Arachnoid and Pia mater (DAP) Cerebrospinal fluid (CSF): – clear, watery medium that surround and maintains homeostasis in the CNS 14  Skull Dura mater Arachnoid mater Pia mater Gray mater White mater 15  Cont’d Neuron (Nerve cell): – structural and functional cell of the NS – types: motor, sensory and intermediate Nerve: – bundle of nerve fibers Nerve plexus: – convergence or network of nerves Somatic motor nerve: – nerve that innervates skeletal muscle Autonomic motor nerve: – nerve that innervates smooth and cardiac muscles and glands 16  Cont’d Ganglion: – cluster of neuron cell bodies outside the CNS Nucleus: – cluster of neuron cell bodies within the CNS Tract: – bundle of nerve fibers interconnecting regions of the CNS 17  Development of the NS appears in the early 3rd week of development dorsal streak/neuroectoderm appears along the length of the embryo later thickens to form a neural plate neural plate sinks and the edges of it thicken and form neural groove and fold neural fold later fuse along the midline and form the neural tube 18  Cont’d by 4th week, the neural tube exhibits three anterior dilations or primary vesicles: – Prosencephalon (forebrain) – Mesencephalon (midbrain) – Rhombencephalon (hindbrain) by 5th week, the neural tube undergoes further development and subdivides into five secondary vesicles: – Prosencephalon (forebrain): Telencephalon – cerebral hemispheres and lateral ventricles Diencephalon – thalamus, hypothalamus and 3rd ventricle – Mesencephalon – midbrain and cerebral aqueduct – Rhombencephalon (hindbrain): Metencephalon – pons, cerebellum and upper portion of 4th ventricle ventricle 1 9  Telenceph alon Prosenceph Diencepha alon l oOnpti Mesenceph c alon vesicle Metencephal Rhombenceph on alon Myelencephal on Spinal cord 2 0  Microscopic anatomy of NS Nervous tissue: – Neurons – Neuroglia or glia cells 21  Neurons signal direction d e n d r i t e s myelin sheath synaptic terminal dendrite → cell body → axon c synapse 22 e  Neuroglia/glia cells Astrocytes Oligodendrocytes Microglia 23  Classification of Neurons Structural classification: Multipolar: – many processes arising from cell body – found in brain and spinal cord Bipolar: – two processes (from each end of cell body) – found in ear, eyes, nose Unipolar: – single process extends from cell body – found outside of brain and spinal cord 2 4  Cont’d Functional classification: Sensory neurons – afferent: – unipolar or bipolar Motor neurons – efferent: – multipolar Interneurons/intermediate neurons: – multipolar 25  How are neurons connected? Synapse: functional connection between the axon terminal (synaptic knob) of a presynaptic neuron and a dendrite of a postsynaptic neuron. 26  CELL COMMUNICATION There are four basic mechanisms for cellular communication: 1.Direct contact 2.Paracrine communication 3.Endocrine communication 4.Synaptic communication Direct contact communication – molecules on the surface of one cell are recognized by receptors on the adjacent cell 28 Paracrine communication – signal released from a cell has an effect on neighboring cells 29 Endocrine communication – hormones released from a cell affect other cells throughout the body 3 0 Synaptic communication – nerve cells release the signal (neurotransmitter) which binds to receptors on nearby cells 3 1  Synapse AXO N What is The synapse - this in the where the membran action e? happens Transpo The next cell’s rt plasma protein membrane 3 2  Synap point of impulse se transmission between neurons; impulses are transmitted from pre-synaptic neurons to post-synaptic neurons Synapses usually occur between the axon of a pre-synaptic neuron & and a dendrite or cell body of a post-synaptic neuron. At a synapse, the end of the axon is 'swollen' and referred to as an end bulb or synaptic knob. Within the end bulb are found lots of synaptic vesicles (which contain neurotransmitter chemicals) and mitochondria (which provide ATP to make more neurotransmitters). Between the end bulb and the dendrite (or cell body) of the post-synaptic neuron, there is a gap commonly referred to as the synaptic cleft. So, pre- and post-synaptic membranes do not  That means that the impulse cannot be transmitted directly. Rather, the impulse is transmitted bythe release of chemicals called chemical transmitters (or neurotransmitters).  When an impulse arrives at the end bulb, the end bulb membrane becomes more permeable to calcium. Calcium diffuses into the end bulb & and activates enzymes that cause the synaptic vesicles to move toward the synaptic cleft. Some vesicles fuse with the membrane and release their neurotransmitter (a good example of exocytosis). The neurotransmitter molecules diffuse across the cleft and fit into receptor sites in the postsynaptic membrane. When these sites are filled, sodium channels (also called chemically gated ion channels) open & permit an inward diffusion of sodium ions. This, of course, causes the membrane potential to  If enough neurotransmitter is released, and enough sodium channels are opened, then the membrane potential will reach the threshold. If so, an action potential occurs and spreads along the membrane of the post-synaptic neuron (in other words, the impulse will be transmitted). Of course, if insufficient neurotransmitter is released, the impulse will not be transmitted. The operation of the nervous system, the most powerful and sophisticated computer known, relies principally on the synaptic mechanisms described above. Synaptic events provide the links between individual neurons that make possible higher processes such as sensation, motor control, behavior, learning, and thought.  Membrane One Potential neuron can possess thousands of these channels, as well as energy-requiring pumps that move ions against their electrochemical gradient across the membrane. Through combinations of pumps and channels, two important gradients: electrical and chemical, can The arebe established either and an maintained. extracellular ligand neurotransmit mediator, e.g. or ter nucleotide intracellular mediator e.g. Nerve cells, in ion particular,have or a made a specialty of using ion channels for receiving, conducting and transmitting signals. They are responsible for the electrical excitability of muscle/nerve cells. They play a critical part in maintaining the membrane potential  Resting Membrane Potential Membrane potentials: It is the difference in electric potential between the interior and the exterior of a biological cell. Definition: It is the potential difference recorded across the cell membrane at rest. Causes: 80% caused by selective permeability of the cell membrane. The K+ diffuses out the cell & Na+ diffuses inside the cell according to concentration gradient. The K+ permeability is 50-75 folds more than Na+ 20% is caused by the Na+ K+ pump an active process that needs energy taken from Sodium-Potassium Exchange Pump Dentistry 07 39  In other words, the inside of the neuron is slightly negative relative to the outside. Such charge differences can result from both electrogenic pumping and from passive ion diffusion. This difference is referred to as the Membrane Potential [MP] Membrane potentials represent the force required to separate charged ion species. Measured MP of neurons are in the order of -40 to -90 mV, the minus means that the inside is negative relative to (or compared to) the outside. It is called a RESTING MEMBRANE POTENTIAL [RMP] because it occurs when a membrane is not being stimulated or conducting impulses  Neurons can respond to stimuli and conduct impulses because a membrane potential is established across the cell membrane. In other words, there is an unequal distribution of ions (charged atoms) on the two sides of a nerve cell membrane. With one electrode placed inside a neuron and the other outside, the voltmeter is 'measuring' the difference in the distribution of ions on the inside versus the outside And, in this example, the voltmeter reads -70 mV (mV = millivolts).  If a suitable pathway exists for the passage of an ion species across the membrane, a net movement down the electrochemical gradient results. to Ion discriminate channels afford such species pathways, is and their among abilityfor ion responsible directly membra normal generating voltages. ne The selective movement of a acrossa single ion species cell membrane potential that can be generates predicted a from knowledge of the membrane concentration difference for that ion species between intracellular and extracellular compartments.  Neurotransmitters Acetylcholine: – transmit signal to skeletal muscle Epinephrine (adrenaline) & norepinephrine: – fight-or-flight response Dopamine: – affects sleep, mood, attention & learning – lack of dopamine in brain associated with Parkinson’s disease – excessive dopamine linked to schizophrenia Serotonin: 4 – affects sleep, mood, attention & learning 3  The Brain 4 Parts – Cerebrum – *Diencephalon – Brain Stem Midbrain Pons Medulla – Cerebellum Gray matter surrounded by White matter w/outer cortex of gray matter  Meninges: 3 membranes around brain and spinal cord Made of Connective tissue Functions – Cover, Protect CNS – Enclose, protect blood vessels supplying CNS – Contain CSF 3 Layers – Dura Mater (external) – Arachnoid Mater (middle) – Pia Mater (internal)  Cerebral features Gyri: elevated ridges “winding” around the brain Sulci: small grooves dividing the gyri Central sulcus: Divides the Frontal Lobe from the Parietal Lobe Fissures: deep grooves, generally dividing large regions/lobes of the brain Longitudinal fissure – divides the two Cerebral Hemispheres Transverse fissure – separates the Cerebrum from the Cerebellum Sylvian/lateral fissure – divides the Temporal Lobe the Frontal from and Parietal Lobes 4 6  Gross anatomy of the spinal cord extends from C1 – L1/2 covered by 3 layers of meninges terminates at L1/2 (conus medullaris) Dura extends to S2 surrounds by CSF – subarachnoid space has 31 pars of spinal nerves has cervical and lumbar 4 7  Cont’d Conus medullaris: – terminal portion of the spinal cord Filum terminale: – fibrous extension of the pia mater; anchors the spinal cord to the coccyx Denticulate ligaments: – delicate shelves of pia mater; attach the spinal cord to the vertebrae Spinal nerves: – 31 pairs attach to the cord by paired roots Cervical nerves are named for inferior vertebra All other nerves are named for superior vertebra Cervical and lumbar enlargements: – sites where nerves serving the upper and lower limbs emerge Cauda equina: – collection of nerve roots at the inferior end of the vertebral canal 48  Cont’d Meningeal layers: Dura mater Arachnoid mater Pia mater 49  MEMBRANES - COVER THE CNS 3 IN ALL Protective coverings 1. DURA MATTER – PACHYMENINX 2. ARACHNOID 3. PIA – 2&3- LEPTOMENINGES 5 0  Meninges Dura mater Arachnoid mater Pia mater 51 Cranial Dura Mater Bone Endoste al Sinus Meninge al 52 53  MENINGEAL LAYER INFOLDS TO GIVE 4 SEPTAE – FALX CEREBRI – TENTORIUM CEREBELLI – FALX CEREBELLI – DIAPHRAGMA SELLA Septae restrict displacemen t of brain associated with acceleration & 5 deceleration 4  Falx Cerebri– the sickle Occupies the longitudinal fissure between cerebral hemispheres. Superior sagittal runs in its upper fixed margin. Inferior sagittal sinus in its lower concave free margin. Straight sinus along its attachment to tentorium cerebelli. 55 Tentorium Cerebelli– the tent – Covers the superior surface of cerebellum. – Supports occipital lobes of cerebral hemispheres. – The opening accommodates the brainstem. Midbrain passes thru the tentorial notch. 56  Falx Cerebelli A small midsagittal septum below the tentorium. Partially separates cerebellar hemispheres 57  Diaphragma Sella Roofs over the pituitary fossa. Perforated by the infundibulum of the pituitary. 58  BLOOD SUPPLY – MID. MENINGEAL – ANT. MENINGEAL – POST. MENINGEAL 59 INTRACRANIAL VENOUS SINUSES 6 0  DURAL VENOUS SINUSES Superior sagittal (SS sinus S) Inferior sagittal sinus Straight sinus Transverse sinus Sigmoid sinus Occipital sinus Cavernous sinus 61 Superior petrosal  Arachnoid Mater Separated from dura by a potential space – the subdural space, filled by a film of fluid. Separated from pia by subaracnoid space, filled with CSF. Outer & inner surfaces covered with flattened mesothelial cells. Bridges over sulci. 62  Arachnoid DELICA TE NON VASCUL AR 63  PI VASCULAR A ADHRENT EXT. LIMITING MEMBRANE 2 LAYERS EPIPIAL – COLLAGENOUS FIBERS; ABSENT ON CONVEXITY OF BRAIN INTIMA PIA – INNER MEMBRANOUS LAYER; FOLLOW BRAIN CONTOUR; AVASCULAR; PERIVASCULAR SPACE; MADE OF RETICULAR & ELASTIC FIBERS. – CEREBRAL VESSELS LIE ON SURFACE OF INTIMA WITHIN SUBARACHNOID SPACE 64  Cranial nerves CN I: Olfactory - Sensory CN II: Optic - Sensory CN III: Oculomotor - Motor CN IV: Trochlear - motor CN V: Trigeminal - Sensory and motor CN VI: Abducens - Motor CN VII: Facial - Sensory and motor CN VIII: Vestibulocochlear (auditory) - Sensory CN IX: Glossopharyngeal - Sensory and motor CN X: Vagus - Sensory and motor CN XI: Accessory (spinal accessory) - Motor CN XII: Hypoglossal - Motor 65  Names of cranial Ⅰ Olfactory nerve Ⅱ Optic nerve nerves Ⅲ Oculomotor nerve Ⅳ Trochlear nerve Ⅴ Trigeminal nerve Ⅵ Abducent nerve Ⅶ Facial nerve Ⅷ Vestibulocochlear nerve Ⅸ Glossopharyngeal nerve Ⅹ Vagus nerve Ⅺ Accessory nerve Ⅻ Hypoglossal nerve  Classification of Sensory cranial nerves: contain only afferent cranial (sensory) fibers nerves – ⅠOlfactory nerve – ⅡOptic nerve – Ⅷ Vestibulocochlear nerve Motor cranial nerves: contain only efferent (motor) fibers – Ⅲ Oculomotor nerve – Ⅳ Trochlear nerve – ⅥAbducent nerve – Ⅺ Accessory nerv – Ⅻ Hypoglossal nerve Mixed nerves: contain both sensory and motor fibers--- – ⅤTrigeminal nerve,  Sensory cranial N. Location of cell Cranial Terminal Main bodynerves and axon exit nuclei action categories Ⅰ Olfactory cells Cribrifom Olfactory Smell (SVA) foramina bulb Ⅱ Ganglion cells Optic Lateral Vision (SSA) canal geniculate body Ⅷ Vestibular Internal Vestibular Equilibri ganglion(SSA) acoustic nuclei um meatus Cochlear Cochlear Hearing ganglion (SSA) nuclei  Motor cranial N. Nucleus of origin and Cranial exit Main action axon categories nerves Ⅲ Nucleus of oculomotor Superior orbital Motor to superior, inferior (GSE) fissure and medial recti; inferior obliqus; levator palpebrae superioris Accessory nucleus of Parasympathetic to sphincter oculomotor (GVE) pupillea and ciliary muscl Ⅳ Nucleus of trochlear Superior orbital Motor to superior obliquus nerve (GSE) fissure Ⅵ Nucleus of abducent Superior orbital Motor to lateral rectus nerve (GSE) fissure Ⅺ Nucleus of accessory Jugular foramen Motor to sternocleidomastoid nerve (SVE) and trapezius Ⅻ Nucleus of hypoglossal Hypoglossal canal Motor to muscles of tongue nerve( GSE) Mixed cranial nerves  SUMMARY OF THE CRANIAL Nerve NERVESLocation of Nerve Cell Components Bodies Cranial Exit Main Action(s) Olfactory Special Olfactory epithelium Foramina in Smell from nasal mucosa of roof of (CN I) sensory (olfactory cells) cribriform plate of each nasal cavity and superior sides ethmoid bone of nasal septum and superior concha Optic (CN Special Retina (ganglion cells) Optic canal Vision from retina II) sensory Oculomotor Somatic Midbrain Motor to superior rectus, inferior (CN III) motor rectus, medial rectus, inferior oblique, and levator palpebrae superioris muscles; raises superior eyelid; turns eyeball superiorly, inferiorly, and medially Superior orbital Visceral Presynaptic: midbrain fissure Parasympathetic innervation to motor Postsynaptic: ciliary sphincter of pupil and ciliary muscle; ganglion constricts pupil and accommodates lens of eye Trochlear Somatic Midbrain Motor to superior oblique that assists (CN IV) motor in turning eye infero-laterally (or inferiorly when adducted)  CON’ Location of Nerve Nerve Trigeminal Components Cell Bodies T Cranial Exit Main Action(s) (CN V) Ophthalmic Superior orbital Sensation from cornea, skin of (CN V1) fissure forehead, scalp, eyelids, nose, and mucosa of nasal cavity and paranasal sinuses Maxillary Foramen rotundum Sensation from skin of face over (CN V2) General maxilla, including upper lip, Trigeminal ganglion maxillary teeth, mucosa of nose, sensory maxillary sinuses, and palate Mandibular Foramen ovale Sensation from skin and over side (CN V3) of head mandible including lower lip, mandibular teeth, temporomandibular joint, mucosa of mouth and anterior two thirds of tongue Branchial Pons Motor to muscles of mastication, motor mylohyoid, anterior belly of digastric, tensor veli palatini, and tensor tympani Abducent Somatic motor Pons Superior orbital Motor to lateral rectus that turns (CN VI) fissure eye laterally  CON’ Location of Nerve Cell Nerve Facial Components Branchial motor Bodies Pons T Cranial Exit Main Action(s) Motor to muscles of facial (CN VII) expression and scalp; also supplies stapedius of middle ear, stylohyoid, and posterior belly of digastric Special sensory Geniculate ganglion Internal acoustic meatus; Taste from anterior two facial canal; stylomastoid foramen thirds of tongue and the palate Visceral motor Presynaptic: pons Parasympathetic Postsynaptic: innervation to pterygopalatine ganglion; submandibular and submandibular ganglion sublingual salivary glands, lacrimal gland, and glands of nose and palate Vestibuloc ochlear (CN VIII) Vestibular Special sensory Vestibular ganglion Vestibular sensation from semicircular ducts, utricle, and saccule related to Internal acoustic meatus position and movement of head Cochlear Special sensory Spiral ganglion Hearing from spiral organ  Location of Nerve Nerve Components Cell Bodies Cranial Exit Main Action(s) Glossopharyngeal Branchial Medulla Motor to (CN IX) motor stylopharyngeus to assist with swallowing Visceral motor Presynaptic: Parasympathetic medulla innervation to parotid gland Postsynaptic: otic ganglion Visceral Superior ganglion Jugular foramen Visceral sensation sensory from parotid gland, carotid body and sinus, pharynx, and middle ear Special Inferior ganglion Taste from posterior sensory third of tongue General Inferior ganglion Cutaneous sensation sensory from external ear Nerve Components Cell Bodies Exit Main Action(s) Vagus (CN X) Branchial Medulla Motor to constrictor muscles of motor pharynx (except stylopha-ryngeus), intrinsic muscles of larynx, muscles of palate (except tensor veli palatini), and striated muscle in superior two thirds of esophagus Visceral Presynaptic: medulla Parasympathetic innervation to motor Postsynaptic: neurons smooth muscle of trachea, bronchi, digestive tract, and cardiac muscle of in, on, or near viscera heart Jugula r Visceral Superior ganglion Visceral sensation from base of foram tongue, pharynx, larynx, trachea, sensory en bronchi, heart, esophagus, stomach, and intestine to left colic flexure Special Inferior ganglion Taste from epiglottis and palate sensory General Superior ganglion Sensation from auricle, external sensory acoustic meatus, and dura mater of posterior cranial fossa Spinal accessory (CN Somatic Spinal cord Motor to sternocleidomastoid and XI) motor trapezius Hypoglossal (CN XII) Somatic Medulla Hypoglossal Motor to intrinsic and extrinsic motor canal muscles of tongue (except palatoglossus) *The traditional cranial root of the accessory nerve is considered here as part of the vagus nerve (CN X); the spinal accessory nerve (CN XI) as listed here refers only to the traditional spinal root of the accessory nerve.  Nerve Summary of Cranial Type(s) and/or Site(s) of Lesion Nerve Lesions Abnormal Findings CN I Fracture of cribiform plate Anosmia (loss of smell); cerebrospinal fluid rhinorrhea CN II Direct trauma to orbit or eyeball; fracture Loss of pupillary constriction involving optic canal Visual field defects Pressure on optic pathway; laceration or intracerebral clot in the temporal, parietal, or occipital lobes of brain CN III Pressure from herniating uncus on nerve; Dilated pupil; ptosis; eye turns down and out; fracture involving cavernous sinus; pupillary reflex on the side of the lesion will aneurysms be lost CN IV Stretching of nerve during its course around Inability to look down when eye is adducted brainstem; fracture of orbit CN V Injury to terminal branches (particularly Loss of pain and touch sensations; CN V2) in roof of maxillary sinus; paraesthesia; masseter and temporalis muscles pathological processes affecting trigeminal do not contract; deviation of mandible to side ganglion of lesion when mouth is opened CN VI Base of brain or fracture involving Eye falls to move laterally; diplopia on lateral cavernous sinus or orbit gaze  Nerve Type(s) and/or Site(s) of Lesion Abnormal Findings CN VII Laceration or contusion in parotid region Paralysis of facial muscles; eye remains open; angle of mouth droops; forehead does not wrinkle Fracture of temporal bone As above, plus associated involvement of cochlear nerve and chorda tympani; dry cornea; loss of taste on anterior two thirds of tongue Intracranial hematoma (stroke) Forehead wrinkles because of bilateral innervation of the frontalis muscle; otherwise paralysis of contralateral facial muscles CN VIII Tumor of nerve (acoustic neuroma) Progressive unilateral hearing loss; tinnitus (noises in ear) CN IX Brainstem lesion or deep laceration of Loss of taste on posterior third of tongue; loss neck of sensation on affected side of soft palate CN X Brainstem lesion or deep laceration of Sagging of soft palate; deviation of uvula to neck normal side; hoarseness owing to paralysis of vocal fold CN XI Laceration of neck Paralysis of sternocleidomastoid and superior fibers of trapezius; drooping of shoulder CN XII Neck laceration; basal skull fractures Protruded tongue deviates toward affected side; moderate dysarthria (disturbance of articulation)  Oculomotor paralysis EN Abducent nerve D injury  APPLIED & CLINICAL ANATOMY Meningitis Subdural hemorrhage- results from tearing of superior cerebral veins where they enter the SSS. More common than middle meningeal bleeding. Subarachnoid hemorrhage- usually results from rupture of congenital aneurysm on circle of Willis Epidural/Extradural hemorrhage- from injuries to meningeal arteries and veins. Anterior division of MMA is the a commonly damaged. 7 9 Thanks for listening QUESTIONS ? 8 08 0