Nerves of Head and Neck (Anatomy) Lecture 11 PDF

 Prof. Dorreia Abd Alla Mohamed Zaghloul Lecture (11): NERVES OF HEAD AND NECK (I) (Anatomy) Source: First aid for the basic sciences (organ systems): chapter 6, pp 472-474. Source: Else...

 Prof. Dorreia Abd Alla Mohamed Zaghloul Lecture (11): NERVES OF HEAD AND NECK (I) (Anatomy) Source: First aid for the basic sciences (organ systems): chapter 6, pp 472-474. Source: Elseviers Integrated Review anatomy and Embryology, pp 315-319, 328,329 Source: Kaplan neuroscience USMLE Lecture notes 2021; Pages 280-281. Specific learning Objectives 1- Formulate a broad differential diagnosis for each problem, based on the clinical encounter and investigations done to date in a stable patient presenting with one of the following straight forward problems: e.g. paralysis, squint, facial nerve palsy, deafness 2- Mention the main principles of gross anatomy of the body including nerves of the head and neck. Contents: By the end of the lecture the student will be able to: List the cranial nerves and identify briefly, component fibers, peripheral distribution, function of each nerve. The main signs of injury. Explain the signs of cranial nerves injury based on anatomical facts. NARS: (1.10, 4.1,). THE CRANIAL NERVES The 12 pairs of cranial nerves are part of the peripheral nervous system (PNS) and pass through foramina or fissures in the cranial cavity. All nerves except one, the spinal accessory nerve [XI], originate from the brain. In addition to having similar somatic and visceral components as spinal nerves, some cranial nerves also contain special sensory and motor components The special sensory components are associated with hearing, seeing, smelling, balancing, and tasting. Special motor components include those that innervate muscles derived embryologically from the pharyngeal arches. Fig. 11-1: Cranial nerves exiting the cranial Fig. 11-2: Cranial nerves on the base of the cavity. brain. 1  Prof. Dorreia Abd Alla Mohamed Zaghloul Table 11.1:Cranial nerve functional components Functional component General function Cranial nerves containing component General somatic afferent Perception of touch, Trigeminal nerve [V]; facial (GSA) pain, temperature nerve [VII]; Glossopharyngeal nerve [IX]; vagus nerve [X] General visceral afferent Sensory input from Glossopharyngeal nerve [IX]; (GVA) viscera vagus nerve [X] Special somatic afferent vision, hearing and optic nerve [II]; (SSA) balance ( from organs vestibulocochlear nerve [VIII] developing in ectoderm of embryo) Special visceral afferent Smell, taste (from Olfactory nerve [I]; facial nerve (SVA) organs developing in [VII];; glossopharyngeal nerve association of gastro- [IX]; vagus nerve [X] intestinal tract) General somatic efferent Motor innervation to Oculomotor nerve [III]; trochlear (GSE) , innervate striated skeletal (voluntary) nerve [IV]; abducent nerve [VI]; muscles that are derived muscles hypoglossal nerve [XII] from somites General visceral efferent Motor innervation to Oculomotor nerve [III]; facial (GVE) (Parasympathetic smooth muscle, heart nerve [VII]; glossopharyngeal outflow) muscle, and glands nerve [IX]; vagus nerve [X] Special visceral efferent Motor innervation to Trigeminal nerve [V]; facial (SVE) or branchial motor skeletal muscles derived nerve [VII]; glossopharyngeal innervate muscles from pharyngeal arch nerve [IX]; vagus nerve [X]; derived from the mesoderm accessory nerve [XI] branchial (gill) arches OLFACTORY NERVE(SVA) It is the first cranial nerve and nerve of smell and form first order neuron of olfactory pathway. Type → Special Sensory type. Origin → From olfactory epithelium (Olfactory receptor cells) in the olfactory region of nasal cavity (superior nasal concha and opposed part of nasal septum). Course → After origin they pass through the cribriform plate of ethmoid bone and within the cranial cavity they end in olfactory bulb (Fig.11.3). Lesion of olfactory nerve results in loss of smell (Anosmia). OPTIC NERVE (SSA) The optic nerve [II] carries SSA fibers for vision. These fibers return information to the brain from photoreceptors in the retina. The optic nerve enters the cranial cavity through the optic canal surrounded by sheaths of pia, arachnoid , and dura maters. 2  Prof. Dorreia Abd Alla Mohamed Zaghloul Lesion of one optic nerve results in blindness (anopia) of the same eye. Fig. 7.3: Olfactory nerve. Fig. 7.4:Intraorbital part of optic nerve. OCCULOMOTOR NERVE(GSE-GVE) It is the 3rd CN supplying extrinsic eye muscles that enable most movements of the eye and that raise the eyelid. It leaves the anterior surface of the brainstem between the midbrain and the pons(Fig 11.2). It enters the lateral wall of the cavernous sinus (Figs11.1&11.2) and leaves the cranial cavity through the superior orbital fissure. In the orbit(Fig 11.6) , the GSE fibers in the oculomotor nerve innervate levator palpebrae superioris, superior rectus, inferior rectus, medial rectus, and inferior oblique muscles. GVE fibers are preganglionic parasympathetic fibers that synapse in the ciliary ganglion and ultimately innervate the sphincter pupillae muscle, responsible for pupillary constriction, and ciliary muscles, responsible for accommodation of lens for near vision. CLINICALLY APPLIED ASPECTS Anatomical basis of clinical features of third nerve palsy(Fig 11.11) A complete and total third nerve palsy is of common occurrence. It may be congenital or acquired. Clinical features of complete third nerve palsy include the following: 1. Ptosis due to paralysis of the LPS muscle. 2. Deviation. Eyeball is turned down and out due to unopposed action of the lateral rectus and superior oblique muscles Fig. 7.5: Diagram of nuclei of cranial nerves (numbered). 3  Prof. Dorreia Abd Alla Mohamed Zaghloul Fig. 7.6: Cranial nerve III, IV, and VI. 3. Ocular movements are restricted due to paralysis of the muscles as follows: Adduction - due to medial rectus. Elevation- due to superior rectus and inferior Oblique. Depression - due to inferior rectus. Extorsion – due to inferior rectus and inferior oblique. 4. Pupil is fixed and dilated due to paralysis of the sphincter pupillae muscle. 5. Accommodation is completely lost due to Fig. 7.7: Oculomotor nerve paralysis. paralysis of the ciliary muscle. 6. Diplopia occurs due to paralytic divergent squint. TROCHLEAR NERVE(GSE) It is the fourth cranial nerve which supplies superior oblique muscle of eyeball(Fig 11.6). It arises in the midbrain and is the only cranial nerve to exit from the posterior surface of the brainstem (Fig 11.2). After curving around the midbrain, it enters the free edge of the tentorium cerebelli, then in the lateral wall of the cavernous sinus (Figs11.1&11.2), and enters the orbit, through the superior orbital fissure(Fig 11.6). 4  Prof. Dorreia Abd Alla Mohamed Zaghloul NB : Trochlear nerve arises from the contralateral nucleus. Features of fourth nerve palsy 1. Hyperdeviation(i.e., hypertropia): The involved eye is higher as a result of the weakness of the superior oblique muscle. 2. Diplopia. when the patient is coming down the stairs Fig. 7.8: Trochlear nerve paralysis. (requires looking down and inward). TRIGEMINAL NERVE (GSA,SVE) It is the fifth cranial nerve and largest of all cranial nerves. It is mixed nerve. The GSA fibers provide sensory input from the face, anterior one-half of the scalp, mucous membranes of the oral and nasal cavities and the paranasal sinuses, part of the tympanic membrane, the eye and conjunctiva, and the dura mater in the anterior and middle cranial fossae; The SVE fibers innervate the muscles of mastication, the tensor tympani, the tensor veli palatini, the mylohyoid, and the anterior belly of the digastric. The trigeminal nerve exits from the anterolateral surface of the pons as a large sensory root and a small motor root(Fig 11.2). In the middle cranial fossa the sensory root expands into the trigeminal ganglion(Fig 11.1) which contains cell bodies for the sensory neurons in the trigeminal nerve and is comparable to a spinal ganglion. Arising from the anterior border of the trigeminal ganglion are the three terminal divisions of the trigeminal nerve, which in descending order are: The ophthalmic nerve, the maxillary nerve and the mandibular nerve The ophthalmic nerve [V1], purely sensory, carries sensory branches from the eyes, conjunctiva, and orbital contents, including the lacrimal gland. It also receives sensory branches from the nasal cavity, frontal and ethmoidal sinuses, upper eyelid, dorsum of the nose, and the anterior part of the scalp. It passes forward in the dura of lateral wall of the cavernous sinus. It terminates by dividing into three branches, those enter the orbit through superior orbital fissure. 5  Prof. Dorreia Abd Alla Mohamed Zaghloul Branches: 1- Frontal nerve: that divides in the orbit into supratrochlear and supraorbital nerves which supply the skin of the forehead. 2- Lacrimal nerve: sensory for lacrimal gland and carries postganglionic secretomotor parasympathetic fibres for lacrimal gland. 3- Nasociliary nerve: It ends by dividing into the anterior ethmoidal and infratrochlear nerves. The maxillary nerve [V2], purely sensory, receives sensory branches from the dura in the anterior and middle cranial fossae, the nasopharynx, the palate, the nasal cavity, teeth of the upper jaw, maxillary sinus, and skin covering the side of the nose, the lower eyelid, the cheek, and the upper lip. It passes forward in the lateral wall of the cavernous sinus then through the foramen rotundum, and enters the pterygopalatine fossa(Fig11.9). It enters the orbit through inferior orbital fissure. It is then named infraorbital nerve It passes through infraorbital groove and canal to exit through infraorbital foramen. Fig.7.9: Distribution of trigeminal nerve. 6  Prof. Dorreia Abd Alla Mohamed Zaghloul Fig.7.10: Distribution of ophthalmic nerve. Fig.7.11: Distribution of maxillary nerve. 3. MANDIBULAR NERVE[V3] : It is the largest division of trigeminal nerve with larger sensory root arises from trigeminal ganglion and smaller motor root from motor nucleus of trigeminal nerve in the pons. Course: The two roots pass through the foramen ovale leaving the cranial cavity to join just below the foramen in the infratemporal fossa forming the main trunk. Distribution: General sensation of anterior two-thirds of tongue except vallate papilla, mucosa of the floor of the mouth, and lingual gingiva. (lingual nerve), skin over buccinator muscle and oral mucosa(buccal nerve) and the buccal gingivae of the lower molars., mandibular teeth, lower lip and chin(Inferior alveolar nerve) , dura and mastoid air cells(nervous spinosum), It contributes to sensory innervation of skin over a large area of the temple, external ear, 7  Prof. Dorreia Abd Alla Mohamed Zaghloul external auditory meatus, tympanic membrane, and temporomandibular joint by the auriculotemporal nerve). this nerve also carries postganglionic secretomotor parasympathetic fibres for parotid gland coming from glossopharyngeal nerve. Motor to muscles of mastication(temporalis, masseter, medial andlateral pterygoids) anterior belly of digastric, mylohyoid, tensor tympani, and tensor palati N.B. As the lingual nerve enters the floor of the oral cavity it is in a shallow groove on the medial surface of the mandible immediately inferior to the last molar tooth. In this position, it is in danger when operating on molar teeth and gingivae. -The lingual nerve passes into the tongue on the lateral surface of the hyoglossus muscle where it is attached to the submandibular ganglion, which contains the secondary cell bodies for the parasympathetic fibers of the chorda tympani nerve. N.B.: The lingual nerve is joined high in the infratemporal fossa by the chorda tympani branch of the facial nerve [VII], which carries: Taste from the anterior two-thirds of the tongue; Parasympathetic fibers to all salivary glands below the level of the oral fissure. It also carries post ganglionic fibres from submandibular ganglion for sublingual salivary and anterior lingual gland. Fig.7.12: Distribution of mandibular nerve. 8  Prof. Dorreia Abd Alla Mohamed Zaghloul Applied anatomy: Lesion of whole of trigeminal nerve, 1) Anesthesia of the corresponding anterior half of scalp, face(except the area at the angle of mouth), cornea(loss of corneal reflex), conjunctiva, mucous membrane of nose, mouth, anterior 2/3rd of tongue. 2) Paralysis and atrophy of muscles supplied by the nerve and so when patient tries to open the mouth the mandible will thrust to the paralysed side. Lingual nerve injury Proximal to where chorda tympani joins it will produce loss of general sensation from anterior two-thirds of the tongue, oral mucosa, gingivae, lower lip, and chin. If a lingual nerve lesion is distal to the site where it is joined by the chorda tympani, secretion from the salivary glands below the oral fissure and taste from the anterior two- thirds of the tongue will also be lost. Trigeminal neuralgia (TN) : is intractable pain in V2 or V3 territory. The pain typically involves the lower face and jaw, although sometimes it affects the area around the nose and above the eye. This intense, stabbing, electric shock-like pain is caused by irritation of the trigeminal nerve. It usually is limited to one side of the face. The pain can be triggered by an action as routine and minor as brushing your teeth or eating. It is thought that TN results from irritation of trigeminal nerve. ABDUCENT NERVE(GSE) It is the sixth cranial nerve, It arises from the brainstem close to the median plane between pons and medulla and passes forward, piercing dura (Figs 11.1,11.2), enters and crosses the cavernous sinus just inferolateral to the internal carotid artery, and enters the orbit through the superior orbital fissure to innervate the lateral rectus muscle(Fig.11.6). APPLIED ANATOMY: Effects of paralysis: Fig.11.14: CN VI palsy. Convergent squint due to unopposed action of medial rectus. Abduction is limited due to weakness of the lateral rectus muscle. Often diplopia with convergent squint will be present. 9  Prof. Dorreia Abd Alla Mohamed Zaghloul NERVES OF HEAD AND NECK (12) Source: First aid for the basic sciences (organ systems): chapter 6, pp.472-474 Source: Kaplan neuroscience USMLE Lecture notes 2021; Pages: 280.281 Source:Elseviers Integrated Review anatomy and Embryology, pp 315-319, 328,329 Specific learning Objectives 1- Formulate a broad differential diagnosis for each problem, based on the clinical encounter and investigations done to date in a stable patient presenting with one of the following straight forward problems: e.g. paralysis, squint, facial nerve palsy, deafness 2- Mention the main principles of gross anatomy of the body including: nerves of the head and neck By the end of the lecture the student will be able to: 1. List the cranial nerves and identify briefly; component fibers, peripheral distribution, function of each nerve. The main signs of injury. 2. Describe the formation and branches of the cervical plexus 3. Explain the signs of cranial nerves injury based on anatomical facts. 4. Distinguish the difference in clinical manifestations between upper and lower lesion of the facial nerve NARS: (1.10, 4.1). THE FACIAL NERVE (GSA, SVA, GVE & SVE) It is the 7th cranial nerve. The GSA fibers provide sensory input from the external acoustic meatus that terminates in the sensory nuclei of 5th nerve. The SVA fibers are for taste from the anterior two-thirds of the tongue. The GVE fibers, parasympathetic, are secretomotor to the lacrimal gland, submandibular and sublingual salivary glands, and nasal and palatine glands. The SVE fibers innervate muscles of the face and scalp , and the stapedius, the posterior belly of the digastric, and the stylohyoid muscles. Nuclei (Fig.12.2) 1- The main motor nucleus lies in the lower pons. The part of the nucleus that supplies the muscles of the upper part of the face receives corticonuclear fibers from both cerebral hemispheres. The part of the nucleus that supplies the muscles of the lower part of the face receives only corticonuclear fibers from the opposite cerebral hemisphere. These pathways explain the voluntary control of facial muscles. 2- The parasympathetic nuclei ,in pons, are superior salivatory and lacrimal nuclei. 3- The sensory nucleus , the upper part of the nucleus of the tractus solitaries, is responsible for taste of anterior ⅔ of the tongue. 1  Prof. Dorreia Abd Alla Mohamed Zaghloul Facial nerve consists of a large motor root and a smaller root (nervus intermedius).The intermediate nerve contains the fibers for taste, the parasympathetic fibers and somatic sensory fibers. The facial nerve [VII] exits the skull through the stylomastoid foramen and passes into the parotid gland, where it divides into five terminal branches. Branches:Intracranial branhes At the geniculate ganglion(Fig.12.1): 1- Greater petrosal nerve arises. It carries secretomotor fibers to the lacrimal gland and glands of nose and palate. It also contains taste fibers from palate. 2- communicating branch for lesser petrosal nerve(Fig.4.1). Fig. 12.1:Course of facial nerve in temporal bone. Fig. 12.2: Distribution of facial nerve. 2  Prof. Dorreia Abd Alla Mohamed Zaghloul IN the facial canal: It gives 1- Nerve to stapedius muscle. 2-Chorda tympani carries taste from the anterior ⅔ of the tongue and preganglionic parasympathetic for the submandibular ganglion In the face: Extracranial branches Distal to stylomastoid foramen, the following nerves branch off the facial nerve: 1-Posterior auricular nerve: controls movements of some of scalp muscles around the ear 2- Branch to posterior belly of digastric muscle as well as the stylohyoid muscle 3- Five major facial branches (in parotid gland) – from top to bottom: Temporal, Zygomatic, Buccal, Marginal mandibular and Cervical branches. Distribution of facial nerve.(See fig. 12.2) Difference between upper and lower motor neuron facial lesion(Fig.12.3) U.M.N.L due to lesion in the cortico- bulbar tract. Upper part of the face (muscles closing eye) is not paralysed, because the upper part of facial nucleus receives corticobulbar fibers from both sides. Only the lower part of the face on the contralateral side will be affected, L.M.N.L due to lesion in facial nucleus or facial nerve itself or idiopathic lesion (Bell's palsy) can result in a CN VII palsy, manifested as both upper and lower facial weakness on the same side Fig. 12.3: Difference between upper and lower of the lesion. motor neuron facial lesion. 3  Prof. Dorreia Abd Alla Mohamed Zaghloul VESTIBULOCOCHLEAR NERVE (SSA) Fig. 12.4: Vestibulocochlear nerve GLOSSOPHARYNGEAL NERVE(9th cranial nerve) (GVA, GSA, SVA, GVE & SVE) ♦ Fiber component 1) Sensory fibers 1- General visceral afferent fibers:carry sensory information from carotid sinus and carotid body that regulate blood pressure and blood gases. 2- Special visceral afferent fibers: It carries taste sensations from the posterior 1/3 of the tongue and circumvallate papillae. 3- General somatic afferent fibers: transmit general sensation from mucosa of the posterior ⅓ of the tongue, soft palate, upper pharynx, the inner surface of the tympanic membrane, and auditory tube and skin of external ear. These fibers synapse with central neurons in the spinal trigeminal nucleus. II) Motor fibers 1- General visceral efferent fibers : parasympathetic innervation to parotid gland. 2- Special visceral efferent fibers : Supply stylopharyngeus muscle. ♦ Nuclei the glossopharyngeal nerve: 1- Main motor nucleus,in medulla oblongata, is formed by upper end of nucleus ambiguus. 2-Parasympathetic nucleus, inferior salivatory nucleus, its preganglionic fibers reach the otic ganglion through tympanic branch of CNIX, the tympanic plexus, and the lesser petrosal nerve. Postganglionic fibers pass to parotid gland carried by auriculotemporal nerve 3- Sensory nucleus is a part of the nucleus of the tractus solitarius. It carries: A- Taste Sensation from the posterior 1/3 of the tongue 4  Prof. Dorreia Abd Alla Mohamed Zaghloul B- General visceral afferent (G.V.S) from the carotid sinus, a baroreceptor situated at the bifurcation of the common carotid artery, travel with the glossopharyngeal nerve. They communicate with the dorsal motor nucleus of the vagus nerve. (The carotid sinus reflex that involves the glossopharyngeal and vagus nerves assists in the regulation of arterial blood pressure). Increase the arterial blood pressure in the carotid sinus-----sinus nerve (IX) -------- dorsal nucleus of vagus----SA node of the heart slow the heart rate. Distribution of glossopharyngeal nerve see Fig. 12.5: Fig. 12.5: Distribution glossopharyngeal nerve. Tympanic nerve participates in the formation of the tympanic plexus. Within the middle ear cavity it provides sensory innervation to the mucosa of the cavity, pharyngotympanic tube, and mastoid air cells. The tympanic plexus gives lesser petrosal nerve, enters the middle cranial fossa, and descends through foramen ovale carrying preganglionic parasympathetic fibers to the otic ganglion. Glossopharyngeal nerve palsy produces absent gag reflex. 5  Prof. Dorreia Abd Alla Mohamed Zaghloul VAGUS NERVE (GSA, GVA, SVA, GVE, & SVE) It is the tenth cranial nerve. ♦Fiber component are I) Sensory fibers l- General somatic afferent fibers carry general sensations from the external auditory meatus. 2- General visceral afferent fibers provide sensory input from the aortic body chemoreceptors and aortic arch baroreceptors, and the mucous membranes of the pharynx, larynx, esophagus, bronchi, lungs, heart, and abdominal viscera in the foregut and midgut; 3-Special visceral afferent fibers: carry taste sensations from the epiglottis. II) Motor fibers 1-General visceral efferent fibers:parasympathetic to the thoracic and abdominal viscera. 2- Special visceral efferent fibers: innervate muscles of soft palate (except tensor palati), pharynx (except stylopharyngeus), and larynx. ♦ Nuclei of vagus nerve: 1- Main motor nucleus (S.V.E), the nucleus ambiguous, in the medulla oblongata. 2- Parasympathetic nucleus (G.V.E) , the dorsal nucleus of vagus. It lies beneath the floor of the 4th ventricle. Its fibers are distributed to the involuntary muscle of the bronchi, heart, esophagus, stomach, small intestine, and large intestine as far as the proximal 2/3 of the transverse colon. 3- Sensory nucleus (GVA & SVA) is the lower part of the tractus solitarius. Distribution of vagus nerve: see Fig. 12.6: Vagus nerve palsy produces: 1. Nasal speech, nasal regurgitation 2. Dysphagia, palate droop 3. Uvula pointing away from affected side 4. Hoarseness/fixed vocal cord 5. Loss of gag reflex with IX, Loss of cough reflex 6. Tachycardia and delayed digestive motility. Lesions involving the vagus nerve in the posterior cranial fossa commonly involve the glossopharyngeal, accessory, and hypoglossal nerves as well. 6  Prof. Dorreia Abd Alla Mohamed Zaghloul Fig. 12.6: Distribution of vagus nerve. ACCESSORY NERVE (CRANIAL NERVE XI) CRANIAL ROOT (SVE) is formed from the axons of nerve cells in the most inferior part of the nucleus ambiguus. The efferent fibers of the nucleus join the vagus nerve and are distributed through the pharyngeal and recurrent laryngeal branches to all muscles of the pharynx, larynx and palate. SPINAL ROOT (SE) is formed from axons of nerve cells in the spinal nucleus, which is situated in the anterior gray column of the spinal cord in the upper six cervical segments. The fibers ascends into the skull Fig. 12.7: Accessory Nerve through the foramen magnum to joins the cranial root as they pass through the jugular foramen. After a short distance, spinal part separates from cranial root and supplies sternocleidomastoid and trapezius mc. 7  Prof. Dorreia Abd Alla Mohamed Zaghloul Lesions of the spinal part of accessory nerve will result in paralysis of the sternocleidomastoid and trapezius muscles. The sternocleidomastoid muscle will atrophy, and there will be weakness in turning the face to the opposite side. The trapezius muscle will also atrophy, and the shoulder will drop on that side. Lesions may result from tumors or trauma from stab or gunshot wounds in the neck. HYPOGLOSSAL NERVE(GSE)(12th CN) General somatic efferent supplying all intrinsic muscles and extrinsic muscles of the tongue( hyoglossus, styloglossus, and genioglossus) except palatoglossus muscle. It arises as several rootlets from the anterior surface of the medulla, passes laterally across the posterior cranial fossa and exits through the hypoglossal canal. ♦The hypoglossal nucleus It is situated near the midline immediately beneath the floor of 4th ventricle. It receives corticonuclear fibers from both pyramidal tracts. However, the cells supplying the genioglossus muscle receive corticonuclear fibers from the opposite cerebral hemisphere only. In the upper part of its course, the hypoglossal nerve is joined by C1.This branch supplies thyrohyoid and geniohyoid. Fig.12.8: Distribution of hypoglossal nerve. 8  Prof. Dorreia Abd Alla Mohamed Zaghloul Lesion of the hypoglossal nerve: In a lower motor neuron lesion , the tongue will curve toward the damaged side, owing to weakness and atrophy of the genioglossus muscle of affected side..In upper motor neuron lesion the tongue will deviate away from the side of damage, due to action of the affected genioglossus muscle. THE CERVICAL PLEXUS The cervical plexus is a nerve plexus of the anterior rami of first four cervical spinal nerves which arise from C1 to C4 cervical segment in the neck. Cervical plexus is located in the neck deep to the sternocleidomastoid. Nerves formed from the cervical plexus innervate the back of the head, as well as some neck muscles. The branches of cervical plexus emerge from the posterior triangle. Fig.12.9: Cervical plexus Sensory Lesser occipital nerveC2 - skin of the neck and the scalp Branches Greater auricular nerve C2,3- skin over the parotid gland, the auricle, and Transverse cervical nerve C2,3 - skin covering anterior triangle of the neck Supraclavicular nerveC3,4 - the skin over the clavicle and shoulder as far inferiorly as rib II. Motor Muscular branches (to sternocleidomastoid, prevertebral and levator Branches scapulae), anterior and middle scalenes Ansa cervicalis, infrahyoid muscles (Strap muscles) Phrenic nerve C3-C5 (primarily C4)- diaphragm, mediastinal pleura, pericardium of the heart Ganglion Input origin of pre- Function ganglionic fibers Ciliary Oculomotor nerve Oculomotor nerve Innervation of sphincter pupillae muscle for pupillary constriction, and ciliary muscles for accommodation of the lens for near vision Pterygo- Greater petrosal nerve Facial nerve Innervation of lacrimal gland, and mucous palatine glands of nasal cavity, maxillary sinus, and palate Otic Lesser petrosal nerve Glossopharyngeal Innervation of parotid gland nerve Sub Chorda tympani nerve Facial nerve Innervation of submandibular and mandibular sublingual glands Table 12.1 showing Parasympathetic ganglia of the head 9 Dr. Merry Beniamen Kostandy Lecture (13): Cerebrum (I) (Anatomy) Source: Oxford handbook of medical sciences. Pages: 708-709. Source: First aid for the basic sciences (Organ Systems): Chapter 6. Pages: 426-436. Source: Kaplan neuroscience USMLE Lecture notes 2021; Pages: 341-358 ,317-321 Specific learning Objectives 1- Describe main gross anatomical features of nervous system including: cerebrum, cerebellum, basal ganglia. 2- Correlate main gross anatomical features of nervous system with the following clinical situations: cranial nerve injuries, brain stem and spinal cord lesions, stroke, hydrocephalus, cerebellar syndromes Contents: By the end of the lecture the student will be able to: 1. List the main cortical areas on the cerebral cortex. 2. Describe the components of the cerebrum, 3. Describe components and connections of basal ganglia 4. Interpret anatomical facts with its major clinical applications (vascular injuries of the cerebral cortex). NARS :(4.1). CORTICAL AREAS  The cerebral cortex is composed of specialized regions that are responsible for specific functions.  Thus, injury and lesions in different areas of the brain produce deficits appropriate to the function of that area. Brodmann labeled different areas of the brain by numbers (Fig.13-1). Major Areas of the different lobes of the cerebral hemisphere: ►►Frontal Lobe Primary motor cortex (area 4).  located anterior to the central sulcus in the precentral gyrus and the anterior part of the paracentral lobule.  Areas of the motor cortex correspond geographically to the body parts they control, as mapped out by the motor homunculus, where the body is represented upside down (Fig.13- 2).  It is connected to the anterior grey column cells of the spinal cord through the corticospinal tract (responsible for voluntary movement). Premotor cortex (area 6).  Located anterior to primary motor area. 1 Dr. Merry Beniamen Kostandy Supplementary motor area:  occupies the medial frontal gyrus in front of paracentral lobule  The frontal eye fields (area 8):  Located on posterior part of middle frontal gyrus. Figure 13-1: Brodmann areas of the brain. Areas of note include areas 3–1–2 = primary sensory cortex; area 4 = primary motor cortex; area 8 = frontal eye fields; area 44 = Broca's area; area 22 = Wernicke area; and area 17 = primary visual cortex  Prefrontal cortex:  Include almost ¼ of the entire cortex.  Present on lateral, inferior and medial surfaces of the frontal lobe.  Broca's area (area 44,45).  Located in the posterior part of inferior frontal gyrus in the left (dominant) hemisphere. o Blood Supply: Anterior cerebral and middle cerebral arteries (Fig. 13-3) ►►Parietal Lobe  Primary sensory cortex (areas 3,1,2).  Secondary (association) sensory area 2 Dr. Merry Beniamen Kostandy  The primary sensory cortex (areas 3,1,2) is just posterior to the central sulcus, occupies the postcentral gyrus and the posterior part of the paracentral lobule.  Like the motor cortex, a sensory homunculus represents the anatomic correlations (Fig.13-2).  The ascending spinothalamic tracts and dorsal column medial lemniscus pathway synapse in the thalamus and project to the primary sensory cortex.  The primary sensory cortex then sends projections to the secondary and association cortices. Blood Supply: Anterior cerebral and middle cerebral arteries (Fig. 13-3) ►►Occipital Lobe Primary visual cortex (area 17)  Includes cortex above and below posterior part of calcarine sulcus. Association visual cortex (areas 18,19)  Surrounds primary visual area. Blood Supply: posterior cerebral artery (Fig. 13-3) Figure13-2: Representation of the body on the primary motor and sensory cortices A- motor B- Sensory homonucli 3 Dr. Merry Beniamen Kostandy Figure 13-3 Blood supply of the cerebral cortex. ►►Temporal Lobe Primary auditory cortex (area 41,42)  Located within the superior temporal gyrus and transverse temporal gyrus (Heschl's gyrus).  Receives auditory sensation mainly from the opposite side and partly from the same side. Auditory association cortex: posterior to primary auditory area. Wernicke's area (area 22).  Located on the superior temporal gyrus and extends to the parietal lobe in the left dominant hemisphere.. DEEP BRAIN STRUCTURES BASAL GANGLIA These are masses of grey matter situated within each cerebral hemisphere. Structures (Fig.13-4,5): 1. Striatum (caudate + putamen), 4 Dr. Merry Beniamen Kostandy 2. Globus pallidus internus and externus. 3. The substantia nigra in midbrain (two parts: pars compacta and pars reticulata). 4. Subthalamic nucleus (in diencephalon). The caudate nucleus: A large C-shaped mass of grey matter that is closely related to the lateral ventricle. Parts: head, body and tail. Lentiform nucleus:  Wedge-shaped mass of grey matter.  A vertical plate of white matter divides the nucleus into a larger, darker lateral portion, the putamen, and an inner lighter portion, the globus pallidus.  Strands of grey matter connecting the caudate nucleus to the putamen of the lentiform nucleus forming the corpus striatum.  The globus pallidus is divided into globus pallidus internus and globus pallidus externus. Figure 13-4: Components of basal nuclei 5 Dr. Merry Beniamen Kostandy Figure 13-5: Coronal section in the cerebral hemispheres Connections of basal ganglia (13-6)  The striatum is the major input center.  Globus pallidus internus and substantia nigra pars reticulata are grouped together as the major output center for the pathways through the basal ganglia.  Connections of the striatum: 1- Afferent connections: a-Cerebral cortex (corticostriate fibers). b-Midline and intralaminar nuclei of thalamus. c-Substantia nigra pars compacta. d-Brain stem raphe nuclei. 2- Efferent connections: a- To globus pallidus externus. b- To globus pallidus internus and substantia nigra pars reticulata.  Connections of the globus pallidus: 1- Afferent connections a-Striatum to globus pallidus externus and globus pallidus internus with substantia nigra pars reticulata. b-Subthalamus to globus pallidus internus and substantia nigra pars reticulata 2- Efferent Connections a-From globus pallidus internus and substantia nigra pars reticulata to anterior ventral and lateral ventral thalamic nuclei (MAIN EFFERENT PATHWAY) 6 Dr. Merry Beniamen Kostandy b- From globus pallidus externus to subthalamus. c- To brain stem (superior colliculus-reticular formation-inferior olivary nucleus) Note. All basal ganglia connections are with ipsilateral cortex. Together with the cerebral cortex and the thalamus, basal ganglia components are interconnected to form 2 parallel but antagonistic circuits known as the direct and indirect pathways (summarized in Figure 13-6). Both pathways are driven by inputs from large areas of cerebral cortex, and both project back to the motor cortex after a relay in the VL and VA nuclei of the thalamus. Figure 13-6: Simplified diagram demonstrating anatomical connections within basal ganglia circuits.)+( Excitatory neurons utilize glutamate (-) inhibitory neurons utilize GABA. Dopaminergic neurons in the substantia nigra pars compacta in the midbrain project to the striatum. Dopamine excites the direct pathway through D1 receptors and inhibits the indirect pathway through D2 receptors. 7  Prof. Sanaa A M Elgayar Lecture (14): Myelination in the central and peripheral nervous systems, types of nerve fibers and nerve terminations (Histology) By the end of the lecture the student will be able to: A.6 Identify the mechanisms of myelination in peripheral and CNS. A.6 Compare between myelination in peripheral and CNS. A.6 Mention the characters of different types of sensory and motor nerve endings. NARS: (4.1, 4.2) Reference books: Integrated systems (p.52-55), The nervous system (pp. 22, 23, 34 &35) & Basic Histology (pp.174- 185). Organization Of The Nervous System The nervous tissue is organized anatomically into central (CNS) and peripheral nervous system (PNS). In the central nervous system (CNS) - The cell bodies of nerve cells (neurons) are aggregated in various forms, these forms include: 1. Nuclei: Are formed of definite clusters of cell bodies. 2. Columns: In which the cells are arranged in a linear manner. 3. Layers: In which the cells form laminar arrays. - The fibers in the CNS form groups or fascicles known as fiber tracts that travel within the central nervous system connecting groups of cells to other groups by what is called synapses. Peripheral Nervous System (PNS): The PNS comprises all nervous tissue outside the brain and spinal cord; It consists of: 166 Prof. Sanaa A M Elgayar 1- groups of neurones called ganglia classified into spinal and autonomic ganglia according to the type of nerve they are associated with. 2- Bundles of parallel nerve fibres that form the nerves and nerve roots. Nerve fibres, which originate from neurones within the CNS and pass out of the CNS in cranial and spinal nerves, are called efferent or motor fibers. Nerve fibres which originate from nerve cells outside the CNS but enter the CNS by way of the cranial or spinal nerves are called afferent or sensory nerve fibres.  Afferent, sensory fibres enter the spinal cord via the dorsal roots, while efferent, motor fibres leave the spinal cord via the ventral roots.  Dorsal and ventral roots merge to form the spinal nerves, which consequently contain both sensory and motor fibres.  As the spinal nerves travel into the periphery they split into branches and the exact composition of the nerve in terms of motor and sensory fibres is, of course, determined by the structures the nerve will innervate. 167 Prof. Sanaa A M Elgayar Histological structure of a peripheral nerve - One nerve fibre consists of an axon and its nerve sheath. - Each axon in the peripheral nervous system is surrounded by a sheath of Schwann cells. - An individual Schwann cell may surround the axon for several hundred micro- meters, and it may, in the case of unmyelinated nerve fibers, surround up to 30 separate axons. - The axons are housed within infoldings of the Schwann cell cytoplasm and cell membrane, the mesaxon. - In the case of myelinated nerve fibres, Schwann cells form a sheath around one axon and this axon with several double layers (up to hundreds) of cell membrane. - The myelin sheath formed by the Schwann cell insulates the axon, improves its ability to conduct and, thus, provides the basis for the fast saltatory transmission of impulses. - Each Schwann cell forms a myelin segment, in which the cell nucleus is located approximately in the middle of the segment. - The node off Ranvier is the place along the course of the axon where two myelin segments abut. 168 Prof. Sanaa A M Elgayar Peripheral nerve fibers contain a considerable amount of connective tissue. The entire nerve is surrounded by a thick layer of dense connective tissue, the epineurium. Nerve fibres are frequently grouped into distinct bundles, fascicles, within the nerve.The layer of connective tissue surrounding the individual bundles is called perineurium. The perineurium is formed by several layers of flattened cells, which maintain the appropriate microenvironment for the nerve fibres surrounded by them. The space between individual nerve fibres is filled by loose connective tissue, the endoneurium. Fibrocytes, macrophages and mast cells are present in the endoneurium. Nerves are richly supplied by intraneural blood vessels, which form numerous anastomoses. Arteries pass into the epineurium, form arteriolar networks beneath the perineurium and give off capillaries to the endoneurium. A)H&E B) EMA stain 169 Prof. Sanaa A M Elgayar Myelination in Peripheral Nervous System I-Myelinated PNF: As the plasmalemma of the Schwann cell encircles the fiber it forms a membranous sheath enclosing it called the myelin sheath. Myelin sheath is composed of successive layers of Schwann cell membrane wrapped spirally around the axon. It is therefore composed of lipid and protein layers. The outermost nucleated cytoplasmic layer of Schwann cells is called neurilemmal sheath. In H&E-stained sections, the lipid dissolve leaving very thin strands of proteins around the axis cylinder. The sheath is sudano-philic and osmeo-philic. Myelinated fibers become naked at intervals between successive Schwann cells. These intervals are called nodes of Ranvier. The impulse jumps from one node to the other node down the full length of an axon, speeding the arrival of the impulse at the nerve terminal. This is termed saltatory conduction. Myelinated fibers are naked at the initial segment, nods of Ranvier and the axon terminal. The thickness of the myelin sheath differs from one fiber to the other according to the speed of the impulse carried by the fiber. 1. Heavily myelinated fibers: (the somatic motor type). 2. Moderately myelinated fibers. 3. Lightly myelinated fibers. II – Non-myelinated PNF: Unmyelinated nerve fibers are also included inside Schwann cells. They lie in deep grooves inside the surface of Schwann cells (i.e. surrounded by neurilemmal sheath) As many as 12 axons may be seen within one Schwann cell. Unmyelinated nerve fibers may be as small as 1um in diameter as in autonomic fibers. 170 Prof. Sanaa A M Elgayar Myelinated nerve fiber in the PNS Unmyelinated nerve fibers in the PNS Myelination in central Nervous System 1. Myelinated fibers in CNS: Schwann cells are only present in the PNS. One type of neuralgia, the oligodendroglia, is responsible for myelin formation in the CNS. The cell sends processes which become flattened and wrap the axons resulting in various degrees of myelination. In this case the myelinated fiber is located far from 171 Prof. Sanaa A M Elgayar the body of the oligodendroglia and is therefore considered to be lacking a neurilemmal sheath. So they are myelinated fibers without neurilemmal sheath. 2. Non-myelinated fibers in CNS: Short dendrites in the central nervous system are not myelinated because they need to integrate information from many inputs and the lengths of the dendrites are small. The smaller axons of the CNS are nonmyelinated. Non myelinated fibers of the CNS are not particularly related to the oligodendrocytes. So, they are nonmyelinated ''without'' neurilemmal sheath. To sum up, according to the presence or absence of myelin sheaths nerve fibers in PNS may be classified into: 1.Myelinated with a neurilemmal sheath as somatic motor fibers. 2.Nonmyelinated with neurilemmal sheath as autonomic motor fibers. According to the presence or absence of myelin sheaths, nerve fibers in CNS may be classified into: 1. Myelinated without neurilemmal sheath as in white matter. 2. Nonmyelinated without neurilemmal sheath as in gray matter. 172 Prof. Sanaa A M Elgayar NERVE TERMINATIONS Nerve terminations may be classified into two groups: A) Terminations of efferent or motor fibers (affectors): The axons which terminate on structures to which they covey impulses. Efferent fibers may be somatic or autonomic; somatic fibers terminate on skeletal muscle fibers, whereas autonomic fibers terminate on smooth muscle fibers. B) Terminations of afferent or sensory fibers (Receptors): They are the fibers which end in tissues freely or in specially organized structures. They receive stimuli and convey them to the CNS. I. MOTOR TERMINATIONS (Somatic motor terminations) Motor End Plate  The cells of origin of these fibers are present either in the ventral grey matter of the spinal cord or in the cranial motor nuclei.  The fibers are myelinated and constitute a good part of peripheral nerves.  As the fiber penetrates the perimysium of the muscle, it bifurcates several times.  When nerve fibers reach individual muscle fiber, it forms what is known as motor end plate where it loses its myelin sheath whereas its endoneurium become continuous with the reticular fibers surrounding muscle fiber.  Schwann cells cover the end of the axon which indents the sarcolemma forming invagination called synaptic gutter or cleft.  The sarcolemma forms infoldings in the region of the gutters whereas the sarcoplasm contains a number of nuclei and numerous mitochondria.  The bulbs of the nerve fiber (similar to the presynaptic part of a synapse) contain numerous vesicles and mitochondria. 173 Prof. Sanaa A M Elgayar 174 Prof. Sanaa A M Elgayar II. SENSORY TERMINATIONS: They are present in various tissues as connective tissue, muscles, tendons and joints to receive a variety of sensations. They are classified as follows: I- Sensory nerve endings They are structurally divided into two types; non-encapsulated nerve endings and encapsulated ones. [Non-encapsulated nerve endings] 1. Free nerve endings They are derived from unmyelinated ends of nerve fibers. A single fiber branches over a wide area. Most of the free nerve endings are specialized for the reception of painful stimuli, warmth, cold and the mechanical displacement of the skin. The free nerve endings are found in the epithelia of the skin, cornea and alimentary tract and in C.T. 2. Merkel's endings It gives touch sensation. As a cutaneous nerve approaches the epidermis, it gives a number of unmyelinated branches that expand to form a flat disc closely applied to a modified epidermal cell (Merkel cell). These Merkel cells are slightly larger than neighboring cells and attached to them by desmosomes. The receptors give touch sensation. Free epidermal nerve endings Merkel,s ending 175 Prof. Sanaa A M Elgayar [Encapsulated nerve endings] They are surrounded by CT lamellae which form a capsule. I-Encapsulated Sensory Endings in C.T.: 1. Krause end bulb & Ruffini corpuscles The Krause end bulb is formed of a few CT lamellae surrounding a bulb called inner bulb. In the bulb terminates a naked end of an axon which may branch several times to give a spherical mass called glomerulus. End bulbs are present in lip, nasal cavity and sex organs. There is another type of receptor called Ruffini's corpuscle which is quite similar to Krause's end bulb but is more flattened. Krause's and Ruffini's corpuscles are mechanoreceptors sensitive to stretch. 2. Meissner's corpuscle Present mainly in finger tips lying within dermal papillae of thick skin found in the (upper dermis). The corpuscle is oval in shape and is formed of flattened Schwann cells surrounded by C.T. lamellae. The end of one or two myelinated nerve fibers branches to form spirals within the corpuscle. Meissner's corpuscles are sensitive to touch. 3. Pacinian corpuscles These are mechanoreceptors are located deep in the dermis and in sites subject to pressure (as periosteum, joint capsules). It is ovoid in shape, supplied by long myelinated nerve fiber which enters at one pole and loses its myelin sheath. The fiber runs axially through the corpuscle to become expanded terminally. Within the corpuscle, the nerve fiber is covered with numerous concentric layers of flattened Schwann cells. So, it is also termed a lamellated nerve ending. 176 Prof. Sanaa A M Elgayar Ruffini corpuscle Meissner corpuscle Pacinian corpuscle 177 Prof. Sanaa A M Elgayar II- Sensory Nerve Endings in Muscles Muscle spindle It provides sensory information necessary for the control of muscle activity. It is an elongated fusiform structure embedded in skeletal muscles and is surrounded by a C.T. capsule. It contains a number of striated muscle fibers (intrafusal) which differ from ordinary muscle fibers outside the spindle (extrafusal) in length, diameter and nuclear contents. Intrafusal muscle fibers are of two types: 1. Nuclear bag type: It is the thicker of the two types. Its middle part is devoid of striations, slightly enlarged and contains a large number of crowded nuclei. 2. Nuclear chain type: It is thinner than nuclear bag fibers; its middle part is also devoid of striations and contains nuclei which are arranged in one raw or a chain. The muscle spindle is innervated by two types of afferent (sensory) fibers (annulospiral & flower spray) and two types of efferent (motor) fibers. Muscle spindle 178 Lecture (15) Lecture (15): Basic pathology of CNS (Pathology) Specific learning Objectives 1- Recognize Basic cellular lesions of CNS. 2- Describe altered cellular structure of the brain in the following cases; Hydrocephalus, cerebral edema and increased Intracranial pressure Contents: By the end of the lecture the student will be able to: 1. Summarize basic cellular lesions of the CNS. 2. Mention definition, causes, types & effects of hydrocephalus. 3. Outline types & causes of cerebral edema. 4. Summarize causes, effects & complications of ↑ICP (brain herniation). NARS: (1.8, 4.6). Referencebooks: Tao Le et al. (2017). Pages: 488, 469.473, 503. Elsevier's integrated pathology (2007). Pages: 337.338, 340. Basic Escourolle& Poirier Manual of Basic Neuropathology (2004). Pages: 120. Kaplan Neuroscience, 2021 pp. 236.237 and 248.249 Basic pathology of CNS Various pathologic processes induce parenchymal injuries with consequent reaction of: Cellular elements Supporting structures (neurons, astrocytes, (meninges, connective tissue & oligodendrocytes & microglia). blood vessels Basic cellular lesions Tissue lesions Demonstrated Recognized microscopically macroscopically Clinical manifestation Radiologic changes due to functional loss. due to extensive gross changes. 1 Lecture (15) ▪ These lesions are not diagnostic in themselves. Basic Cellular Lesions Neuronal reaction to injury Neurons of different types & in different locations have distinct properties; as functional roles, distribution of connections, neurotransmitters used, metabolic requirements, and levels of electrical activity show selective vulnerability to various insults. 1- Acute neuronal necrosis (red neuron/anoxic neuron) Irreversible cell damage due to acuteinjury as;anoxia, ischemia, hypoglycemia & excessive amounts of excitotoxic neurotransmitters. ▪ Morphology: 1- Cytoplasmic microvacuolation due to swelling of mitochondria & endoplasmic reticulum. 2- Disappearance of Nissl bodies with eosinophilic condensation of cytoplasm “red neuron” (Fig.15-1) 3- Shrinkage of cell body. 4- Nuclear pyknosis & Fig.15-1 Karyorrhexis. 2- Nerve cell atrophy Irreversibleslow cell death (loss) due to slow injuriesas in; degenerative disorders selectively involving functionally related group of neurons. ▪ Morphology: 2 Lecture (15) 1- Retraction of the cell body. 2- Diffuse basophilia of the cytoplasm. 3- Pyknosis and hyperchromasia of the nucleus. 4- Absence of inflammatory reaction (Fig.15- Fig.15-2 2). In many of these diseases cell loss occurs by Apoptosis. 3- Subcellular alteration (on level of organelle or cytoskeleton) ▪ Intraneuronal inclusions: are important indicators of neuronal injury occur in degenerative, metabolic, and viral diseases as; - Aging: intracytoplasmic lipofuscin. - Genetic disorders of metabolism (storage diseases). - Viral infections: Herpes simplex virus (intranuclear), Negri bodies with rabies (intracytoplasmic), CMV with (intranuclear & intracytoplasmic). ▪ Aggregation of abnormal proteins: as in Neurodegenerative diseases e.g. Lewy bodies in Parkinson disease (Fig.15-3a) & Fig.15-3 Neurofibrillary tangles in Alzheimer disease (Fig.15- 3b). 4- Central Chromatolysis: ▪ Reparative reaction of cell body to axonal injury(retrograde degeneration) as: in lower motor neurons injury (anterior horn cells of spinalcord). ▪ Fate: depending on reversibility of axonal lesion: - Recovery of normal neural morphology (reversible) or, - Progressiontonerve cell degeneration. ▪ Morphology: 1- Swelling of the cell body and rounding. 3 Lecture (15) 2- Disappearance of Nissl bodies, begin centrally &extend outward. 3- Flattening & eccentric displacement of the nucleus to the periphery (Fig.15-4). Fig.15-4 Glial reaction to injury (A) Astrocytesreaction 1-Gliosis (Astrogliosis) - It is an astrocytic reaction to tissue damage. - Astrocyte is the principle cell responsible for repair& scar formation in Brain (gliosis). - It is the best microscopic indicator of pathologic abnormality. - Its morphologic changes include expansion of astrocytic cytoplasmic arborization: (Fig.15-5). Fig.15-5 Fig.15-6 4  Lecture (15) 1- Early: astrocytes undergo hypertrophy & hyperplasiagemistocytic astrocytes (hypertrophic & eccentrically placed nucleus + expanded homogeneouseosinophilic cytoplasm) (Fig.15-6). 2- In chronic states and slowly degenerative processes, astrocyte nuclei regain their resting size and shape. The cytoplasmic networks of cell processes are extensive (best seen with silver stains or immunostain [GFAP]) (Fig.15-7). Fig.15-7 2- Rosenthal fibers: -Thick elongated brightly eosinophilic protein aggregate in astrocyte processes (Fig.15-8). -Seen in gliosis (around multiple sclerosis plaques& in tumor as pilocytic astrocytoma). Fig.15-8 (B) Microglial Lesions 1-Macrophage proliferation and phagocytosis. -Microglia activated by tissue injury; they proliferate & become more prominent (with demyelinating processes, with traumatic or ischemic tissue destruction & hemorrhage). -In CNS, macrophages are known as compound granular corpuscles, foam cells, lipid phagocytes or gitter cells. -They are rounded cells 20-30µm with small, darkly staining, and sometimes eccentric nuclei and a clear, granular cytoplasm that contains lipids or hemosiderin pigment. Fig.15-9 5  Lecture (15) (Fig.15-9a) -In inflammatory conditions: they develop elongated nuclei (rod cell). 2- Microglial nodules(Fig.15-9b) Aggregates of elongated microglial cells typically found in: chronic encephalitis & around and phagocytosing injured neurons (neuronophagia). Axonal lesions Axonal Degeneration (Wallerian Degeneration). It is the response of the distal part of an axon to transection of the nerve. 1- Breakdown of the axon and its myelin sheath. 2- Proliferation of Schwann cells within the tube formed by the original schwannian basal lamina. 3- Sprouting of axons from proximal stump (1 to 3mm/ day). Axonal swellings or spheroids Localized, eosinophilic enlargements of the axon dueto transport system interruption with focal accumulation of the materials that conveyed along the axon due to axonal damage by extrinsic insult as trauma or ischemia (Fig.15-10). Fig.15-10 Axonal swelling due neurodegenerative disease called (dystrophic neuritis). General CNS Tissue Reactions to Injury 1- Hydrocephalus ⮚ Definition: Marked increase in the amount of CSF withdilatation of brain ventricles associated with increased intracranial pressure (ICP) and brain atrophy. ⮚ Mechanism and causes: 6 Lecture (15) 1) Over production: rare (choroid plexus papilloma). 2) Obstruction of the flow: common a- Congenital: as: - stenosis of aqueduct or foramina - Arnold-Chiari malformation. b- Acquired: - obstruct pathway by neoplasm, abscess or intracranial hemorrhage. 3) Defective absorption: as in - Post meningitic fibrosis (pneumococcal & TB).- Subarachnoid Hemorrhage. - Dural sinus thrombosis. - Deficiency of arachnoid villi. Fig.15-11 ⮚ Types: 1) Non-communicating: if obstruction up to IV ventriclei-e CSF can't reach subarachnoid space. 2) Communicating: the obstruction is beyond the foramina of IV ventricle. ⮚ Effects & Clinical Presentation 1- In infant and young child: - enlargement of the head, the fontanel remains open, mental deficiency. 2- In older child and adult: - dilated ventricles (radiologic), atrophy of brain and bone, increase ICP with its cardinal signs of: headache, vomiting and papilledema. Normal-pressure hydrocephalus: 7 Lecture (15) 1- Chronic form of communicating hydrocephalus with equilibration of CSF formation and absorption. 2- Hydrocephalus ex vacuo:Compensatory enlargement of ventricles secondary to brain atrophy (as in Alzheimer disease & stroke). 2- Cerebral edema ⮚ Definition: Accumulation of excess extravascular fluid. It is a common complication of many diseases because: there is a little room to expand and it has no lymphatic to carry excess fluid. It either initiates or aggravates increased ICP. The process may be localizedor generalized depending on the initiating disorder. Localized Generalized - Tumor. - Metabolic disturbance. - Abscess. (osmotic disequilibrium S.). - Infarction. - Generalized hypoxia. - Severe head injury. - Malignant hypertension (Arteriolar fibrinoid necrosis). ⮚ Types & Mechanisms: 1) Vasogenic edema: - Extracellular (protein rich)fluid accumulation in white matter due to: disturbance of blood brain barrier (BBB) (disturb vascular permeability): as damage of capillaries or new capillary formation - causes: - Space occupying lesion (SOL) ( tumor or abscess). 8 Lecture (15) - Infection. - lead encephalopathy. 2) Cytotoxic edema: - Intracellular (watery) fluidaccumulation in gray matter (in neurons, glia, endothelial cells, or myelin sheaths) due to: destruction of cell membrane or metabolicmechanism. - Causes: ischemia & water intoxication (plasma hypo-osmolality. N.B: (Both types 1&2 occur in infarction and meningitis). 3) Interstitial edema: - Fluid in periventricular white matter with non-communicating hydrocephalus. ⮚ Clinico-pathologic features: Gross: brain swollen, soft & pale volume of content ICP, flattening of gyri & narrowing of sulci and narrowing of ventricle at site of edema (Fig.15-12). ▪ If edema is diffuse, ventricles are compressed. Fig.15-12 ▪ If localized it is marked in imaging studies by increased densities. 3- Increased intracranial pressure Fixed and restricted volume of the skull is most important anatomical feature of the brain. ICP is a reciprocal relation between intracranial space volume and volume of tissues (brain, blood & CSF). Increase ICP is an increase in the mean CSF pressure above 15mm.Hg (200mm water). ⮚ Causes: 1- Intracranial Expanding lesions: as: -Hemorrhage (cerebral or meningeal). 9 Lecture (15) - Infarction. -Tumors (cerebral or meningeal). The severity of the effect depend on the size of the lesion and the rapidity of expansion. 2- Obstruction of the CSF flow (hydrocephalus). ⮚ Effect: 1) cardinal signs of headache, vomiting and papilledema. 2) Distortion: - flattened convolutions. - deviation of interventricular septum distorted ventricle. 3) Displacement(herniation): = is displacement of brain tissue from one compartment to another due to ICP - Subfalcine (cingulate) herniation - Transtentorial (uncinate) herniation - Tonsillar herniation (Fig.15-13). ⮚ Complications: a- Vascular compression: Fig.15-13 - Arteries ---- ischemia & infarction. - Veins ------ edema (papilledema). - Vessel stretching ---- Hemorrhage. b- Nerve compression. c- Vital centers compression. d- CSF flow obstruction. 10 Lecture (15) e- Skull bone erosion of clinoid & sphenoid process and thinning of inner table in children. 11 Lecture (16) Lecture (16): Infections of CNS (meningitis and encephalitis) (Pathology) Specific learning Objectives 1- Clarify CNS infection, meningitis, encephalitis and brain abscess. Contents: By the end of the lecture the student will be able to: 1. Define meningitis & encephalitis. 2. List routes of CNS infection. 3. Outline different types of meningitis. 4. Identify morphological changes of suppurative meningitis. 5. Explore complication of meningitis. 6. Compare between pyogenic & Aseptic meningitis. 7. Describe types, morphology & complications of brain abscess. NARS: (2.9). Referencebooks: Robbins Basic Pathology10th edition (2018). Pages: 862.865. Elsevier's integrated pathology (2007). Pages: 343.344. Basic Escourolle& Poirier Manual of Basic Neuropathology (2004), pp. 120. Infections of CNS (meningitis and encephalitis) Infection of CNS is uncommon compared with infection in general because of pia matter (act as a barrier) and blood brain barrier. Meningitis: inflammation of the leptomeninges & subarachnoid space (pachymeningitis = inflammation of dura). Encephalitis: inflammation of the brain substance. Meningioencephalitis. ❖ Routes of infection of nervous system 1- Hematogenousspread via arterial blood supply (most common), or retrograde venous spread through anastomoses between veins of face & the venous sinuses of the skull. 2- Direct implantation: Almost due to open or penetrating trauma (Fig.16-1). 1 Lecture (16) Rarely iatrogenic (lumbar puncture needle or in surgery). Compound fracture Fracture base----- infected air sinuses Fig.20-1 3- Local extension: with infections of skull or spine from air sinuses (mastoid or frontal), infected teeth, suppurative otitis media and cranial or spinal osteomyelitis (Fig.16-2). Fig.16-2 4- Peripheral nerves in particular, viruses such as rabies and herpes zoster. ❖ Aetiology of Intracranial infection Bacterial ViralMiscellaneous Acute chronic -Fungal 2  Lecture (16) cryptococcosis Supp. ˃ non-Supp. TB asperigellosis - Protozoal Diffuse Localized - Metazoal Intracranial Suppurative inflammation Fig.16-3 The epidural and subdural spaces can be infected by bacteria or fungus usually as a consequence of direct local spread from adjacent sinusitis or osteomyelitis. 1-Epidural abscesses: Spinal epidural abscess cause spinal cord compression 2-Subdural empyema: Lead to: - Mass effect if large - Thrombophlebitis in the bridging veins resulting in venous occlusion and infarction of the brain. Clinically: meningitis = fever, headache and neck stiffness, if untreated 3  Lecture (16) may develop focal neurologic signs, then lethargy, and coma. 3-Suppurative meningitis: Acute diffuse suppurative inflammation of leptomeninges & subarachnoid space which contain purulent exudate maximal in sulci & around brain base cisternae (Fig.16-4). Fig.16-4 Causes: E-coli & streptococci B in infants. Hemophilus influenza in children. *Neisseria meningetidis in adolescent & adult (epidemic). Streptococcal pneumoniae in old. Gross: Meninges: opaque + congested meningeal vessels. Subarachnoid space: contain purulent exudates (mainly on base). Brain: swollen, edematous with congested vessels (Fig.16-4&5). Microscopic Picture: Subarachnoid space contains fibrin threads, polymorphs, macrophages and dilated capillaries. CSF: Turbid with increased tension, markedly increased protein, decreased 4  Lecture (16) glucose, increased neutrophils and organisms could be demonstrated. Complications: 1- Increase ICP. 2- Spread thrombophlebitis hemorrhagic infarction. to brain ( if severe) focal cerebritis. 3- Fibrosis obstruction & hydrocephalus. compression of cranial nerves. Fig.16-5  4-Brain abscess: Localized suppurative inflammation of brain tissue. Causes: Staphylococci & Streptococci. Route: 1- Hematogenous: - From Suppurative lung diseases. - Systemic pyaemia acute bacterial endocarditis. congenital cyanotic heart disease. 2- Local extension (mastoiditis & sinusitis). Site: According to the cause. Types: 5  Lecture (20) - Multiple pyaemic abscesses. - Single: acute or chronic. Morphologic changes: - Central liquefactive necrosis surrounded by rim of granulation tissue &fibrosis. - Outside fibrous capsule is a zone of reactive gliosis (Fig.16-6&7). - Late leave a cyst with thick wall. Clinically: - progressive focal deficits + signs of increased ICP - abscess is often silent early * CSF WBC’s (neutrophilic) count and protein may be elevated. * N.B: if there is significant mass effect lumbar puncture can result in downward herniation. Complications: 1- increased ICP that may cause fatal brain herniation. 2-abscess rupture can lead to ventriculitis, meningitis, and venous sinus thrombosis. Fig.16-6: Parietal lobe cortical / subcortical abscesses with central necrosis and surrounding granulation tissue. 6  Lecture (20) Fig.16-7: Abscess with purulent necrosisand surrounding granulation tissue. Tuberculosis of Nervous system Route of infection: 1- Hematogenous : - Secondary to lung or kidney in adult. - Component of miliary TB in children. 2- Direct from Pott’s disease. Pathologic lesions: 1- Tuberculous meningitis. 2- Tuberculoma. 3- Miliary tuberculosis. 4- Cold abscess (squeezed & collected caseous material adjacent to site of bony lesion of Pott’s disease in epidural space).  Tuberculous meningitis Morphologic changes: Diffuse meningitis with - exudate: early clear then be thick, gelatinous & caseous contain lymphocytes & fibrin and - tubercles: around vessels (Fig.16-8). CSF: Increased pressure, mild to moderate increased protein, fibrin web on standing, mild decreased glucose, increased cells (lymphocytes mainly) & TB bacilli could be detected. Complications: Meningeal fibrosis & hydrocephalus. 7  Lecture (20) Epithelioid cells Fig.16-8. Tuberculoma: - It is a localized tuberculous cerebral granulomatous inflammation. - Rare lesion. - Associated with increased ICP and small infarctions due to end arteritis obliterance (EAO). Fig.16-9. Viral infection of nervous system - Nervous system is particularly susceptible to certain viruses as rabies virus and poliovirus. - Some viruses infect specific CNS cell types, while others involve particular regions. - Tissue damage through direct effect of virus on cell 8 Lecture (20) immunologic (cell mediated or humeral immune response). Route of infection: 1- Via blood: Virus multiply at primary site of entry (GIT, nasopharynx & skin) reach blood viraemia CNS. 2- Through peripheral nerves (from bite). Commonest types of viruses - Enterovirus. - (Herpes simplex virus (HSV), cytomegalovirus (CMV). - Human immunodeficiency virus (HIV) can directly infect neurons and result in HIV dementia. - Poliovirus & rabies (affect brain stem & spinal cord). Pathologic lesions: 1- viral meningitis (aseptic meningitis) - The commonest form of acute meningitis. - Usually mild, self-limiting& recovery is complete. - CSF: opalescent, increased pressure, mild increased protein, normal glucose, cells (lymphocytes). 2- Viral encephalitis: - Subclinical encephalitis occurs in many viral illnesses, but only a limited number produce clinically significant encephalitis. - Severe with residual damage. - Microscopic Picture: - Perivascular cuffing of mononuclear cell infiltrates, - Microglial nodules, - Neuronal damage &neuronophagia, - Cytoplasmic or nuclear inclusion bodies, 9  Lecture (20) Poliovirus: - An enterovirus that most often causes a subclinical or mild gastroenteritis; - In small fraction of cases, it secondarily invades CNS causing aseptic meningitis &(paralytic poliomyelitis). - Virus show tropism to motor neurons in spinal cord (anterior horn cells often localized & unilateral). - Loss of motor neurons results in flaccid paralysis with muscle wasting. Rabies Virus - Rabies is a fatal encephalitic infection transmitted to humans from rabid animals by bite. - Enters the CNS by ascending along the peripheral nerves from wound,. - Affect gray matter and Negri bodies (viral inclusion) found in neurons. - CNS excitability; painful touch with violent motor responses progressing to convulsions, hydrophobia, Periods of mania and stupor progress to coma and death. Summary: -Types of meningitis: Infectious meningitis: - Acute pyogenic (usually bacterial). - Aseptic (usually viral) acute viral meningitis. - Chronic (usually tuberculous or fungal). -Differential diagnosis of meningitis by CSF analysis 10  Lecture (25): Physiology of pain I (Physiology) By Professor Minerva K Fahmy Specific learning Objectives: 1- The basic physiological concepts of pain and pain analgesic system. Contents: By the end of the lecture the student will be able to: 1. Define pain. 2. Identify nociceptors (location, categorization and adequate stimulus). 3.Explain mechanisms of pain sensory transduction. 4.Define hyperalgesia and List the differences between primary and secondary hyperalgesia. 5.Compare fast and slow pain. 6.Know classification of pain. 7.Differentiate allodynia from hyperalgesia. NARS: (1.16). References books: Integrated Neuro BookBasic sciences and clinical conditionsAdina MichaelTitus and Peter Shortland pp. 65; 80-93. Definition of pain: Pain is a specific sensation separate from other sensations. It is a protective mechanism, because if any harmful agent gets in contact 1 with the body, the person feels pain andalso reacts reflexly to move away the body from the painful harmful agent. Also, many patients seek medical advice, only when they feel pain. Its perception is associated with unpleasant effect. Nociceptors:  The receptors for pain, are called nociceptors to indicate that they respond to noxious stimuli, are on the free nerve endings of small myelinated (A) and unmyelinated (C) fibers.  Nociceptors are specific for painful stimuli, responding to damaging or potentially damaging mechanical, chemical and thermal stimuli. Cutaneous receptors that respond to nonpainful levels of these stimuli do not elicit pain sensations no matter how intense the stimulus.  Although the adequate stimulus for nociceptors is not known, it is assumed that a chemical such as substance P histamine or bradykinin is released from damaged cells by the pain stimulus and that the chemical substance activates the nociceptors.  Nociceptive reflexes are prepotent reflexes i.e. they would inhibit other reflexes that may occur simultaneously. Fast and Slow Pain: Two types of pain sensation result from the application of a strong, noxious stimulus to the skin; fast and slow pain(Table 12.1). (1) Fast (Initial) Pain: 2 a- Is well-localized, pinprick sensation that result from activating the nociceptors on the A fibers. b- Action potentials that are propagated by the fast pain fibers travel faster and, thus, reach the brain before those conducted by the slow pain fibers. c- The sensory fibers for fast pain have small receptive fields, travel to the cortex through the neo spinothalamic pathway. (2) Slow (Delayed) Pain: a- Is a poorly localized, dull, burning sensation that results from activating the nociceptors on the C fibers. b- Has a more diffuse pathway, travels to the brain through the spinoreticulothalamic system (paleospinothalamic pathway). c- Collaterals of this system pass through the reticular formation to activate fiber tracts that produce the emotional perceptions accompanying pain sensations. These pathways account for the intense unpleasantness associated with slow pain. Dissociation of the fast and slow components of pain may occur under various experimental and pathological conditions; asphyxia of a nerve trunk blocks the fast component first, while cocaine blocks the slow component before the fast one. In Tabes dorsalis, the thicker fibers are damaged before the thinner and only the slow component of pain may be perceived by the patient. 3  The presence of rapidly conducting pain fibers is very important. They also carry afferent impulses of protective withdrawal reflex which takes place before great damage affects tissues. Cutaneous Pain: Allodynia. A condition in which normally innocuous stimuli such as touch cause pain, i.e., pain is caused by a stimulus that does not normally elicit pain, e.g. bad sunburn can cause temporary allodynia and touching sunburned skin can be very painful. Hyperalgesia. An extreme exaggerated reaction to a stimulus which is normally painful, i.e. stimuli in the injured area that would normally cause only minor pain produce an exaggerated response. Table 12.1 Summary classification of some major characteristics of different types of pain Types of Hyperalgesia: Primary hyperalgesia: 1- It is localized to the injured area (red area). 2- The threshold of pain receptors is lowered. 3- It does not extend beyond the area of redness. 4 Mechanism of primary hyperalgesia (Local axon reflex): Axons of pain afferents branch near the skin. One branch ends around an arteriolewhile the other end as free nerve ending around skin cells. Histamine is released from skin cells when they are injured. It lowers the threshold of pain receptors. So, receptor become very sensitive to sensory stimuli. So that innocuous stimuli become painful. Redness is also due to local axon reflex. Secondary hyperalgesia: 1- It occurs in the healthy skin around the injured area. 2- Pain threshold is not lowered but even increased. Mechanism of secondary hyperalgesia (Convergence-Facilitation theory) (Figure 12.1): Several afferent impulses from the area of primary hyperalgesia and from healthy skin around it (area of secondary hyperalgesia) converge on a fewer number of neurons of lateral spinothalamic tract. So, impulses from injured area facilitate those from healthy skin around it. This convergence and facilitation occur also at the thalamus and sensory cortex. 5 Figure 12.1: Diagram showing convergence facilitation mechanism. S: Nocuous stimulus; T: Afferent neuron from traumatized area; P.H: Area of primary hyperalgesia; S.H: Area of secondary hyperalgesia and its afferent neuron; Sp.Th.: Spinothalamic tract. Itching: Itching is an unpleasant sensation that follows skin injury. It is also a manifestation of various skin diseases, e.g. eczema. It is one of the cutaneous manifestations of allergy. This sensation is transmitted by small type C, unmyelinated fibers similar to those that transmit the aching slow type of pain. The purpose of the itch sensation is to call attention to mild surface stimuli such as flea moving on the skin or fly to bite, and the movement excite the scratch reflex. Rubbing the skin results in a temporary relief of itching, which indicates that the arrival of touch impulses to the nerve centers inhibit the effect of the discharge in the slow pain fibers. Also scratching relieves the itching sensation through inhibition by the fast pain 6 impulses. Similar inhibition is also produced by the fast pain impulse since scratching also relieves the itching sensation. Deep Pain: Deep pain arises from structures deep to skin like muscles, joints, tendons, ligaments and periosteum. Characters of Deep Pain: 1- Deep pain is continuous, dull, aching and not well localized. 2- Deep pain is transmitted by somatic sensorimotor nerves. 3- Deep pain may be caused by trauma, muscle ischemia. 4- It may show the phenomenon of false localization or referred pain. Effects Associated with Deep Pain: 1- Somatic reflexes: Muscle rigidity which is reflex contraction of the somatic muscles in response to deep or visceral pain. For example, meningitis produces neck stiffness. 2- Cutaneous hyperalgesia. 3- Autonomic reflexes: Mostly parasympathetic as bradycardia, hypotension, vomiting and salivation. Ischemic Pain: This is pain evoked when muscles contract without an adequate blood supply e.g. The pain of angina pectoris and intermittent claudication from the legs. Ischemic pain results from accumulation of a chemical substance (P) - a product of the metabolic activity of muscle. When the 7  substance reaches a certain concentration, it stimulates the pain endings. The pain factor is a normal product of muscular metabolism, with adequate circulation. It is removed from the muscles and its concentration is prevented from increasing to the threshold value required to stimulate the pain endings. Visceral Pain: Sensation of pain from internal viscera is rare due to the rarity of pain free nerve endings in viscera. For this reason, visceral pain is poorly localized. Causes of Visceral Pain: 1. Ischemia: It is caused by formation of acidic metabolic end products or tissue degenerative products such as bradykinin or proteolytic enzymes that stimulate the pain nerve endings. It results from arterial embolism or occlusion of blood supply of the viscera. 2. Chemical stimuli: Damaging substances leak from the gastrointestinal tract into the peritoneal cavity. An example for this the leakage of acidic gastric juice through a ruptured gastric or duodenal ulcer. This juice causes widespread digestion of the visceral peritoneum, thus stimulating broad area of pain fibers causing severe pain. 8 3. Spasm of a hollow viscus: This pain occurs in the form of cramps (colic). This type of pain occurs frequently in gastroenteritis, constipation, menstruation, gallbladder disease or ureter obstruction. The pain is caused by mechanical stimulation of the pain nerve endings or the spasm may cause decrease in the blood flow to the muscle in addition to the muscle's increased metabolic needs for nutrients. 4. Overdistension of a hollow viscus: Marked overfilling of a hollow viscus results pain because of overdistension of the tissues themselves. Also, overdistension can collapse the blood vessels of the viscus which lead to ischemic pain. Effects of Visceral Pain: Like deep pain, visceral pain is subject to false localization (referred pain). It results in: 1. Hyperalgesia. 2. Somatic reflexes as rigidity in muscles. 3. Autonomic reflexes (nausea, vomiting, increased heart rate and blood pressure). 4. Can sometimes be relieved by applying an irritant to the skin 9  Lecture (26): Physiology of pain II(Physiology) By Professor Minerva K Fahmy Specific learning Objectives 1.The basic physiological concepts of pain and pain analgesic system Contents: By the end of the lecture the student will be able to: 1.Distinguish mechanism of referred pain. 2.Explain mechanisms of peripheral and central pain inhibition. 3.Explain the action of opioid peptides and the receptors of opioid peptides. NARS: (1.16). References books: Integrated Neuro BookBasic sciences and clinical conditionsAdina MichaelTitus and Peter Shortland pp. 65; 80-93. Referred Pain: The person feels pain in a part away from the tissues causing pain. The pain usually is initiated in one of the visceral organs and referred to an area of the body not exactly coincident with the location of the viscus producing pain. Examples: 1. Cardiac pain: is referred to inner side of left arm. 2. Inflammation of the gall bladder: is referred to the tip of the right shoulder. 1 3. Ureteric spasm e.g. in renal colic is referred to the testis and scrotum. 4. Inflammation of appendix is referred to umbilicus. Mechanism of Referred Pain: 1- Branching of single afferent fibers of the dorsal root (Figure 13.1) One of the axon branches supplies the pain endings of the skin while another branch supplies the pain endings in a viscus. A third branch of the same axon may supply a deep muscle. In this manner, pain impulses from the skin, the viscus or the muscle will be conducted to the spinal cord by the same afferent neuron and will activate the same cortical neuron. The cortical neurons will project the sensation to the dominant area from which the impulses used to be received (namely from the skin), whatever may be the source of the impulses.Visceral pain is referred to the dermatome supplied by the same dorsal root. 2- The convergence - projection theory: Separate pain afferents from the skin and from the internal viscera converge into the same neuron of the spinothalamic tract. Further convergence may also occur at the thalamic and cortical levels. On reaching the brain, the visceral pain impulses are projected to the skin because the same tract fibers used to be stimulated by cutaneous afferents. Pain Suppression ("Analgesia") System in the Brain and Spinal Cord 2  The analgesia system consists of 3 major components: (Figure13.2) 1- The periaqueductal gray and periventricular areas of the mesencephalon and upper pons surrounding the aqueduct of Sylvius and adjacent to portions of the third and fourth ventricles. Neurons from these areas send signals to raphe magnus. 2- The raphe magnus nucleus located in the lower pons and upper medulla and the reticular nucleus paragigantocellularis located laterally in the medulla. From these nuclei, the signals are transmitted down the dorsolateral columns in the spinal cord to pain inhibitory complex. 3- Pain inhibitory complex (P.I.C.): located in the dorsal horns of the spinal cord. At this point, the analgesia signals can block the pain before it is relayed to the brain. Electrical stimulation of the periaqueductal gray area or of raphe magnus nucleus can almost completely suppress many strong pain signals which enter by the way of the dorsal spinal roots. Also, stimulation of periventricular nuclei in the hypothalamus lying adjacent to the third ventricle and the medial forebrain bundle can suppress pain. 3 Figure 13.1 Diagram showing theories of referred pain. Left: Branching of dorsal root; Right:Convergence facilitation theory; D.R.G. = Dorsal root ganglion. Sp.Th.T. = Spinothalamic tract. 4  Figure 13.2Analgesia system of the brain and spinal cord, showing inhibition of incoming pain signals at the cord level and the presence of enkephalin-secreting neurons that suppress pain signals in both the cord and the brain stem. Transmitter Substances Involved in Analgesic System: Many of the nerve fibers derived from periventricular nuclei and periaqueductal gray area secrete enkephalin at their endings. The endings of many of the fibers in the raphe magnus nucleus release enkephalin. The fibers originating in this nucleus but terminate in the dorsal horns of the spinal cord secrete serotonin at their endings. The serotonin in turn causes local cord neurons to secrete enkephalin. Enkephalin is believed to cause presynaptic inhibition and postsynaptic inhibition of both incoming type C and type A pain fibers where they synapse in the dorsal horns. Action of Opioid peptides: Opioids are chemical substances that can bind to the opioid receptors of the central nervus system providing pain relief. There are at least 3 sites at which opioids act to produce analgesia: 1- Peripherally, at the site of injury leading to inflammation causes the production of opioid peptides by immune cells, and these act on the receptors in the different nerve fibers to reduce the pain that would otherwise be felt. 5  2- In the dorsal horn, where nociceptive fibers synapse on dorsal root ganglion cells. The opioid receptors in the dorsal horn region could act presynaptically to decrease release of substance P. 3- Injection of morphine into the Periaquiductal gray matter of the midbrain relieve pain by activating descending pathways that produce inhibition of primary afferent transmission in the dorsal horn. There is evidence that this activation occurs through projections from the Periaquiductal greywater to the nearby raphe magnus nucleus and that descending serotonergic fibers from this nucleus intern causes local cord neurons to secret encephalin. As mentioned before, encephalin is believed to cause presynaptic inhibition and postsynaptic inhibition of both incoming type C and type A δ pain fibers where they synapse in the dorsal horns. The Brain's Opiate System (The Endorphins and Enkephalins): - Morphine-like agents, mainly the opiates act at many points in the analgesia system, including the dorsal horns of the spinal cord. - Morphine receptors of the analgesia system act as receptors for some morphine, like neurotransmitter which is naturally secreted in the brain. - About a dozen of opiate-like substances have now been found in different points of the nervous system. These are all the breakdown products of 3 large protein molecules. These are: Pro-opiomelanocortin, Pro-encephalin and Pro-dynorphin. 6 The most important opiate like-substances are: β-endorphin, met-enkephalin, leu-enkephalin and dynorphin. The two enkephalins are found in brain stem and spinal cord in the portions of analgesia system described before, β-endorphin is present in both the hypothalamus and the pituitary gland. Dynorphin is found mainly in the same area as the enkephalins, but in much lower quantities. Receptors of opioid peptides: The brain and gastrointestinal tract contain receptors that bind morphine. There are 3 types of receptors: µ, K, δ. They differ in physiologic effects, distribution in the brain and elsewhere and in the affinity for vrious opioid peptides. Mechanism of action of the receptors: 1- Activation of µ receptors increase K⁺ conductance leading to hyperpolarization of central neurons and primary afference. 2- Activation of K receptors and δ receptors closes Ca⁺⁺ channels. The affinity of individual legends for the 3 types of the receptors differs. Endorphins bind only to µ receptors, the main receptors that mediate analgesia. Other opioid peptides bind to multiple opioid receptors. The following table shows the physiologic effects produced by stimulation of opiate receptors: 7  Receptor Effect µ Analgesia Site of action of morphine Respiratory depression Constipation Euphoria Sedation Increased secretion of growth hormone and prolactin Miosis K Analgesia Diuresis Sedation Miosis Dysphoria δ Analgesia Stress Analgesia: Pain transmission and perception are subject to inhibition or modification during stress (stress analgesia). For example, soldiers wounded in the battle may feel no pain until the end of the battle. 8 It is believed that the cortex plays an important role in interpreting the quality of pain. Descending signals from the brain activate enkephalinergic interneurons in the substantia gelatinosa of the dorsal horn, which act presynaptically to inhibit transmission of impulses from the dorsal root pain fibers to spinothalamic neurons. Pain Transmission Transmission of pain to the brain is through the lateral spinothalamic tract. - First order neurons (branch of the dorsal root ganglion) after entering the spinal cord ascend for one or a few segments at the tip of the posterior horn forming the Lissauer's tract and then ascend around small cells capping the posterior horn of grey matter called the substantia gelatinosa of Rolandi. - The second order neurons consist of the cells of the substantia gelatinosa and their axons. The axons cross to the opposite side, in the anterior commissure near the central canal. They ascend in the lateral column of the spinal cord and then in the brain stem, to terminate in the posteroventral nucleus of the thalamus. - The third order neurons start from the thalamus and terminate in the post-central sensory area of the cerebral cortex. 9 Prof. Moustafa Mahmoud Hamdy Lecture (19): Antidepressants (Pharmacology) By the end of the lecture the student will be able to: 1- Identify Principles of drug action and pharmacokinetics of drugs used in different CNS diseases e.g., epilepsy, Parkinsonism and depression, etc. 2- Recognize the side effects and interactions of drug used in depression, psychosis, epilepsy and neurodegenerative diseases 3- Choose categories of Individual drugs in each of the following neurological conditions: depression, psychosis, epilepsy and neurodegenerative diseases. Contents: By the end of the lecture the student will be able to: 1. Explain classification of antidepressants. 2. Understand the clinical uses and adverse effects of antidepressants. 3. Explain the pharmacological actions and the mechanism of action of antidepressants. NARS: (1.16, 2.3, 4.7) Ref. books: Kaplan Neuroscience, 2021 pp. 119.121. Kaplan Medical USMLE Step 1 Lecture Notes 2021 Pages: 135-138. Lippincott Illustrated Reviews: Pharmacology, Sixth Edition. Pages: 135-143. Antidepressants Depressed mood may be: Reactive depression: (N.B. reaction to some stressors or adverse life situations like loss of a person by death, divorce, financial crisis or chronic major illness. The symptoms range from mild sadness, anxiety, irritability, worry, and impairment in social and occupational functioning). Endogenous depression (Major depressive disorder, MDD): It may have genetic factors (neurotransmitter dysfunction), physiologic or metabolic disturbances. The patient frequently suffers from lack of interest, withdrawal from activities & feeling of guilt, inability to concentrate, feeling of worthlessness, somatic complaints (e.g. headache, disturbed sleep) thoughts of death and suicidal tendency. (N.B. Episodes may be recurrent (unipolar depression) or alternative with mania (bipolar; manic depressive psychosis). 1 Prof. Moustafa Mahmoud Hamdy Pathophysiology of Major Depression 1- Neurotrophic Hypothesis  (N.B. There is substantial evidence that nerve growth factors such as) brain- derived neurotrophic factor (BDNF) are critical in the regulation of neurons.  Depression is ass