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Ovid: Oxford Handbook of Medical Sciences

Editors: Wilkins, Robert; Cross, Simon; Megson, Ian; Meredith, David Title: Oxford Handbook of Medical Sciences, 1st Edition Copyright ©2006 Oxford University Press, 2006, except ‘Clinical aspects’ section of Chapter 2 (Copyright by Keith Frayn) > Table of Contents > Chapter 11 – Head and neck Chapter 11 Head and neck Organization The skull and cervical vertebrae The bones of the skull form the cranium and facial skeleton (Figs. 11.1,11.2,11.3,11.4,11.5,11.6,11.7 and 11.8). The cranium contains the brain and immediate relations and is divided into:

  • The upper vault—comprising four flat bones:
    • The frontal bone anteriorly
    • The occipital bone posteriorly
    • Two lateral parietal bones
  • The lower base, characterized by stepped fossae:
    • Anterior (containing the frontal lobes of the brain) formed from:
      • Orbital plates of frontal bone
      • Cribriform plate of the ethmoid bone
      • Lesser wing of the sphenoid bone
    • Middle (containing the temporal lobes of the brain) formed from:
      • Greater wing and body of the sphenoid bone
      • (Vertical) squamous and (horizontal) petrous parts of temporal bone
    • Posterior (containing cerebellum, pons. medulla oblongata)formed from:
      • Petrous part of temporal bone
      • Squamous part of occipital bone
      • Body of the sphenoid bone.

There are a number of important features in the base of the skull (Figs. 11.3,11.4 and 11.6):

  • Anterior fossa
    • In the cribriform plate of the ethmoid bones
      • Foramina convey the olfactory nervecrania l nerve I
        Fig. 11.1 Posterior aspect of skull.
        Fig. 11.2 Skeletal components of skull and anterior part of the neck. Cervical vertebrae (not shown) are formed from cervical sclerotomes
        Fig. 11.3 Cranial fossae.
        Fig. 11.4 Basal aspect of skull. The hypoglossal canal is covered by the occipital condyles.
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  • Middle fossa
    • In the greater wing of the sphenoid bone
      • The foramen ovale conveys the mandibular division of trigeminal nerveVII and the lesser petrosal nerve
      • The foramen rotundum conveys the maxillary division of trigeminal nerveVIII
      • The foramen spinosum conveys middle meningeal artery and vein
    • At the medial edge of the petrous part of the temporal bone
      • The upper part of the foramen lacerum conveys the internal carotid artery (from the carotid canal)
    • Between the body and lesser wing of the sphenoid bone
      • The optic canal conveys the optic nerveII and ophthalmic artery
    • Between the greater and lesser wings of the sphenoid
      • The superior orbital fissure conveys the occulomotor nerveIII, trochlear nerveIV, ophthalmic branch of trigeminal nerveVI, abducent nerveVI
    • In the body of the sphenoid
      • The sella turnica is a depression in which sits the pituitary gland
      • The junction of the frontal, parietal, and temporal bones—the pterion—is the thinnest and weakest point of the lateral skull (Fig. 11.5)
  • Posterior fossa
    • In the occipital bone
      • The foramen magnum conveys the medulla oblongata, spinal part of accessory nerveXI, upper cervical nerves, vertebral arteries
      • Anterior to the foramen magnum the brainstem lies on the clivus (fused basiocciput and basispheoid)
      • The hypoglossal canal conveys the hypoglossal nerveXII
    • In the petrous temporal bone
      • The internal acoustic meatus conveys facial nerveVII, vestibulocochlear nervesVIII, labyrinthine artery
    • Between the petrous temporal bone and the occipital bone
      • The jugular foramen conveys the glossopharyngeal nerveIX, vagus nerveX, accessory nerveXI, sigmoid sinus.

The pyramidal pterygopalatine fossa is defined by the sphenoid, palatine, and maxilla bones: it contains the maxillary division of the trigeminal nerve, maxillary artery, and accompanying veins and lymphatics. The bones which comprise the facial skeleton (Fig. 11.7) are suspended below the anterior cranium and comprise:

  • Two nasal bones, joined to form the ridge of the nose
  • Two maxillary bones which form the floor of orbit, lateral wall of the nose, floor of the nasal cavity, and carry upper teeth
  • Two lacrimal bones which form medial wall of orbit
  • One ethmoid bone which forms the roof of the nose
    • The cribriform plate of the ethmoid, along with the vomer and septal cartilage, form the nasal septum
  • Two zygomatic bones which form lateral wall of the orbit, cheek bone
  • Two palatine bones with:
    • A perpendicular plate which contributes to lateral wall of orbit
    • A horizontal plate which, together with the palatine processes of the maxillary bones, forms the hard palate.
Fig. 11.5 Lateral aspect of skull, pterion circled.
Fig. 11.6 Interior of skull. The foramen rotundum is hidden by the anterior clinoid process.

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There are four paired paranasal air sinuses, contained within the frontal, maxillary, ethmoid, and sphenoid bones. The mandible carries the lower teeth. It articulates with the cranium at the temporomandibular joint which is:

  • Between the head of the mandible and the mandibular fossa of the temporal bone
  • A synovial joint containing a fibrocartilaginous disc
  • Encapsulated, with reinforcement by temporomandibular, sphenomandibular, stylomandibular ligaments.

Seven cervical vertebrae form the skeleton of the neck. C1 (the atlas), C2 (the axis), and C7 are atypical. The long spine of C7 is the vertebra prominens—the superior-most process which can be palpated. The lateral masses of the C1 vertebra articulates with condyles on the occipital bone at the alanto-occipital joint, which is a loosely encapsulated synovial joint which permits flexion and extension (nodding movements). Lateral masses of the atlas articulate with superior facets of the axis at alanto-axial joints to permit rotation. In addition, the odontoid process or dens makes a midline articulation with an anterior facet. The transverse part of the cruciate ligament of the atlas holds the dens in place, prevents the dens impinging on the spinal cord. Alar ligaments from the dens to the margin of formane magnum prevent excessive rotation. Longitudinal ligaments attach to the anterior and posterior aspects of the vertebral bodies. Joints between the C2–T1 vertebrae possess anterior and posterior longitudinal ligaments. Supraspinous and infraspinous ligaments are replaced by the nuchal ligament between occipital bone and C7; these joints permit flexion and extension.

Fig. 11.7 Bones of orbit.
Fig. 11.8 Temporomandibular joint and its ligaments: (a) lateral aspect; (b) medial aspect.
Fig. 11.9 Atlas (C1), axis (C2) and C7 vertebrae.
Fig. 11.10 Ligaments of occipito-atlanto-axial region: midline section.

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The meninges (Figs. 11.11,11.12 and 11.13) Three connective tissue layers surround the brain and spinal cord. The inelastic dura mater comprises:

  • Outer endosteal layer (the periosteum) which lines the bones of the cranium and at openings of the skull and is continuous with that on outer surface
  • Inner meningeal layer which is continuous with that of the spinal cord.

Meningitis is inflammation of the meninges caused by bacteria, viruses or fungi (OHCM6 p.368). At some points, the meningeal layer doubles-back on itself to form dural folds. These provide four septa:

  • The midline falx cerebri, between the cerebral hemispheres, which meets
  • The horizontal tentorium cerebelli, the roof of the posterior fossa, and separates the cerebrum from the cerebellum
  • The falx cerebelli which descends from the tentorium and separates the cerebellar hemispheres
  • The diaphragm sellae which provides the roof of the turnica sella.

The middle layer—the arachnoid mater—follows the folds of the meningeal layer of dura mater, to which it is loosely attached. Between the two is the subdural space; the innermost layer—the pia mater—closely envelopes the brain and spinal cord. It is separated from the arachnoid mater by the subarachnoid space, filled with cerebrospinal fluid (CSF) which cushions the brain (Fig. 11.12). Bleeding can occur into the potential spaces created by the dura folds. Extradural haemorrhage can occur following head trauma, and results from laceration of middle meningeal artery and vein (OHCM6 p.366); subdural bleeds can occur insidiously following minor trauma and result from damage to bridging veins between cortex and venous sinuses (OHCM6 p.366); subarachnoid haemorrhages are spontaneous, most commonly due to rupture of an aneurism (OHCM6 p.362). CSF is secreted by the choroid plexus (a vascularized epithelial structure) into each of the ventricles of the brain. CSF escapes from the fourth ventricle of the brain into the subarachnoid space. CSF exchanges freely with the extracellular fluid surrounding neurones across the pia mater covering the surface of the brain and across the epithelial lining (ependyma) of the ventricles. Failure for this to happen is a cause of hydrocephalus (OHCM6 p.351, 374, 382). In the choroid plexus, the epithelial cell barrier dictates the composition of CSF and insulates it from the blood. Elsewhere, the capillary endothelium prevents free diffusion from the blood into the brain extracellular fluid. In these ways, the blood—brain barrier is established.

Fig. 11.11 Dural venous sinuses.
Fig. 11.12 Circulation of cerebrospinal fluid.
Fig. 11.13 Coronal section through cranium to show scalp, meninges, and arachnoid granulations.

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Blood and lymphatic vessels of the head and neck (Figs. 11.14, 11.15) (Colour Plates 10,11,12 and 13) Arterial supply Blood is supplied to the brain by:

  • The vertebral arteries (from subclavian artery)
    • They unite midline on the clivus as the basilar artery and, together, these supply the brainstem and cerebellum
    • The basilar artery divides into left and right posterior cerebral arteries; these provide posterior communicating arteries which anastomose with the internal carotid artery
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  • The internal carotid artery (from the common carotid artery; Figs. 11.16, 11.17)
    • Passes into the middle fossa in the carotid canal, through the foramen lacerum, then in the medial wall of the cavernous sinus
    • Gives rise to the opthalmic artery, the central artery of the retina, and ciliary arteries
    • Terminates as anterior and middle cerebral arteries for medial and lateral cerebral hemisphere, respectively
    • The anterior communicating artery unites the anterior cerebral arteries, completing the anastomosis between carotid and vertebral systems (the circle of Willis which equalizes blood pressure)
Fig. 11.14 (a) Arteries, (b) veins of the face.
Fig. 11.15 Verterbral artery and its main branches.
Fig. 11.16 Common and internal carotid arteries and their mail branches.
Fig. 11.17 Intracranial branches of vertebral artery; circle of Willis.

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The second division of the common carotid artery is the external carotid artery (Fig. 11.18). This artery has many branches which supply the structures of the head and neck other than the brain: superior thyroid; ascending pharyngeal; superficial temporal; lingual; facial; occiptal; posterior auricular; superficial temporal. It has two terminal branches which arise within the parotid gland:

  • The (larger) maxillary artery, giving rise to three groups of branches which supply the temporal fossa, infratemporal fossa, cranial dura, nasal cavity, oral cavity, and pharynx
  • The superficial temporal artery.

Between the two layers of dura mater, intracranial venous sinuses lie in grooves on the overlying bone. These drain tributary veins from the brain, eye, and skull interior, diploic veins from the marrow of the cranial bones, and cerebrospinal fluid (CSF) from the subarachnoid space. The superior saggital sinus runs in the attached margin of the falx cerebri, with lacunae along its length containing arachnoid granulations to reabsorb CSF. The sinus drains into:

  • The transverse sinus which runs along the attached margin of the tentorium cerebelli, then turns inferiorly to become the sigmoid sinus
  • The inferior saggital sinus which runs in the free margin of the falx cerebri
  • The straight sinus which forms from the unification of the inferior saggital sinus and the great cerebral vein
  • The intercommunicating cavernous sinuses are positioned either side of the sphenoid, pituitary gland and drain into the superior and inferior petrosal sinuses which drain into the transverse and sigmoid sinuses, respectively
  • The sigmoid sinus which drains into the internal jugular vein.
Fig. 11.18 External carotid artery and its branches.

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There are also extracranial veins:

  • The supratrochlear vein and supraorbital vein drain the forehead
  • The facial vein, superficial temporal vein, and posterio-auricular veins drain the face and scalp
  • The superior temporal vein unites with the maxillary vein to form the retromandibular vein which bifurcates to unite with:
    • The facial vein (anteriorly) as it enters the internal jugular vein
    • The posterior auricular vein to establish the external jugular vein.

In the neck:

  • The external jugular vein receives the anterior jugular vein which has drained the superficial chin and neck, then itself drains into the subclavian vein
  • The internal jugular vein receives tributaries from the neck, then unites with the subclavian vein to establish the brachiocephalic vein.

Lymphatic drainage (Fig. 11.19) Superficial vessels accompanying superficial veins drain into a collar of nodes around the neck, including submental, submandibular, parotid, mastoid, and occipital groups. The nodes in turn drain to deep cervical nodes draining deeper structures. These nodes drain through jugular trunks into the venous circulation at the junction of the internal jugular and subclavian veins. The lingual and palatine tonsils, together with the retropharyngeal lymphatic tissue, form a ring of lymphatic tissue in the mucosa and submucosa of the nose, pharynx, and mouth.

Fig. 11.19 Venous drainage of head and neck (intracranial venous sinuses not shown); position of major groups of lymph nodes.

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Muscles of the head and neck (Colour Plate 11) Nerve supply is indicated bysuperscript Muscles of the neck (Figs. 11.20,11.21 and 11.22)

  • TrapeziusXI elevates, retracts, and laterally rotates scapula
  • PlatysmaVII depresses skin of lower face and mouth, depresses mandible
  • SternomastoidXI flexes and rotates neck
  • Scalene musclesC3–8 laterally flex, rotate neck
  • Suprahyoid muscles elevate the hyoid: digastricVII; stylohyoidVII; mylohyoidVII; geniohyoidC1
  • Infrahyoid (‘strap’) muscles
    • Depress the hyoid: sternohyoidC1–3; thyrohyoidC1; omohyoidC1–3
    • Depress the larynx: sternothyroidC1–3.

The muscles of the neck define two triangles:

  • The posterior triangle boundaries are:
    • Anterior—sternomastoid
    • Posterior—trapezius
    • Base—clavicle
    • Contents include:
      • Roots of bracial plexus
      • Subclavian artery and branches
      • Spinal part of accessory nerve
      • Branches of cervical plexus
      • Subclavian vein
      • Lymph nodes
  • The anterior triangle boundaries are:
    • Superior—mandible
    • Lateral—sternomastoid
    • Medial—midline of the neck
    • Contents include:
      • Pharynx, larynx, oesophagus, trachea
      • Thyroid, parathyroid, submandibular, parotid glands
      • Suprahyoid and infrahyoid muscles
      • Glossopharyngeal, vagus, hypoglassal nerves, and sympathetic chain
      • Strap muscles and their nerve supply (ansa cervicalisC1–3)
      • Carotid arteries and branches
      • Internal and external jugular veins.
Fig. 11.20 Anatomical relations used to describe movements of the head and neck.

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Within the anterior triangle, four smaller triangles—the superior carotid, inferior carotid, suprahyoid (submandibular), and submaxillary (submental)—are created by the digastric and omohyoid muscles.

Fig. 11.21 Muscles of the neck.
Fig. 11.22 Fascial planes of the neck.

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Muscles of facial expressionVII, with exceptions noted(Fig. 11.23) Sphincters and dilators, between bone and overlying skin:

  • Of the orbit
    • Sphincter: orbicularis oculi
      • Palpebral portion in the eyelids
      • Orbital portion around the orbital margin
    • Dilator: occipitofrontalis, levator palpebrae scapularis (skeletal III and smooth muscleSNS)
  • Of the nose
    • Compressor and dilator nares
  • Of the mouth
    • Sphincter: orbicularis oris
    • Dilator:
      • Levator labii superioris, levator anguli oris, zygomaticus major and minor
      • Depressor labii inferioris, depressor anguli oris
    • Buccinator defines the size of the cavity between cheek and teeth.

Platysma in the lateral neck pulls the mouth downwards.

Fig. 11.23 Muscles of facial expression.

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Muscles of the eye (Fig. 11.24, 11.25) Extrinsic muscles, made of striated (skeletal) muscle fibres. Actions on cornea:

  • Superior rectusIII: up, medial
  • Inferior rectusIII: down, medial
  • Medial rectusIII: medial rotation
  • Lateral rectusVI: lateral rotation
  • Superior obliqueIV: down, lateral
  • Inferior obliqueIII: up, lateral

Intrinsic muscles, made of smooth muscle. Actions:

  • Sphincter pupillae of irisIII: constriction of pupil
  • Dilator pupillae of irisSNS: dilation of pupil
  • Ciliary muscleIII: fattens lens.
Fig. 11.24 Sagittal section through orbit.
Fig. 11.25 Extrinsic muscles of eyeball.

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Muscles of mastication (Fig. 11.26) Acting on the mandible:

  • Elevate the madible, close the mouth
    • MasseterVIII
    • TemporalisVIII (also retracts)
    • Medial pterygoidVIII
  • Depress the mandible, open the mouth
    • Lateral pterygoidVIII.

In addition, digastric, stylohyoid, and mylohyoid depress and geniohyoid elevates the mandible. Muscles of the tongue (Fig. 11.26) Extrinsic muscles:

  • GenioglossusXII provides the bulk, draws forward, retracts tip
  • StyloglossusXII elevates, retracts
  • HyoglossusXII depresses
  • Palatoglossuspharyngeal plexus elevates.

Intrinsic muscles:

  • Interlaced longitudinal, transverse, vertical fibresXII alter shape of tongue.

Muscles of the soft palate

  • Tensor palatiniVIII tenses soft palate
  • Levator palatiniX, X I via pharyngeal plexus elevates soft palate
  • Palatopharyngeuspharyngeal plexus depresses soft palate
  • Palatoglossus depresses soft palate
  • Uvular musclepharyngeal plexuselevates uvula.

Muscles of the pharynx There are three circular overlapping muscles—superior, middle, and inferior constrictor musclespharyngeal plexus—which contract sequentially during swallowing to propel the bolus of food downwards. Inner, longitudinal muscles—palatopharyngeuspharyngeal plexus, salpingopharyngeuspharyngeal plexus, and stylopharyngeusIX—shorten the pharynx and elevate the larynx to close the laryngeal inlet against the base of the tongue during swallowing. Muscles of the larynx Intrinsic musclesX modify the shape of the airway through the larynx. They include:

  • Cricothyroid
  • Thyroarytenoid
  • Cricoarytenoid
  • Interarytenoid.

These muscles play roles in regulating airway diameter during swallowing, coughing, and vocalization.

Fig. 11.26 Progressively deeper dissections (a), (b), and (c) of the side of the floor of the mouth; viewed from below and to the left.

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Nerves of the head and neck (Colour Plates 10, 11, 13) The cranial nerves (Figs. 11.27, 11.28) (Examination of cranial nerves, OHCM6 p.56) There are twelve cranial nerves—see Table 11.1 (pp.686–7) Function

  • Sensory functions are performed by I (smell); II (vision); VIII (balance and hearing)
  • Motor functions are performed by IV (eye); VI (eye); XI (pharynx, larynx, shoulder, neck); XII (tongue)
  • Mixed sensory, motor, and autonomic (parasympathetic: III—motor; VII and IX—secretomotor (see page 219)) functions are performed by the remaining five nerves.

The cervical plexus (Fig. 11.29) Formed from anterior rami of C1–5 and located behind the carotid sheath. C1 emerges above the atlas, whilst C2–4 pass through the intervertebral foramina above the corresponding cervical vertebra. Segmental branches supply the prevertebral muscles. In addition, the ansa cervicalis supplies the strap muscles though upper (C1) and lower limbs. Sensory fibres carried in C2–4 are arranged as the lesser occiptal nervenerve rootC2, the great auricular nerveC2,3, the transverse cutaneous-nerveC2,3, and the supraclavicular nerveC3,4. The phrenic nerve formed from C3–5 passes to the diaphragm to provide motor supply and sensory supply to the overlying pleura and peritoneum. Posterior primary rami of cervical nerves segmentally supply extensors of the neck.

Fig. 11.27 (a) Motor and (b) sensory nerves of the face.
Fig. 11.28 Origin of cranial nerves from brainstem.
Fig. 11.29 Cervical plexus. The ansa cervicalis has been deflected medially; it normally lies anterior to the plexus.
Table 11.1 Cranial nerves
Origin Cranial nerve Component fibres Structures innervated Functions
Forebrain I Olfactory Sensory Olfactory epithelium Olfaction
II Optic Sensory Retina Vision
Midbrain III Oculomotor Motor Superior, medial and inferior rectus, inferior oblique and levator palpebrae eye muscles Movement of the eyeball
Parasympathetic Pupillary constrictor and ciliary muscle of the eye Pupil constriction and accommodation
IV Trochlear Motor Superior oblique eye muscle Movement of the eyeball
Pons V Trigeminal Sensory Face, scalp, cranial dura mater, nasal and oral cavities, cornea Sensation
Motor Mastication muscles, tensor tympani muscle Opening and closing the mouth, mastication, tension on tympanic membrane
VI Abducens Motor Lateral rectus eye muscle Movement of the eyeball
VII Facial Sensory Anterior 2/3 tongue Taste
Motor Muscles of facial expression, stapedius muscle Movement of the face, tension on middle ear bones
Parasympathetic Salivary and lacrimal glands Salivation and lacrimation
VIII Vestibulocochlear Sensory Vestibular apparatus of ear Position and movement of head
Cochlea Hearing
Medulla IX Glossopharyngeal Sensory Pharynx, posterior 1/3 of tongue Sensation and taste
Eastachian tube, middle ear Sensation
Carotid body and sinus Chemo- and baroreception
Motor Stylopharyngeus muscle Swallowing
Parasympathetic Parotid salivary glands Salivation
X Vagus Sensory Pharynx, layrnx, oesophagus, external ear Sensation
Aortic bodies, aortic arch Chemo- and baroreception
Thoracic and abdominal viscera Visceral sensation
Motor Soft palate, pharynx, larynx, and upper oesophagus Speech and swallowing
Parasympathetic Thoracic and abdominal viscera Control of gastrointestinal, cardiovascular, and respiratory systems
XI Accessory Motor Trapezius and sternomastoid muscles Head and shoulder movement
XII Hypoglossal Motor Intrinsic and extrinsic muscles of the tongue Movement of the tongue

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Structure of the eye and ear The eye (Figs. 11.30, 11.31) A sphere, ~2.5cm in diameter, with the cornea bulging forwards. The anterior chamber is situated between the cornea and the iris. The iris defines the pupil, which leads to the posterior chamber between the muscular iris and lens. The anterior and posterior chambers contain aqueous humour. The vitreous chamber behind the lens contains vitreous humour. In coronal section, three layers can be discerned:

  • The sclera, which anteriorly gives rise to the transparent cornea covered by stratified epithelium
  • The pigmented choroid, lining the posterior eyeball, which becomes the iris and, in the posterior chamber, establishes a ciliary body from which ciliary processes secrete aqueous humour
  • The retina (the innermost layer), comprises a pigmented epithelium under which lie receptor cells the rods and cones. Neuronal ganglion cells from the rods and cones converge on the optic disc to unite as the optic nerve.

The intrisic muscles of the eye sphincter and dilator pupillae control pupil diameter. The lens is suspended from the ciliary body by the circular suspensory ligament; the tension of the ligament, and hence the curvature of the lens, is determined by the ciliary muscle. The macula lies lateral to the optic disc; it is the site of sharpest vision (the fovea) and contains only cones. Retinal arteries and veins, derived from the central artery of the retina and associated veins, pass with the optic nerve, and run on the vitreous aspect of the retina. Two folds of skin constitute the eyelids, separated by the palpebral fissure. The inner surface of the eyelids is covered by a mucosal layer (the conjunctiva) which is continuous with the surface of the eyeball to form the conjunctival sac. The fibrous orbital septum acts as a framework for the eyelid and is thickened at the margins to form tarsal plates and medial and lateral palpebral ligaments. Lacrimal gland secretions (tears) enter the conjunctival sac at the lateral upper eyelid. Tears drain into the lacrimal puncta, through canals to the lacrimal sac, and then, via the nasolacrimal duct, to the nose (Fig. 11.32).

Fig. 11.30 Coronal section of front eye.
Fig. 11.31 Internal features of eye: horizontal section.
Fig. 11.32 Eye and lacrimal apparatus.

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The ear The ear is divided into three structures—the outer ear, the middle ear, the inner ear. The outer ear Comprising the auricle—a fold of skin reinforced by cartilage from which the external auditory meatus made of cartilage and then bone extends to the tympanic membrane. The middle ear (Figs. 11.33, 11.34) Within the petrous temporal bone, and comprising the vertical tympanic cavity which is fluted at its upper end as the epitympanic recess. The oval and round windows (fenestra ovale and rotundum) provide connections with the inner ear. Three articulated bones (the ossicles) are present:

  • The malleus (hammer), connected to the tympanic membrane articulates with
  • The incus (anvil) which in turn articulates with
  • The stapes (stirrup) which is attached to the oval window.

The chain of synovial joints transmits vibration from the tympanic membrane to the oval window. The tensor tympani muscle dampens vibrations of the tympanic membrane; stapedius limits vibration of the stapes. The tympanic cavity is continuous with the nasal cavity through the bony and then cartilaginous auditory tube, which is lined by mucosa. This connection equalizes the pressure in the middle ear with atmospheric pressure. The inner ear (Fig. 11.35) Within the petrous temporal bone, which comprises a bony labyrinth lined with endosteum and filled with perilymph (continuous with CSF through the perilymphatic duct—the aqueduct of the cochlea). Within the bony labyrinth lies a membranous labyrinth, filled with endolymph, which resembles intracellular fluid. The bony labyrinth comprises:

  • The cochlea, containing the organ of hearing
  • The vestibule and semi-circular canals, for perception of orientation.

The cochlea makes 2.5 turns around the central modiolus in which the cochlear nerve travels. The vestibule is continuous with the cochlea and with the three semi-circular canals which lie perpendicular to each other. The aqueduct of the vestibule reaches the posterior cranial fossa at the internal auditory meatus. The membranous labyrinth forms a series of ducts and sacs. The spiral cochlear duct (scala media) is wedge-shaped. It defines two channels—the vestibular and tympanic canals—which meet at the tip of the cochlea. The vestibular membrane separates the duct from the vestibular canal; the basilar membrane separates the duct from the tympanic membrane. Vibrations of the oval window initiate vibrations of the perilymph in the canals and then of the endolymph in the duct. The organ of Corti lies on the basilar membrane and detects these vibrations. The three semi-circular canals contain semi-circular ducts, which are enlarged to form ampullae where they join with a sac-like structure, an otolith organ (the utricle). The utricle is continuous with the other otolith organ, the saccule, which in turn is continuous with the cochlear duct. P.691
Endolymph within this network is reabsorbed into the bloodstream from the endolymphatic duct within the aqueduct of the vestibule.

Fig. 11.33 Anterior view of right middle ear cavity showing ossicles.
Fig. 11.34 Walls of the middle ear (diagrammatic) in the form of an opened-out box. The incus is not shown.
Fig. 11.35 Inner ear with sectional views of a semicircular canal (left) and the cochlea (right).

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The structures of the central nervous system (Figs. 11.36,11.37,11.38,11.39,11.40 and 11.41) The structures of the central nervous system can be grouped as:

  • The cerebrum
  • The diencephalon
  • The mesencephalon
  • The rhombencephalon
  • The spinal cord.

The cerebrum The cerebrum comprises two lateral cerebral hemispheres, defining a horizontal fissure but connected by white matter, the corpus callosum. Each hemisphere extends from frontal to occiptal bones. It lies above the anterior and middle cranial fossa and then above the tentorium cerebelli. The falx cerebri descends into the horizontal fissure. The frontal lobe is the largest component and is separated from the parietal lobe by the central sulcus. The lateral sulcus separates the temporal lobe from the parietal and frontal lobes. The parietal lobe is separated from the most caudal cerebrum, the occipital lobe, by the parietooccipital sulcus. Grey matter (cell bodies and myelinated axons) on the surface of the cerebrum constitutes the cortex. A central mass of white matter (largely myelinated axons) lies within and contains a number of clusters of grey matter (basal ganglia or nuclei). These nuclei are:

  • The corpus striatum, situated laterally to the thalamus and composed of the caudate and lentiform nuclei
  • The amygdaloid nucleus, situated in the temporal lobe
  • The claustrum, lateral to the lentiform nucleus.

Within the white matter, a fan of nerve fibres (the corona radiata) runs between the cortex and the brainstem. The lateral ventricles located within each hemisphere are continuous with the third ventricle within the thalamus via the interventricular formamina, which in turn communicates with the fourth ventricle anterior to the cerebellum by the cerebral aqueduct. The diencephalon The largely inaccessible diencephalon comprises the ovoid dorsal thalamus and ventral hypothalamus. The thalamus is formed of grey matter and is expanded at its posterior end as the pulvinar. The subthalamus contains cranial parts of the substantia nigra and red nucleus. The epithalamus contains the habenular nuclei and the pineal gland. The hypothalamus is located between the optic chiasma and the caudal border of the mammillary bodies. It consists of a number of interposed clusters of cells (the hypothalmic nuclei) which include the supraoptic and paraventricular nuclei.

Fig. 11.36 Median sagittal section of the brain to show the third ventricle, the cerebral aqueduct, and the fourth ventricle.
Fig. 11.37 Posterior view of the brainstem showing the two superior and the two inferior colliculi of the tectum of the midbrain.
Fig. 11.38 Some structures of the cerebral hemispheres cannot be seen from the surface of the brain. For example, the basal ganglia (caudate nucleus and globus pallidus) and insular cortex can be seen only after the brain has been sectioned. Large cavities in the brain called ventricles are filled with CSF.
Fig. 11.39 Several brain regions are shown in these sections of the human brain. The sections are from rostral (a) to caudal (d) and the approximate location of these sections are shown on the lateral surface view of the brain shown above. Reproduced with permission from Kandel ER et al. (2000). Principles of Neural Science, 4th edn. © The McGraw-Hill Companies, Inc.

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The mesencephalon The midbrain, or mesenchepalon, connects the forebrain to the hindbrain and contains the cerebral aqueduct. Posterior to the aqueduct lies the tectum, the surface of which demonstrates four raised structures—the superior and inferior colliculi. The cerebral peduncles, comprising the anterior crus cerebri and the posterior tegmentum, lie anterior to the aqueduct. The anterior and posterior components are separated by the substantia nigra. At the level of the superior colliculus, the tegmentum contains the red nucleus. The rhombencephalon The hindbrain, or rhombencephalon, comprises:

  • The medulla oblongata
  • The pons
  • The cerebellum.

The medulla oblongata (or myelencephalon) connects the superior pons to the inferior spinal cord. The anterior surface has a median fissure, on either side of which is a pyramid. Posterior to the pyramids are the bulges of the olivary nuclei (the olives). The cerebellum is connected to the medulla by the inferior cerebellar peduncles which lie posterior to the olives. The posterior aspect of the medulla shows medial gracile tubercles of the gracile nucleus and the laterally placed cuneate tubercles of the cuneate nucleus. The pons (or metencephalon) lies inferior to the midbrain, superior to the medulla, and on the anterior surface of the cerebellum. It contains transverse fibres connecting the two hemispheres of the cerebellum. The cerebellum is situated posterior to the medulla and pons, within the posterior cranial fossa. Two hemispheres are united in the midline by the vermis. Superior and middle cerebral peduncles provide connections to the midbrain. The cerebellum displays a highly ridged cortex of grey matter within which lies white matter. Cerebellar nuclei of grey matter are situated within the white matter, comprising the dentate, emboliform, globose, and fastigial nuclei. The spinal cord (Figs. 11.40, 11.41) The spinal cord arises from the medulla and runs from the foramen magnum to the lower border of the first lumbar vertebra. It is cylindrical and lies within the vertebral canal defined by the vertebral column. An outer coat of white matter (in anterior, lateral, and posterior columns) envelopes an inner core of grey matter. The grey matter defines a cross shape, with anterior and posterior horns. Cervical (C7–8) and lumbosacral (L4–5) enlargements occur at the points at which the cervical plexus and lumbosacral plexus arise. At its temination, the spinal cord tapers into the conus medullaris. There is a deep anterior median fissure and a shallower posterior median sulcus along the longitudinal length of the cord. Thirty-one pairs of spinal nerves arise along the cord as anterior (motor) and posterior (sensory) roots. Posterior roots display a posterior root ganglion.

Fig. 11.40 Main divisions of the central nervous system.
Fig. 11.41 Transverse section through lumbar part of spine: (a) oblique view; (b) face view, showing anterior and posterior roots of a spinal nerve.

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Function Neurones There are approximately 1020 neurones in the human nervous system, of which 1011 are in the brain. The basic morphology of a neurone consists of a cell soma, from which arise a dendritic tree and an axon. Different types of neurone can be distinguished by morphology, especially in the number and configuration of the neurone’s processes. Neuronal morphology The dendritic tree

  • Comprises branch-like processes (dendrites) containing cytoskeletal elements radiating from the cell soma
  • Accounts for up to 90% of the neurone’s surface area and is the main region for receiving synapses from other neurones
  • Dendrites may be spiny (e.g. pyramidal cells) or non-spiny (e.g. most interneurones)
  • Spines are the primary region for receiving excitatory input; each spine generally contains one asymmetrical synapse (under electron microscopy synapses are asymmetric and excitatory, or symmetric and inhibitory)
  • Dendrites cannot propagate action potentials, but Ca2+ signalling may be involved in dendritic processing of incoming information.

Cell soma

  • Contains most of the neurone’s organelles (nucleus, Golgi apparatus, rough endoplasmic reticulum and mitochondria, plus neurofilaments and microtubules)
  • Macromolecules required in the rest of the neurone are synthesized in the cell soma and transported by axoplasmic transport
  • Receives very few synapses compared with dendrites
  • Contains the axon hillock (where the axon arises from the soma) which is the point where action potentials are initiated for propagation along the axon (i.e. where integration of synaptic signals occurs).

Axon

  • Carries the output of the neurone to other neurones or to effect organs (e.g. muscle and glands)
  • Contains smooth endoplasmic reticulum and a prominent cytoskeleton
  • Is of variable length and is generally unmyelinated when short, as in local circuit neurones (e.g. inhibitory interneurones), and myelinated in longer neurones
  • Myelination increases the speed of action potential propogation
  • All axons are sheathed by Schwann cells (PNS) or oligodendrocytes (CNS), whether myelinated or not
  • Several branches arise at end of axon, the telodendria, each with one or more synaptic boutons containing synaptic vesicles for storing neurotransmitter
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  • The number and form of the branches of the telodendria depends on the type of neurone
  • In local circuit neurones there can be many short axonal collaterals, while in neurones projecting to subcortical centres, such as motor neurones that extend axons to the ventral horn of the spinal cord, there is a single long axon to the distant site with a small number of recurrent collaterals
  • Most nervous system cells are multipolar (cell body gives rise to several processes—an axon and multiple dendrites)
  • Cell bodies of bipolar neurones (e.g. retinal bipolar cells and dorsal root ganglion cells) give rise to two processes (one true axon and one which eventually branches forming dendrites)
  • Bipolar cells form no synapses on their cell body
  • Unipolar cells have a single process from the soma, and are occasionally found in the ganglia of the autonomic system but generally are only found in invertebrates.

Examples of neuronal cell types Pyramidal cells

  • The main type of excitatory neurone in the brain
  • All cortical output is carried in pyramidal cell axons
  • Roughly pyramidal cell soma, the axis of which lies perpendicular to the cortical surface
  • Dendrites are either short and arise from the base of the cell soma, or long and arise from the apex
  • Form of the dendritic tree and axonal projections depends on the laminar location of the cell soma
    • The pyramidal cells of cortical layer V and deep in layer III have extensive dendritic trees, and axons that project to distant cortical and (layer V only) subcortical sites (e.g. basal ganglia, brain stem and spinal cord)
    • Pyramidal cells of cortical layers II and III have a small soma and dendritic tree, and their axon gives rise to many recurrent collaterals that extend into neighbouring areas of cortex, thus providing a major intrinsic excitatory input to other cortical areas.

Spiny stellate cells

  • Glutaminergic neurones which are another main source of intrinsic excitatory input
  • Found mostly in cortical layer IV of primary sensory areas
  • High density of dendritic spines
  • Influence extends only locally through small dendritic and axonal trees
  • Suggested role in local cortical circuits between the neurones in layer IV that receive thalamic input and neurones in layers III, V, and VI which carry the cortical output.

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Inhibitory interneurones

  • Majority of other interneurones are GABAergic and inhibitory
  • Regulate pyramidal cell function (GABA antagonists such as picrotoxin are potent convulsants)
  • Many subtypes distinguishable by their morphologies
  • Most common are:
    • Basket cells, axonal endings of which form a ‘basket’ around the somas of pyramidal cells with which they synapse. They synapse with many pyramidal cells as their axons extend horizontally for up to 2 mm across cortex, and several basket cells may contribute to a single pyramidal cell’s ‘basket’
    • Chandelier cells, which have characteristic axonal endings that consist of a string of synaptic boutons spread along the distal segment of the axon forming axo-axonal synapses with pyramidal cells and can inhibit pyramidal cell firing
    • Double bouquet cells, which have strictly vertically oriented dendritic and axonal trees which thus extend little into neighbouring areas of cortex. Their axons form tight bundles that project across cortical layers II to V, and their axonal terminals contain a wide range of neurotransmitters
    • Chandelier and double bouquet cells vary morphologically depending on their connectivity and cortical location.

Purkinje cells

  • Found only in the cerebellar cortex
  • Characteristic dendritic tree—highly branched and in only two dimensions like the veins on a pressed leaf
  • The dendritic trees of all Purkinje cells are aligned in parallel across the whole of cerebellar cortex.

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Neuroglia Glia are a relatively poorly understood part of the CNS. From the Greek word for glue, since it was originally thought that their role was simply to glue the brain together, ‘glia’ is an umbrella term for all the non-neuronal cell types in the CNS. In fact, the different types of glial cells have widely differing morphologies and functional roles, which extend far beyond simply providing neuronal scaffolding. There are two major classes of glia: macroglia and microglia. Macroglia

  • Derived embryologically from precursor cells that line the neural tube constituting the inner surface of the brain
  • Comprise astrocytes, oligodendrocytes, and ependymal cells.

Astrocytes

  • Irregular star-shaped cells, often with relatively long processes
  • Make up between 20% and 50% of the CNS by volume
  • Subdivided into fibrous astrocytes, which are found among bundles of myelinated fibres in CNS white matter, and protoplasmic astrocytes, which contain less fibrous material and are found around cell bodies, dendrites and synapses in the grey matter
  • Embryonically, astrocytes develop from radial glial cells, which provide the framework for the migration of neurons and their subsequent organization, and thus play a critical role in defining the cytoarchitecture of the CNS. Once the CNS has matured, radial glial cells retract their processes and serve as progenitors of astrocytes. Some specialized astrocytes retain their radial morphology in the adult cerebellum (Bergmann glial cells) and the retina (Müller cells)
  • Astrocytes have multiple roles in the CNS:
    • Isolation of the brain parenchyma: the glia limitans is formed by long processes projecting to the pia mater and the ependyma, and astrocytes processes ensheath capillaries and the nodes of Ranvier. However, astrocytes do not themselves form the blood-brain barrier, but induce and maintain the tight junctions between endothelial cells that create the barrier. Astrocytes are a major source of extracellular matrix proteins and adhesion molecules in the CNS, which help to maintain connections between nerve cells
    • CNS homeostasis: astrocytes are connected to each other by gap junctions, forming a syncytium that allows ions and small molecules to diffuse across the brain parenchyma. Astrocyte processes around synapses are thought to be important for removing transmitters from the synaptic cleft. They contain transport proteins for the reabsorption of many neurotransmitters, such as glutamate, which is converted into glutamine by astrocytes and then released into the extracellular space. Glutamine is taken up by neurones as a precursor for both glutamate and γ-amino-butyric acid (GABA)
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      act as perfect K+ electrodes, and their resting potential is determined purely by their high permeability to K+. They are thus able to buffer excess K+ released by neurones when their activity is high. There is a greater concentration of K+ channels at the end-feet of astrocyte processes, which contact blood vessels and the pial membrane, than at any other point on their surface membrane, so they can balance out high K+ uptake in one part of the cell, in an area of high neuronal activity, by extruding it through their end-feet. High K+ concentrations are also distributed further across the parenchyma via the syncytial gap junctions between neighbouring astrocytes. Furthermore, a raised K+ concentration in the extracellular space between the capillaries and the astrocyte end-feet causes local vasodilation, thus providing a mechanism for autoregulation of the blood flow to maintain appropriate oxygen and nutrient delivery
    • Response to infection and injury: astrocytes have been shown to react with T lymphocytes, whose activity they can stimulate or suppress. Astrocytes therefore qualify as inducible, facultative antigen-presenting cells. In addition, they help microglia remove neuronal debris and seal off damaged brain tissue after injury
    • Production of growth factors: astrocytes produce a great many growth factors, which act singly or in combination to regulate selectively the morphology, proliferation, differentiation, or survival, or all four, of distinct neuronal subpopulations. Most of the growth factors also act in a specific manner on the development and functions of astrocytes and oligodendrocytes. The production of growth factors and cytokines by astrocytes and their responsiveness to these factors are a major mechanism underlying the developmental function and regenerative capacity of the CNS. The growth factors are also important for angiogenesis, again especially in development and repair of the CNS. This role is poorly understood.

Oligodendrocytes

  • Form sheaths around nerve axons, like Schwann cells in the PNS. However, unlike Schwann cells, which sheathe single axons, the pressure for space in the CNS means that oligodendrocytes sheathe several axons. Around larger diameter fibres the sheath is myelinated to increase the speed of axonal transmission with nodes of Ranvier at regular intervals of 1mm in most nerve fibres. Around smaller diameter fibres oligodendrocytes do not produce myelin. How the CNS determines which fibres will be myelinated is not well understood. The signal between nerve axons and myelin-producing glia is thought occur early in development. Schwann cells that do not produce myelin in their normal environment can if ‘transplanted’, so the neurones appear to provide the switch signal
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    regenerating axons to grow along, and also attract neurones to grow towards them from a distance. Thus it appears to be an inhibitory influence from oligodendrocytes that prevents regeneration, although the role and mechanism is not understood.

Ependymal cells

  • Line the inner surface of the brain in the ventricles
  • No known physiological role.

Microglia

  • Develop from bone-marrow-derived monocytes that enter the brain parenchyma during early stages of brain development
  • Numerous processes extending symmetrically from a small rod-shaped cell body
  • Primary function is as immune response mediators in the CNS
    • Most are derived from monocytes early during brain develop-ment—they retain the ability to divide and have the immunophenotypic properties of monocytes and macrophages
    • Respond rapidly to immune activation or injury in the CNS, and play a role in the immune-mediated response itself and also in scavenging debris from dying cells
    • Reactive microglia divide more rapidly than resting microglia, and differ both in their morphology and in the increased expression of monocyte-macrophage molecules
  • Also thought that they can secrete cytokines and growth factors that are important in fibre-tract development, gliogenesis, and angiogenesis.

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Central synaptic transmission CNS neurones often form up to 10,000 synapses, rather than the single synapse the motor neurone forms at the NMJ. However, activation of any single synapse is not sufficient to trigger a neurone to fire. Instead, excitatory and inhibitory post-synaptic potentials (epsps and ipsps) from each of the many synapses over the neurone’s dendrites are summed together over time and space (known as temporal and spatial summation). The point where the cell body meets the axon is called the axon hillock, and it is here that action potentials are triggered, if the sum total of the depolarization over the neurone’s dendritic tree is great enough. There are many central neurotransmitters—unlike the PNS which only uses acetylcholine—and they can be ionotropic (directly-gated):

  • Glutamate (NMDA and quisqualate A AMPA)
  • Nicotinic acetylcholine (Ach)
  • GABAA
  • Glycine

or metabotropic (indirectly-gated via a G protein):

  • Glutamate (quisqualate B AMPA)
  • GABAB
  • Adrenaline and noradrenaline
  • Muscarinic acetylcholine
  • Serotonin (S-HT)
  • Dopamine
  • Various neuropeptides such as substance P and opioids such as enkephalin.

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Excitatory synapses Glutamate is the most widespread excitatory neurotransmitter in the CNS. Glutamate receptors have been typed as either AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors or NMDA (N-methyl-D-aspartate) receptors, named after the agonists that were first used to distinguish them. There are three subtypes of AMPA receptor: kainate receptors are dir-ectly-gated Na+- and K+-permeable cation channels. Quisqualate activates both ionotropic and metabotropic glutamate receptors, thus the quisqualate A receptor is a directly-gated Na+ and K+ channel, while the quisqualate B receptor is G-protein coupled and opens a Na+ and K+ channel via a phosphoinositide-linked second-messenger system (IP3). The NMDA receptor is a cation channel that is permeable to Ca2+ ions in addition to Na+ and K+. The main effect of the NMDA receptor appears to be Ca2+-mediated, however, since they make little contribution to the epsp when the neuronal membrane is at resting potential, when extracellular Mg2+ blocks the NMDA receptor channel. As the membrane becomes depolarized, the Mg2+ is removed and the channel can open allowing Na+, K+, and Ca2+ ions through. Thus, in effect, the NMDA receptor is both ligand- and voltage-gated. NMDA receptors have been implicated in the excitotoxicity that occurs following stroke or ischaemia, and in persistent seizures in status epilepticus. Excessive influx of Ca2+ ions through NMDA receptors, caused by the continuously elevated glutamate levels that appear to occur in these conditions, allows intracellular Ca2+ to reach catatonic levels. Cell damage and death may result from the subsequent activation of Ca2+-dependent proteases and production of toxic free radicals. NMDA receptors play a critical role in the induction of long-term potentiation (LTP), at least in the dentate gyrus and area CA1 of the hippocampus where LTP has been most studied, and also appear to be involved in the formation of the eye-blink conditioned reflex. P.708
Inhibitory synapses γ-amino-butyric acid (GABA) and glycine are the primary inhibitory neurotransmitters of the CNS. GABA is predominant in the brain and its main function is in local circuit interneurones, although there are also long-axoned GABAergic projection neurones. The functional morphology of GABAergic interneurones varies widely, with their effects extending over as small an area as a single cortical column, or to regions many columns wide. GABA receptors can be divided into ionotropic and metabotropic subtypes. The ionotropic GABAA receptor is the most common GABA receptor and opens a Cl- anion channel. The anion selectivity is produced by positively charged amino acids positioned near the ends of the ion channel. The metabotropic GABAB receptor is G-protein coupled and can block Ca2+ channels or activate K+ channels. GABAA receptors also bind benzodiazepines, such as diazepam (Valium) and chlordiazepoxide (Librium), and barbiturates, such as phenobarbital and secobarbital. The effect of GABA is allosterically modulated by benzodiazepines, increasing the frequency of channel opening, and thus also GABA-induced Cl- current. Barbiturates act by increasing the length of time that a Cl- channel remains open. This dampening, inhibitory effect on generalized CNS activity underlies the use of benzodiazepines and barbiturates as anti-convulsants and anxiolytics. Picrotoxin and bicuculline inhibit GABA receptor function and produce widespread and sustained seizure activity due to a generalized dampening of inhibitory synapses throughout the CNS. Penicillin inhibits GABA receptors in a similar way and, at a high enough concentration, is also a potent convulsant. Glycine is the main inhibitory neurotransmitter in the spinal cord. It activates a Cl- anion channel that is functionally very similar to the GABAA receptor. It is blocked by strychnine. Glutamate and GABA metabolism are similar, since the molecules are chemically closely related and both synthesized from the same precursor, α-ketoglutarate, which is a product of the Kreb’s cycle. α-ketoglutarate is transaminated to glutamate by GABA α-oxoglutarate transaminase (GABA-T). The conversion of glutamate to GABA is catalysed by glutamic acid decarboxylase (GAD). GABA-T is mitochondrial, while GAD is cytosolic, and it is not clear how transport is arranged in and out of the mitochondria for vesicular storage. Once glutamate or GABA have been released into the synaptic cleft, they are deactivated by reuptake into the surrounding glia or the presynaptic neurone. There is no enzymatic deactivation in the synaptic cleft. Glutamate receptors are more densely expressed in astrocytes than in neurones. Glia convert glutamate and GABA to glutamine, which is recycled back to the presynaptic neurone. Up- or down-regulation of transmitter release from glutaminergic and GABAergic neurones is mediated by metabotropic autoreceptors. P.709
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Sensory System Somatosensory system The somatosensory system comprises touch, nociception (pain), temperature, and proprioception (pp.252, 732). Each relies on different types of receptors, pathways (Fig. 11.42), and processing. Receptors Touch is mediated by mechanoreceptors. In non-glabrous skin, there are four types of mechanoreceptor.

  • acinian corpuscles are found deep in the dermis, thus having large receptive fields, and are rapidly adapting
  • eissner’s corpuscles are also rapidly adapting, but are superficial and thus have small receptive fields
  • erkel’s disks are superficial, slowly adapting receptors
  • uffini receptors are deep, slowly adapting receptors. No conscious sensation is associated with direct stimulation of Ruffini receptors and a role has been postulated for them in proprioception.

In glabrous skin, there are three types of follicle receptor (hair-guard, hair-tylotrich and hair-down receptors) and the same deep receptors as in non-glabrous skin. Temperature is sensed by two types of thermoreceptor, one for heat (responding in the range of 30–45°C) and one for cold (responding in the range of 1–20°C). Cold receptors are also activated by extreme heat (at over 45°C), resulting in the sensation of ‘paradoxical cold’. Thermal sensitivity is punctate: hot and cold thermoreceptors are grouped in non-overlapping heat- or cold-sensitive zones. Heat nociceptors also respond to extreme heat. Pain is mediated by nociceptors, which can be mechanical, thermal, or polymodal (mechanical nociceptors that can be activated or sensitized by inflammatory mediators and other indicators of tissue damage such as bradykinin, K+ ions, serotonin, prostaglandin, and histamine). Transduction by mechanoreceptors relies on a simple mechanical deformation of the nerve ending, which opens mechanically-gated cation channels, ion flow through which triggers an action potential that is transmitted along the nerve axon. Rapidly adapting mechanoreceptors have a large capsule around the nerve ending, formed by multiple foldings of a Schwann cell. These act to absorb a constant pressure, so that rapidly adapting mechanoreceptors are only activated by changes in pressure. This can be demonstrated by stripping the capsule off the nerve ending, which no longer adapts to constant pressure. Slowly adapting mechanoreceptors have a much smaller capsule around the nerve ending, so they respond with a more constant rate of firing to the absolute level of pressure. Nociceptors are all free nerve endings. Fibre types are different for different modalities. All mechanoreceptors are carried by fast myelinated Aβ (type II) fibres. Mechanical nociceptors are carried by thinner, slower, myelinated Aδ (type III) fibres. Polymodal nociceptors are carried by thin, unmyelinated C (type IV) fibres, which are the slowest of all. Thus sharp, acute pain, mediated by mechanical P.711
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nociceptors, is felt faster than dull inflammatory pain, which is mediated by polymodal nociceptors. The sensation of cold from thermal receptors is carried by Aδ fibres, while that of heat is carried by slower C fibres.

Fig. 11.42 The main ascending somatory sensory pathways: (left) the lemniscal system; (right) the neo-spinothalmic and paleo-spinothalmic divisions of the anterolateral system. (Reproduced with permission from Carpenter R (2003), Neurophysiology, 4th edn, Edward Arnold.)

Central pathways All sensory fibres enter the spinal cord through the dorsal roots, with their cell bodies lying just before the dorsal root in the dorsal root ganglia. Axons from mechanoreceptors and proprioceptors ascend the spinal cord in the dorsal columns. These carry fibres from the ipsilateral side of the body and continue to the dorsal column nuclei at the level of the medulla. The dorsal columns are divided into the gracile and cuneate fascicles, which contain fibres representing the lower limb and trunk, and the upper limb and neck, respectively. The fascicles are divided by the dorsal intermediate septum. Similarly, the dorsal column nuclei are divided into the gracile and cuneate nuclei. At this level, the sensory axons synapse onto internal arcuate fibres, which decussate and continue to ascend on the contralateral side in the medial lemniscus. Fibres from the sensory trigeminal nucleus, representing touch sensation from the face and head, ascend from this level in the neighbouring trigeminal lemniscus. The medial lemniscus fibres synapse in the ventral posterior lateral nucleus of the thalamus, and trigeminal lemniscus fibres synapse in the ventral posterior medial nucleus, whence all tertiary fibres proceed to the primary somatosensory cortex on the postcentral gyrus. Through all levels of the pathways, fibres remain somatotopically arranged. Nociception and temperature sensation are carried by the anterolateral system. Axons entering the spinal cord through the dorsal horns may ascend or descend one or two spinal segments in the tract of Lissauer, before synapsing onto secondary fibres and interneurones in the dorsal horn laminae. Aδ fibres synapse in laminae I (marginal zone) and V (part of the nucleus proprius), while C fibres synapse in lamina II (substantia gelatinosa). Referred pain is thought to be a result of cutaneous and visceral nociceptive afferents converging on the same secondary fibres through interneurones in the dorsal horn laminae. The secondary fibres decussate at the same spinal segment as they arise, and ascend in one of three tracts that form the anterolateral system on the contralateral side. The spinothalamic tract is the largest tract, arising from dorsal horn laminae I and V–VII (the nucleus proprius and Clarke’s nucleus), and ascends to the central lateral and the ventral posterior lateral nuclei of the thalamus. The spinoreticular tract arises from laminae VII (Clarke’s nucleus) and VIII. Some fibres terminate in the reticular formation of the pons and medulla, while others continue on to the central lateral nucleus of the thalamus. Fibres that terminate in the thalamus, from both spinothalamic and spinoreticular tracts, synapse onto fibres that project to primary somatosensory cortex. Fibres in the spinomesencephalic tract arise from laminae I and V, and project to the periaqueductal grey and the mesencephalic reticular formation. These projections provide inputs to the limbic system via the hypothalamus. P.713
Primary somatosensory cortex (area S1) is located on the postcentral gyrus. The representation of the body in area S1 is somatotopic, with the head represented laterally, and the feet medially. Area S1 is divisible into four distinct cytoarchitectonic areas—Brodmann’s areas 1, 2, 3a, and 3b. Although all four areas receive thalamic input, most thalamic fibres terminate in areas 3a and 3b. Areas 3a and 3b have been implicated by lesion studies in discrimination of texture, size, and shape. Cells in areas 3a and 3b then project to area 1, which is associated with texture discrimination, and area 2, which is associated with size and shape. Each area has its own somatotopic map, in which the representations of fast and slowly adapting receptors are kept separate. Within these fast and slowly adapting regions, different receptor types are represented in separate cortical columns. Thermal and nociceptive sensitivity is usually not affected by lesions of area S1. Beyond area S1 is area S2, the secondary somatosensory cortex, which receives projections from all four areas of S1, and the posterior parietal cortex. Area S2 is involved with higher order aspects of touch, such as stereognosis, while in the posterior parietal cortex, somatosensory information is integrated with information from other sensory modalities such as vision and audition. Lateral inhibition through inhibitory interneurones operates at all levels of the somatosensory pathways from the dorsal column nuclei upwards. Thus, secondary and tertiary afferent neurones have antagonistic centre-surround receptive fields. At each synaptic relay on the pathway, several presynaptic neurones converge on a single post-synaptic neurone, so that at each level, the size of the neurone’s receptive fields grow. Receptive field sizes depend on the area of the body in question, due to the density of somatic receptors. Thus, without lateral inhibition, two-point discrimination (the minimum distance between two points on the skin that can be discriminated apart) would be very poor. However, lateral inhibition at each synaptic level keeps the central, excitatory zone of the neurone’s receptive field small, so that two-point discrimination is not affected by neuronal convergence. Distal inhibition of afferent fibres by regions of cerebral cortex operates in the thalamus and the dorsal column and trigeminal nuclei, and may contribute to selective attention. Nociception pathways can also be modulated by distal inhibition from the periaqueductal grey in the midbrain. Noradrenergic and serotonergic efferent fibres from the Raphe nucleus, driven by neurones from the periaqueductal grey, descend through the dorsolateral funiculus to inhibit nociceptive afferent fibres via enkephalinergic interneurones in laminae I and II of the dorsal horn. In another mechanism of pain modulation, called dorsal horn gating, Aβ afferent fibres inhibit secondary nociceptive afferents arising in lamina V via inhibitory interneurones. P.714
Visual system: the retina The retina is composed of five layers (starting nearest the lens):

  • The ganglion cell layer contains the cell bodies of the ganglion cells
  • The inner plexiform layer contains the dendrites of amacrine, bipolar, and ganglion cells, and synapses between them
  • The inner nuclear layer contains bipolar cell axons and the cell bodies of amacrine, bipolar, and horizontal cells
  • The outer plexiform layer contains the dendrites of horizontal cells and synapses between rods, cones, horizontal cells, and bipolar cells
  • The outer nuclear layer contains the rods and cones.

Cells in the retina are unmyelinated, in order to reduce visual distortion as light passes to the photoreceptors at the back of the retina. However, at the centre of the retina, in the fovea, maximal acuity is achieved by displacing to the side all but the photoreceptors themselves. Behind the retina, adjacent to the outer nuclear layer, is the pigment epithelium. Photoreceptive cells The photoreceptive cells of the retina are the rods and cones. These cells contain photosensitive pigment made up of a light-absorbing molecule called retinal, bound to a membrane protein called opsin. Each cell type, rods, and the three types of cone, contains a different visual pigment, made up of retinal and a different opsin molecule, each of which has a different peak light absorption energy. Colour vision relies on the three types of cone which are maximally excited by light with short (blue—437nm), middle (green—533nm), and long (red—564nm) wavelengths. In contrast, the rod system is achromatic, since there is only one visual pigment, known as rhodopsin, with a peak absorbency at 498nm. Rods and cones have an inner and an outer segment. The inner segment is where the nucleus, mitochondria, and other cellular apparatus are found. The outer segment comprises a comb-shaped series of folds of the cell’s membrane which, in rods, often seal off to form free-floating disks within the rod. These folds provide a large surface area over which to collect photons with the photosensitive transmembrane proteins. The outer segments of rods are larger than those of cones, making the rods much more sensitive than cones in dim light. Transduction (Fig. 11.43) Transduction occurs via a cascade of events triggered by the absorption of a photon by pigment molecule. In rods the retinal usually exists as the 11-cis isomer. Excitation of the rhodopsin by a photon causes a series of conformational changes in the retinal, ending ultimately in the all-trans state. Rhodopsin is unable to bind all-trans retinal, so the retinal becomes detached. A semi-stable intermediate configuration called metarhodopsin II activates transducin, a G-protein, which in turn activates phosphodiesterase to convert cyclic GMP (cGMP) to 5′GMP. The lowered cGMP concentration decreases Na+ influx through a cGMP-gated channel. Thus in the dark, cGMP concentrations are raised, and so there is a constant Na+ current, known as the dark current. The resting membrane potential is therefore relatively depolarized, at around 40mV, and light causes a hyperpolarization to around 70mV. A similar cascade operates in cones. P.715
Detached retinal is recycled in the pigment epithelium by converting the all-trans retinal to all-trans retinol (vitamin A). All-trans retinol is the precursor for 11-cis retinal and is not synthesized in the body. Dietary vitamin A deficiency can therefore cause night-blindness or, if severe, even total blindness. The dynamic range of photosensitivity of cones is maintained through light adaptation. The transduction cascade also inactivates a cGMP-gated Ca2+ channel: Ca2+ inhibits guanylate cyclase (GTP→cGMP), thus a negative feedback loop operates to maintain a fairly constant cGMP concentration through a range of absolute levels of brightness, and so keep the cell maximally sensitive to changes in light level.

Fig. 11.43 Pigment epithelium. The cyclical sequence by which light leads to isomerization of retinal and its dissociation from opsin, followed by the relatively slow processes that lead to the final regeneration of rhodopsin. (Reproduced with permission from Carpenter R (2003), Neurophysiology, 4th edn, Edward Arnold.)

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Retinal pathways Cones synapse onto bipolar cells and horizontal cells. Bipolar cells synapse onto ganglion cells, which are the output cells of the retina. Horizontal cells and amacrine cells are interneurones that affect the information passed between photoreceptors and bipolar cells, and between bipolar cells and ganglion cells, respectively. Horizontal cells are inhibitory and synapse back onto the same cones that supply them. However, neighbouring horizontal cells are also all connected to each other through electrical synapses, forming one continuous sheet along which cone inputs are conducted electrotonically. Each cone is therefore inhibited by the activity of a number of neighbouring cones, producing the centre-surround antagonism that characterizes the receptive fields of cells in the very early stages of the visual system. Cones release glutamate, which has one of two effects, depending on the type of bipolar cell.

  • In off-centre bipolar cells, glutamate opens Na+ channels, which causes depolarization
  • In on-centre bipolar cells, glutamate closes Na+ channels and opens K+ channels, causing hyperpolarization.

Bipolar cells signal using electrotonic conduction, so there is a continuous, graded membrane potential rather than an all-or-nothing action potential. The ganglion cells onto which bipolar cells synapse are the first cells in the visual system to fire action potentials. In photopic vision, rods synapse via gap junctions onto nearby cones. However, they are sufficiently sensitive that normal levels of brightness bleach them of visual pigment and their input is negligible. For scotopic vision, there is a process called dark adaptation, during which the rod pathways change. The gap junctions onto nearby cones close and, instead, rods synapse onto rod bipolar cells, which in turn synapse onto AII amacrine cells. A2 amacrine cells synapse both onto off-centre ganglion cells and on-centre bipolar cells, which synapse onto on-centre ganglion cells. As discussed, colour vision is mediated by the cone system. The principle of univariance means that it is the ratio of activities between the three cone types that carries colour information. A single cone type (or rod) cannot alone convey colour information. Colour blindness is a result of a defect in or absence of one or more cone pigments. Defects of a visual pigment are classified as protanomaly, deuteranomaly, or tritanomaly, while an absence of a pigment is classified as protanopia, deuteranopia, or tritanopia (with prot-, deuter-, and trit- denoting the long-, middle- and short-wavelength pigments). An absence of two cone pigments is classified as atypical monochomatopsia, while an absence of all cone pigments is classified as typical monochromatopsia. All these are congenital defects of colour vision. However acquired, retinal disease can also damage colour vision. Tetrachromatopsia is sometimes found in women, who have an extra visual pigment. P.717
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Visual system: central visual pathways (Figs. 11.44, 11.45) The output of the retina is via the ganglion cells, which have circular, centre-surround antagonistic receptive fields. They can be either on-centre, off-surround, meaning that they are excited by light falling on the receptive field centre and inhibited by light falling on their receptive field surround, or off-centre, on-surround. Ganglion cell axons converge at the optic disc and leave the retina as the optic nerve. The ganglion cells are closer to the lens than the rods and cones, so where these axons pass through the retina at the optic disc, there are no photoreceptors. The resulting small scotoma is known as the blind-spot. The optic nerves from each eye meet at the optic chiasm. Fibres arising from the nasal retinae from each eye cross, so that when the fibres continue as the optic tract, each tract carries information about left and right hemifields, rather than from left and right retinae. The optic tract continues to the lateral geniculate nucleus (LGN), when the ganglion cell fibres synapse. The LGN is divided into six layers, with layer 1 being the most ventral, and layer 6 the most dorsal. Layers 1, 4, and 6 contain fibres arising from the contralateral retina, while layers 2, 3, and 5 contain ipsilateral fibres. The six layers of the LGN are also split into magnocellular (‘M’—layers 1 and 2) and parvocellular (‘P’—layers 3 to 6) streams. M cells have larger receptive fields and have good temporal resolution, but have poor spatial resolution and are monochromatic. P cells have smaller receptive fields, have good spatial resolution, and carry colour information, but poor temporal resolution. M cells are thought to be the substrate for processing of motion in the visual cortices, while P cells are thought to contribute to fine feature processing and colour vision. The visual pathway continues from the LGN as the optic radiation, which passes back to the primary visual cortex at the occipital pole. Some fibres initially travel forward around the front of the temporal horn of the lateral ventricle. The loop that is formed is known as Meyer’s loop. The LGN also projects to the pretectum, which controls pupillary reflexes via the IIIrd (oculomotor) cranial nerve, and to the superior colliculus, which controls saccadic eye movements via the IIIrd, IVth (trochlear), and VIth (abducens) cranial nerves. The primary visual cortex, also known as striate cortex or area V1, is located at the occipital pole continuing along the calcarine sulcus on the medial surface of each cerebral hemisphere. The visual field is represented contralaterally in strict retinotopic order, with the central visual field represented most posteriorly, and the upper half of the visual field on the inferior banks of the calcarine sulcus and the lower half on the superior banks. As in all neocortex, area V1 is divided into six layers. Inputs from the LGN arrive in layer 4, which is further subdivided into layers 4A, 4B, 4Cα, and 4Cβ. Fibres from the magnocellular layers of the LGN arrive in layer 4Cα, and fibres from the parvocellular layers of the LGN arrive in layer 4Cβ.

Fig. 11.44 The functional destinations of fibres in the optic nerve. LCV (lateral geniculate nucleus); HThal (hypothalamus); PT (prectum and other visual proprioceptive areas); SC (superior colliculus); Par, Temp (parietal and temporal cortex). (Reproduced with permission from Carpenter R (2003), Neurophysiology, 4th edn, Edward Arnold.)
Fig. 11.45 Cerebral cortex, showing the general location of visual areas 17, 18, and 19. (Reproduced with permission from Carpenter R (2003), Neurophysiology, 4th edn, Edward Arnold.)

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Receptive fields in area V1 have ‘on’ and ‘off’ bands running side-by-side, rather than the centre-surround structures of LGN cells. These cells are therefore selective for the orientation of visual features. Visual cortex is compartmentalized into columns of cells, through all six layers, that have similar receptive field structures. Neighbouring columns in area V1 will have selectivities for slightly different orientations and, thus, as one travels over a length of cortex there is a trend for a smooth rotation of orientation selectivity. Orientation columns are achromatic. Primary visual cortex is the first stage in the visual pathway at which cells receive inputs from both eyes. Some cells have a preference for one eye over the other, and so area V1 is also compartmentalized by ocular dominance. Neighbouring columns will usually have a similar ocular dominance and, thus, there is often a complete representation of all orientations within each region of a particular ocular dominance. A complete set of orientation columns for both left and right ocular dominance has been termed a hypercolumn. Interspersed between orientation columns are columns in which all the cells are selective for particular wavelengths. These columns of colour-sensitive cells are known as blobs, after their appearance when visual cortex is stained for the enzyme cytochrome oxidase. Another aspect of the processing of information from left and right eyes in area V1 is a sensitivity to retinal disparity—a slight mismatching of the relative positions of a visual feature on each retina. This difference in retinal position of the feature is a strong cue to the feature’s depth. This early processing of visual information about feature orientation, colour, and depth is further refined in higher visual areas. Visual information from area V1 passes to the first extrastriate area, known as area V2, and thence to a multitude of other visual areas. These visual areas are broadly divisible into dorsal and ventral streams, deriving from the earlier magnocellular and parvocellular pathways.

  • The dorsal stream includes areas V5 and MST, where cells have strong selectivities for direction of motion and motion-in-depth, and has been labelled the ‘where’ pathway
  • The ventral stream includes areas V4 and IT, where cells have strong selectivities for colour and depth contours, and has been labelled the ‘what’ pathway.

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Auditory system A sound is a pressure wave transmitted through a medium, such as the air, consisting of alternate compression and rarefaction of the medium caused by the vibration of an object, such as vocal cords or the strings on a violin. The auditory system gathers information about the frequency composition and intensity of a sound and the direction of the source of the sound. The auditory system is composed of the ear itself, in which the sound is transduced into neuronal impulses, and the central pathways in which the transduced signal is analysed. The ear comprises three compartments:

  • Outer ear—the pinna and external auditory meatus change the intensity of frequencies in the range of 2–7kHz (‘colouration’). This is important for zenith and front/back localization. It is separated from the middle ear by the tympanic membrane (ear drum)
  • Middle ear—the ossicles (malleus, incus, and stapes—in order from outer to inner ear) are necessary for mechanical impedance matching between the tympanic membrane and the oval window, because the outer ear is filled with air, while the inner ear is filled with fluid. The tensor tympani and stapedius muscles alter the efficiency of impedance matching, and can thus protect the inner ear from extremely loud sounds. They are also active during speech. It is separated from the inner ear by the oval window, and joined to the naso-pharynx by the Eustacian tube
  • Inner ear—the inner ear is divided into two portions: bony and membranous labyrinths. The sensory organs of the auditory system are in the auditory division of membranous labyrinth (the cochlea). The cochlea consists of three scalae, in a spiral around the modiolus. The scala vestibuli begins at the oval window and joins the scala tympani at the helicotrema, at the head of the spiral, which runs back to another membrane between the middle and inner ears, just beside the oval window (the round window). In between these runs the scala media, which is completely enclosed by Reissner’s membrane towards the scala vestibuli and by the basilar membrane towards the scala tympani. The scala media is filled with endolymph, which has a similar chemical constitution to intracellular fluid. The scalae vestibuli and tympani are filled with perilymph, which has a similar chemical constitution to cerebrospinal fluid.

Transduction of sound waves into neuronal impulses occurs in the organ of Corti, which is found on the basilar membrane in the inner ear (Fig. 11.46). When the oval window is moved by the ossicles in the middle ear, a travelling wave is set off along the basilar membrane. The basilar membrane is thin and stiff at its base, at the oval window, and becomes increasingly wide and less stiff towards its apex, at the helicotrema. Thus, high-frequency travelling waves have a maximum amplitude near the oval window, while low-frequency travelling waves have a maximum amplitude near the helicotrema. The organ of Corti contains rows of hair cells, which have stereocilia arranged either in linear rows (inner hairs cells) or in V or W formations (outer hair cells). P.723
There are three rows of outer hair cells and one row of inner hair cells along the length of the basilar membrane. The stereocilia rest against the tectorial membrane, which lies above the organ of Corti. The tectorial membrane is stiff, so the stereocilia are bent sideways by a shearing force when the basilar membrane vibrates. The stereocilia on each hair cell are arranged in graded height order, with the tallest being thicker and known as the kinocilium. The tips of the stereocilia are linked, such that when the basilar membrane moves downwards, the stereocilia bend in one direction and the tip-links slacken, and when the basilar membrane moves upwards, the stereocilia bend the other way and the tip-links tighten. Tightening of the tip-links opens stretch-activated non-selective cation channels, which allow K+ influx from the endolymph in the scala media. There is no chemical gradient, but there is an electrical gradient, resulting in an oscillatory membrane potential. At the basal end of the hair cells the oscillatory membrane potential causes oscillatory transmitter release.

Fig. 11.46 (a) Section through the cochlea, showing the organ of Corti—shown in (c) in more detail; (b) a representation of the scala vestibuli, scala media, and scala tympani, and the path of sound through them. OHC, IHC (outer and inner hair cells); E (endolymph); P (perilymph). (Reproduced with permission from Carpenter R (2003), Neurophysiology, 4th edn, Edward Arnold.)

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Innervation of the inner ear is by the VIIIth cranial (vestibulocochlear) nerve. It carries both afferent and efferent fibres. ~90% of afferent fibres are from the inner hairs cells, which synapse one-to-one. The rest innervate the outer hair cells, which are pooled ~20 outer hair cells per afferent fibre. Efferent fibres are from the superior olive and innervate mostly the outer hair cells. They are thought to contribute to the sharpening of the frequency tuning along the basilar membrane. Outer hair cells contribute to sharpening frequency tuning by changing the length of their stereocilia. Destruction of the outer hair cells (e.g. by drugs such as furosemide and gentamicin) can lead to hearing deficits. Electrical resonance does not contribute to the sharpness of frequency tuning in mammals. Afferent fibres in the auditory nerve have a characteristic frequency, determined by the hair cells they innervate. Other nearby frequencies will also stimulate the nerve fibre but require a greater sound intensity, resulting in a V-shaped frequency tuning curve. The afferent fibres carry the frequency of a sound in two ways, the combination of which is known as Duplex theory. With frequencies of up to ~10kHz, phase-locking is used. The firing of the nerve fibre coincides with the rising of the basilar membrane causing a depolarization of the hair cell. The firing of the fibre is thus at the same frequency as that of the sound whose signal it carries. This is important because the fibre may not fire on every cycle, especially at the higher frequencies. The position of the hair cell along the basilar membrane is the other way in which frequency is encoded in the afferent fibres (known as tonotopicity). Intensity is encoded simply in the number of action potentials. An increased amplitude of the sound wave causes an increased depolarization in the hair cells, and thus an increased amount of transmitter is released. Sound localization, although contributed to by colouration in the outer ear (see above), is primarily mediated by two binaural processes:

  • The sound-shadow of the head causes intensity differences between the two ears. Intensity differences are measured by cells in the lateral superior olive that receive excitatory inputs from the contralateral cochlea and inhibitory inputs from the ipsilateral cochlea. Thus, the cells are activated if the sound source is on the contralateral side. Intensity differences are used for frequencies in the range of ~1.5–20kHz
  • Phase differences occur because the distance to the sound source is different from each ear when the head is turned towards or away from the source. This cue is used for lower frequencies, in the range of ~40Hz–3kHz, and is measured by coincidence detectors in the medial superior olive (Deafness, OHCM6 p.348).

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Primary auditory cortex (area A1) is located on the superior temporal gyrus. Area A1 contains several tonotopic maps, in a typical columnar organization. The columns are arranged in patterns of summation (binaural) and suppression (one ear dominant). Pitch is represented bilaterally, so that unilateral lesions have little effect on pitch discrimination, while sound source location is represented contralaterally. Higher auditory areas concerned with speech are:

  • Wernicke’s area, which is located in the temporal lobe (usually left) and is involved in speech perception
  • Broca’s area, which is located in the frontal lobe (usually left) and is involved in speech expression.

Lesions of these sites result in receptive and expressive dysphasias, respectively (OHCM6 p.58). There is much feedback to earlier stages of the auditory pathways (to the MGN, IC, and D/VCN, but not to the cochlea), most likely having a role in attention, giving rise to the ‘cocktail party effect’ of being able to single out a sole voice amid a noisy crowd. P.726
Vestibular system The vestibular system measures linear and angular acceleration of the head. The sensory organs of the vestibular system are found in the inner ear, which is divided into two portions: bony and membranous labyrinths. There are two principle structures in the vestibular part of the membranous labyrinth:

  • The otolith organs (utricle and saccule)
  • The semi-circular ducts.

Both the otolith organs and the semi-circular ducts are filled with endolymph, which has a similar chemical constitution to intracellular fluid. Each semi-circular duct arises and joins back to the utricle in a circular loop. Each duct is oriented at 90° to the other two. At one end of each duct there is a dilation of the duct (the ampulla) containing the hair cells. The hair cells are similar to those of the auditory system, each having a row of stereocilia arranged in order of height at their apex, of which the tallest is thicker and known as the kinocilium. The apices of the hair cells are embedded in the cupula, a gelatinous membrane stretching from the ampullary crest to the roof of the duct, thus completely occluding the lumen of the duct. Angular acceleration of the head causes the cupula to move, due to the inertia of the endolymph in the ducts and, therefore, the stereocilia on the hairs cells are pushed to one side. The tips of the stereocilia on each hair cell are linked, so when the cupula moves and the stereocilia bend, the tip-links slacken or tighten, depending on which way the head is rotated. Tightening of the tip-links opens stretch-activated non-selective cation channels, which allow K+ influx from the endolymph down an electrical gradient (there is no chemical gradient). The utricle has a zone called the macula, which is covered with hair cells. The otolithic membrane—a layer of a gelatinous substance in which are embedded crystals of calcium carbonate (the otoliths)—lies over the stereocilia of these hair cells. The macula lies in the horizontal plane such that when the head is upright, the otoliths rest on it. When the head tilts, the otoliths deform the gelatinous membrane and therefore bend the stereocilia on the hairs cells. The utricle is thus sensitive to horizontal, linear forces. The axes of the stereocilia on the hair cells form an approximately radial pattern over the macula, in order to sense linear forces in any horizontal direction. The saccule has a similar structure, but is vertically orientated so it is sensitive to any vertically directed linear force. Pathways The vestibular organs are innervated by the VIIIth cranial (vestibulocochlear) nerve. These fibres terminate in the vestibular nuclei. The vestibular nuclear complex comprises four nuclei.

  • The lateral vestibular nucleus is functionally related to the control of posture, with vestibular inputs primarily in the ventral portion of the nucleus and cerebellar and spinal inputs going to the dorsal portion
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  • The medial and superior vestibular nuclei control the vestibulo-ocular reflexes. These reflexes are important for maintaining a stable eye position when the head is moved
  • The inferior vestibular nucleus (along with input from the cerebellum) mediates the vestibulospinal and vestibuloreticular pathways.

Disorder of vestibular system or its central connections results in vertigo, an illusion of rotatory movement (OHCM6 p.346). P.728
Gustatory system Taste is mediated by chemical receptor cells. The chemoreceptors are epithelial cells clustered in sensory organs called taste buds. Each taste bud contains around 50 to 150 taste receptors. Taste buds are found in the papillae (numerous projections) of the tongue. There are three types of papillae:

  • Fungiform papillae contain between one and five taste buds and are found on the anterior two thirds of the tongue
  • Foliate papillae contain thousands of taste buds and are found on the posterior edge of the tongue
  • Circumvallate papillae also contain thousands of taste buds and are found on the posterior one third of the tongue.

Receptors have microvilli on their apical membrane that extend through an opening in the surface of the tongue, known as a taste pore, to reach the oral cavity. There are four classes of taste receptor: bitter, sweet, sour, and salty. There is also mixed evidence for a fifth class for monosodium glutamate. Different receptor classes are distributed in broadly distinct regions around the tongue. There is a maximum density of each type in different locations, but each type can be found all over. Taste receptors contain voltage-gated Na+, K+, and Ca2+ channels, similar to those in neurones, which are capable of generating action potentials. However, receptors appear to signal taste through graded subthreshold membrane potentials. The mechanism of transduction differs between the four submodalities:

  • Bitter stimuli cause release of Ca2+ from intracellular stores, triggered by IP3 or cAMP second-messenger pathways. The raised Ca2+ concentration leads to transmitter release
  • There are two putative mechanisms for transduction of sweet tastes. In the first, the ‘sweet’ molecule directly activates a Na+-specific channel that depolarizes the cell. This hypothesis is supported by evidence that the depolarization has a reversal potential near the Na+ equilibrium potential, and that the depolarization is blocked by amiloride. In the second, adenylate cyclase is activated via a G-protein, causing an increase in intracellular cAMP concentration. cAMP closes a voltage-dependent K+ channel that is open at the normal resting potential, causing depolarization. It is possible that both mechanisms act in ‘sweet’ receptors, or that there are two types of sweet receptor, one with each mechanism
  • Sourness is the taste associated with acids, which are thought to pass directly into the receptor cells through the cell membrane. The acids block voltage-dependent K+ channels in the apical membrane, but do not diffuse across the cell in sufficient quantities to block voltage-gated Na+ and Ca2+ channels in the basolateral membrane. This alteration in the balance of the resting ion flux results in the depolarization of the cell
  • Saltiness is thought to be mediated through a direct binding of the active molecules to a voltage-independent, amiloride-sensitive, cation channel. Opening of this channel allows Na+ influx and thus depolarization.

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Central pathways Receptor cells form chemical synapses with primary afferent fibres. Primary afferent fibres innervate several receptor cells within a number of taste buds in several papillae. Fibres thus have highly distributed innervations with complex and overlapping receptive fields. A branch of the VIIth (facial) cranial nerve (the chorda tympani) innervates the anterior two thirds of the tongue, while the lingual branch of the IXth (glossopharyngeal) nerve innervates the posterior third. Cell bodies of the chorda tympani are in the geniculate ganglion, and those of the glossopharyngeal nerve in the petrosal ganglion. There are also some taste buds on the palate, innervated by the greater superficial petrosal branch of VII, and on the epiglottis and oesophagus, innervated by the superior laryngeal branch of X (vagal), whose cell bodies lie in the nodose ganglion. Gustatory afferents from VII, IX, and X enter the solitary tract in the medulla, synapse in the gustatory nucleus, in the rostral and lateral part of the solitary nuclear complex, and project, via the central tegmental tract, to the ventral posterior medial nucleus of thalamus, and thence to the area of primary somatosensory cortex that represents the tongue, on the postcentral gyrus, and to the insular cortex deep in the Sylvian sulcus. Taste is represented in a specialized area of primary somatosensory cortex, next to the area that represents touch sensation on the tongue. Spatial segregation of receptor subtypes in the tongue is preserved in the gustatory nucleus, thalamus, and cortex. P.730
Olfactory system Smell is mediated by chemoreceptor, that have a very high sensitivity to odorant molecules. They can detect molecules at concentrations as low as a few parts per trillion. Receptors are located in a specialized region of olfactory epithelium, deep in the nasal cavity, which consists of receptor cells, supporting cells and basal cells. Olfactory receptors are bipolar cells (Fig. 11.47). One end is short and extends to the mucosal surface where it expands into an olfactory knob. The other end is longer and forms an unmyelinated axon that projects through the cribriform plate to the ipsilateral olfactory bulb, on the undersurface of the frontal lobe. These axons join together in bundles of ten to a hundred, surrounded by Schwann cells, to pass through the cribriform plate as olfactory nerves. Olfactory receptors have a lifetime of ~60 days and so, unusually for neurones, are constantly replaced. However, the post-synaptic cells in the olfactory bulb do not regenerate, and must continually make fresh connections with each new generation of receptors. Transduction The olfactory knob has several cilia, which form a dense mat at the mucosal surface. Odorants in the mucus are bound by an olfactory binding protein to enable cilia to interact with odorant molecules in the layer of mucus that covers this surface. Binding of odorants by membrane proteins causes an increase in intracellular cAMP concentration via a G-protein effect on adenylate cyclase. Depolarization arises through a cAMP-gated Na+ channel, in a process homologous to phototransduction in the retina. There is also evidence for depolarization mediated through an IP3 (inositol triphosphate) second-messenger system, without a change in the cAMP concentration. There is a large family of olfactory receptors which are thought to act together, rather like the three cone types in colour vision, to give a very wide range of smells that can be discriminated. Central pathways The olfactory bulb is divisible into four layers:

  • In glomeruli, receptor axons synapse onto mitral cells, tufted cells, and periglomerular cells
  • The external plexiform layer contains tufted cell bodies and the dendritic trees of granule cells
  • The mitral body layer contains mitral cell bodies
  • The granule layer contains the axons of mitral cells and granule cells, and granule cell bodies.

Mitral and tufted cells form the output from the olfactory bulbs, and their axons form the olfactory tract. Periglomerular cells and granule cells are inhibitory interneurones. Granule cells also receive efferent fibres from both olfactory nuclei. Axons in the olfactory tract project to the anterior olfactory nucleus, the olfactory tubercle, the pyriform cortex, the cortical nucleus of the amygdala, and the entorhinal cortex. The anterior olfactory nucleus projects to the contralateral olfactory bulb via the anterior P.731
commissure, and thence back to the contralateral olfactory bulb. The olfactory tubercle and pyriform cortex project to other olfactory cortical regions and to the medial dorsal nucleus of the thalamus, and thence to orbitofrontal cortex, which is associated with conscious perception of smell. The amygdala and entorhinal cortex are part of the limbic system, and are involved in the affective components of smell perception. There is no topographic central representation of olfaction, as there is with other sensory modalities. However, glomeruli seem to have preferential sensitivities to certain odours over others, so there is clearly a distributed representation of odour.

Fig. 11.47 Simplified representation of the cell types of the olfactory bulb and their connections—p (periglomerular cells); g (granule cells). (Reproduced with permission from Carpenter R (2003), Neurophysiology, 4th edn, Edward Arnold.)

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Motor Control The reflex arc Movement of muscles can broadly be divided into two categories: reflex and voluntary. Reflex movements are involuntary; they do not require a command from the brain to happen. Voluntary movements are entirely dependent on a signal from a specific region of the brain—the motor cortex—to be implemented.

  • Reflex responses are movements that are made very rapidly (~20msec; 0.02sec) in response to a stimulus that is sensed by specific sensory receptors. These tend to be defensive reflexes that must be made quickly in order to avoid injury (e.g. hand withdrawal when placed on a hot surface)
  • The speed of the response is facilitated by limiting the number of neurones (and hence synapses) involved. The fastest responses are mediated by monosynaptic reflexes (Fig. 11.48), whereby there is only one synapse, located in the spinal cord, between the sensory neurone and the motor neurone (e.g. the knee-jerk reflex)
  • Polysynaptic reflex arcs include interneurones in the spinal cord (Fig. 11.49) which connect the sensory neurone to the motor neurone. These reflexes are marginally slower than monosynaptic reflexes but are still considerably faster than conscious movements that require input from the brain. The role of the interneurone is often to modulate the signal to the motor neurone; an excitatory signal from a sensory neurone can stimulate an inhibitory interneurone, resulting in inhibition of the motor neurone (e.g. Golgi tendon organs)
  • Far more complex reflexes are constantly called upon to react to assimilated information from sensory organs like the eyes and balance centre of the ear, just to stay upright.
Fig. 11.48 Monosynaptic reflex arc.
Fig. 11.49 Polysynaptic reflex. An interposed inhibitory interneurone results in reduced stimulation of the α-motor neurone, leading to muscle relaxation.

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Motor cortex ‘Conscious’ movement is a collective term that includes those movements that we actually think about before we carry them out, as well as those which we are so familiar with that we don’t apparently think about, but that still originate from the brain (e.g. movements associated with walking—p.738). Instructions for these movements originate in the motor cortex, an area of the cerebral cortex, located just anterior to the somatic sensory cortex (Fig. 11.50). Movement of a particular part of the body is controlled from a clearly defined area of the motor cortex—the more highly used a particular muscle, the bigger the area devoted to that muscle in the motor cortex. The relative size of areas devoted to different regions of the body are often represented as a ‘map’ or motor homunculus (Fig. 11.51), distorting those areas of the body that have large areas of the cortex devoted to them so that they are considerably larger than those that are poorly represented in the motor cortex. The motor homunculus for humans shows that most of our cortex is devoted to our hands, face, and tongue, indicative of the importance of these features to us. Different species will have vastly different homunculi, reflecting those motor skills that are most important to each species. Descending pathways Signals originating in the motor cortex are transmitted by either the pyramidal (corticospinal) system or the extrapyramidal (extracorticospinal) system to α and γ motor neurones in the relevant segment of the spinal cord for a specific muscle.

  • The pyramidal system (Fig. 11.52) employs a single neurone with an axon that passes all the way from the cerebral cortex to the relevant segment of the spinal cord without any intervening synapses. The nerves from the left motor cortex cross over to the right side of the spinal cord at the base of the brain, in the pyramidal decussation. Thus, the left hemisphere of the brain controls the movement of muscles on the right side and vice versa
  • The extrapyramidal system (Fig. 11.53) is far more complex than the pyramidal system, largely because it includes a number of different pathways and involves a greater number of synapses. Although the extrapyramidal system is anatomically distinct from the pyramidal system, the two interact because the extrapyramidal system assimilates information from a wide range of sensory inputs, whereupon it modifies the motor signals in the pyramidal tract. For this reason, the extrapyramidal tract is seen to be central to producing smooth, controlled movements and maintaining posture. The extrapyramidal system includes nerves in the basal ganglia of the brain (p.736), the reticular formation in the brainstem (which determines the level of consciousness—p.754), and the brainstem nuclei.
Fig. 11.50 Location of motor cortex and associated areas of the brain.
Fig. 11.51 Motor homunculus (right hemisphere). Reproduced with permission from Kandel E, Schwartz JH, and Jessell TM (2000). Principles of Neural Science, 4th edn. © The McGraw-Hill Companies Inc.

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Basal ganglia and cerebellum The basal ganglia at the base of the brain receive nervous input from both the sensory and motor cortex. Nervous outflow from the basal ganglia is exclusively to the areas involved in higher processing of movement, namely the pre-frontal, pre-motor, and supplementary motor cortex; there is no output to the spinal cord. The primary role of basal ganglia is thought to be related to the planning and control of complex motor behaviour by selectively activating some movements and suppressing others. These functions are highlighted in patients with Parkinson’s disease, where the cells of the basal ganglia degenerate and motor control is compromised (OHCM6 p.386) (p.775). The cerebellum acts in concert with the motor cortex and basal ganglia to co-ordinate movement. In simple terms, the cerebellum can be seen to control fine motor tasks by constantly comparing ‘intention’with ‘performance’. It receives input from a vast array of sensory nerves that allow it to compute the actual position of limbs and compare this information to the intended position. The net result is an error calculation, which is translated into an output signal via Purkinje fibres to make fine adjustments to correct the error. The role of the cerebellum in modulating motor output from the pyramidal and extrapyramidal systems, rather than instigating movement itself, is highlighted in patients with damage to the cerebellum. These individuals are not paralysed and still receive sensory information as normal, but they are unable to co-ordinate movements in complex, or even quite simple tasks requiring motor control and timing. Lesions to the cerebellum give rise to a characteristic set of clinical signs (OHCM6 p.387). It is now recognized that the cerebellum is also important in some aspects of speech recognition and learned responses, but not memory.

Fig. 11.52 The pyramidal system for motor control.
Fig. 11.53 Main structures of the extrapyramidal system. Reproduced with permission from Kandel E, Schwartz JH, and Jessell TM (2000). Principles of Neural Science, 4thedn. © The McGraw-Hill Companies Inc.

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Locomotion Walking may seem an automatic and straightforward task, but from a neuromuscular standpoint, it is highly complex and involves motor control of the majority of our skeletal muscles. The key to the neuronal control of locomotion is so-called ‘pattern generation’, where a set of commands are relayed to all the relevant muscles so that they contract and relax in the correct order; on completion of one cycle of the task, the same set of commands is repeated so that a pattern of movement is instigated. The neural circuit must also include suitable facilities to modify the pattern to take into account any changes in the environment and to stop the pattern of movement. Pattern generators Neural control of locomotion stems from the spinal cord—it does not necessarily require instructions from the brain but does require sensory information from the limbs that are involved. Locomotion can be best described as a series of reflexes in response to incoming sensory information (e.g. from the Golgi tendon organs and the muscle spindles) about the position of the limb in motion. Much of the experimental work relating to pattern generation has been conducted in more primitive vertebrates, where neural circuits can be more easily identified and characterized. These studies clearly show that although basic pattern generation originates in the spinal cord in response to sensory information, higher centres in the brain, including the cerebellum, basal ganglia, sensory and motor cortices are necessary to accommodate variation in locomotion and adaptability in response to the environment (e.g. response to a trip) (Fig. 11.54).

  • The cerebellum sends modulating signals to motor neurones, via the descending pathways, to fine-tune the movements of the crude, ungainly gait that originates from pattern generators in the spinal cord. It also modulates activity to adjust the walking pattern to accommodate changes in the terrain (e.g. going up or down stairs)
  • The basal ganglia are required to initiate movement and to help compute visual and sensory information from the parietal cortex, and generate appropriate spatially directed movement towards a given goal
  • The parietal cortex collects visual and somatosensory information and collates it into a 3D representation of position with respect to environment.
Fig. 11.54 Pattern generation for locomotion originates in the spine; modulation is controlled by the cerebellum.

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Thalamus and Hypothalamus Anatomy and function of the thalamus The thalamus (Fig. 11.55) is a bilateral structure located in the diencephalon, a brain structure found between the midbrain (the most rostral part of the brainstem) and the cerebral hemispheres. Almost all of the sensory and motor information that reaches the cortex is processed by the thalamus. As such it is composed of several sensory nuclei that receive input from distinct sensory stimuli such as vision, hearing, and somatic sensation. The main exception is olfaction, that has a direct pathway to the sensory cortex. Projections from the thalamus to the sensory cortex initiate the processing of sensory information, while projections to the association cortex (a region associated with movement, perception, and motivation) results in the initiation of a behavioural response to sensory input. Other thalamic nuclei relay information concerning motor activity to the motor cortex. For example, extrapyramidal motor information from the cerebellum and basal ganglia is relayed, via the thalamus, to the primary motor cortex. A large fibre bundle (the internal capsule) carries thalamic projections to and from the cortex. As a consequence, the function of the thalamic nuclei is also modulated by feedback from the cortex through recurrent projections from the same cortical regions to which they project. Nuclei within the thalamus function either as relay nuclei or diffuse projection nuclei:

  • Relay nuclei generally process either sensory information resulting from a specific type of stimulus (e.g. vision, hearing, somatic sensation) or input from a particular part of the motor system. These relay nuclei send axonal projections to a region of the cerebral cortex that is also anatomically restricted and defined by the source of input it receives. For example, visual information from the retina is processed by the lateral geniculate nucleus in the thalamus and this projects to a spatially restricted region of the cortex termed the visual cortex
  • Diffuse projection nuclei are perceived to be involved in mechanisms that regulate the state of arousal of the brain. Their connections are more widespread than the relay nuclei and they include projections to other thalamic nuclei.

The functional anatomy of the thalamus

  • Nuclei of the thalamus are anatomically divided into six groups, separated by a Y-shaped collection of fibres termed the internal medullary lamina
  • Lateral, medial, and anterior nuclei are named by their location relative to this lamina, the remaining groups being the intra-laminar, reticular, and midline nuclei
  • The lateral nuclei are subdivided into dorsal and ventral groups and each sub-division can be defined by its restricted connections with a specific region of motor or sensory cortex. These relay nuclei therefore perform processing of specific sensory or motor input.
Fig. 11.55 The major subdivisions of the thalamus. The thalamus is the critical relay for the flow of sensory information to the neocortex. Somatosensory information from the dorsal root ganglia reaches the ventral posterior lateral nucleus, which relays it to the primary somatosensory cortex. Visual information from the retina reaches the lateral geniculate nucleus, which conveys it to the primary visual cortex in the occipital lobe. Each of the sensory systems, except olfaction, has a similar processing step within a distinct region of the thalamus. Reproduced with permission from Kandel E, Schwartz JH, and Jessell TM (2000). Principles of Neural Science, 4th edn. © The McGraw-Hill Companies Inc.

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Motor relay nuclei (Fig. 11.56) Motor signals are principally relayed by the ventral lateral and ventral anterior nuclei. The ventral lateral nucleus receives information from the cerebellum and sends axons to both motor and premotor cortices, while the ventral anterior nucleus is innervated by the globus pallidus and projects primarily to the premotor cortex. Sensory relay nuclei (Fig. 11.57)

  • Somatic sensation is processed in the ventral posterior nucleus. The lateral division of the ventral posterior nucleus receives input via the spinothalamic tract and dorsal column, while the medial division receives input from the sensory nuclei of the trigeminal nerve. Thus, the former is involved in processing of somatic sensation from the body, while the latter is involved in facial sensory information processing. Both nuclei project to appropriate regions in the somatosensory cortex (parietal lobe)
  • The medial geniculate nucleus processes auditory information, receiving its major input from the inferior colliculus, and sends axons to the auditory cortex (temporal lobe)
  • Visual processing is performed by the lateral geniculate nucleus. It receives a direct input from the retina via the optic nerve and projects to the visual cortex
  • The lateral posterior and pulvinar nuclei play primary roles in the integration of sensory information by virtue of reciprocal connections between the parietal lobe and the temporal, occipital, and parietal lobes, respectively.

Limbic relay nuclei (Fig. 11.58)

  • The anterior group receives inputs from the hypothalamus and sends projections to the cingulate gyrus. This pathway constitutes part of the limbic system contributing to awareness and emotional aspects of sensory processing (p.756).
  • The lateral dorsal nucleus is involved in emotional expression and receives signals from, and sends them to, the cingulate gyrus
  • The medial dorsal nucleus is also involved in limbic processing, receiving input from the amygdala, hypothalamus, and olfactory system and sending axons to the prefrontal cortex.

Diffuse projection nuclei (Fig. 11.59)

  • The thalamic midline and intra-laminar nuclei are diffuse projection nuclei receiving input from the reticular formation, hypothalamus, globus pallidus, and several cortical areas
  • The reticular nucleus receives information from the cortex, other thalamic nuclei, and the brainstem. This information is largely distributed to other thalamic nuclei where it is used in the modulation of thalamic activity.
Fig. 11.56 Principal thalamic motor relay nuclei and their connections.
Fig. 11.57 Principal thalamic sensory relay nuclei and their connections.
Fig. 11.58 Principal thalamic limbic relay nuclei and their connections
Fig. 11.59 Thalamic diffuse projection nuclei and their connections.

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Cellular physiology of the thalamus-relationship with the sleep-wake cycle In the waking state, thalamic neurones that project to the cortex (TC neurones) are tonically depolarized by cholinergic, aminergic (noradrenergic, serotonergic, and histaminergic), and peptidergic (orexins) inputs from the brainstem and hypothalamus. This allows TC neurones to respond faithfully to incoming sensory and motor signals and, thus, ensures accurate transfer of this information to higher cortical areas. During NREM sleep (SWS p.750, Fig. 11.61), these brainstem and hypothalamic inputs diminish and TC cells first hyperpolarize, then switch to a pattern of slow membrane potential oscillations driven by intrinsic voltage-dependent ionic conductances in their neuronal membrane. Under these conditions, processing of externally sourced sensory and motor information is depressed. Thus, cortical processing is regulated by intrinsic excitation within the cortex and, possibly to some extent, waves of activity known as ‘spindle’ waves (because of their relatively high frequency) generated in the thalamus as a result of disinhibition of inhibitory GABA (γ-aminobutyric acid) neurones in the thalamic reticular nucleus. During REM sleep, it is thought that an internal representation of the external world becomes the input to the thalamo-cortical circuitry. This change in thalamic and cortical activity is thought to be important in the iteration of information and essential for processes such as learning and memory. P.745
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Anatomy of the hypothalamus The hypothalamus (Fig. 11.60), in addition to the thalamus, is also located in the diencephalon. Observed in a frontal section, three divisions—lateral, medial, and periventricular (immediately bordering the third ventricle)—can be identified. In medial section it can be divided into anterior, middle, and posterior areas along the rostro-caudal axis.

  • The medial forebrain bundle acts as a pathway from the hypothalamus to the neocortex and other parts of the brain. However, it also carries fibres not of hypothalamic origin such as aminergic fibres from brainstem nuclei
  • The lateral region sends both long-distance connections to the cortex and spinal cord as well as shorter axons to ascending and descending pathways
  • Defined nuclei in the medial region of the hypothalamus include:
    • The preoptic and suprachiasmatic nuclei (SCN) in the anterior region (sleep and circadian regulation)
    • The dorsomedial, ventromedial, and paraventricular nuclei (PVN) in the middle region
    • The posterior nucleus and mammillary bodies in the posterior region.

Most nuclei have bidirectional fibre systems, sending and receiving signals via the medial forebrain bundle, mamillotegmental tract, and dorsal longitudinal fasciculus. There are two exceptions—supraoptic and paraventricular neurones project, via the hypothalamohypophyseal tract, to the posterior pituitary (see below), while the SCN receives a unidirectional input from the retina (see below and p.714). Afferent hypothalamic connections and function The hypothalamus has a major role in maintaining homeostasis through its regulation of the autonomic nervous system, the endocrine system, and visceral function. These functions are carried out through both conventional, direct, synaptic contacts and indirect neurohormonal pathways that involve an intimate regulatory influence over the function of the pituitary. By receiving information from, and acting directly on, the internal environment, the hypothalamus regulates body functions including temperature, heart rate, blood pressure, blood osmolarity, and water and food intake. In addition, extensive connections throughout the central nervous system provide routes for both direct and processed sensory information to modulate hypothalamic activity and influence behavioural processes. Direct connections between the limbic system (p.756) and the hypothalamus regulate autonomic and visceral responses associated with motivation and adaptive emotional behaviour. The limbic system also exerts control over the endocrine system through its regulation of the secretion of hypothalamic hormones. The influence of the cortex on the hypothalamic expression of emotional behaviour is through a pathway involving the cingulate gyrus and hippocampus, while a reciprocal P.747
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influence of the hypothalamus exists via the mammillary bodies, the anterior nucleus of the thalamus, and the cingulate gyrus.

Fig. 11.60 The structure of the hypothalamus. A. Frontal view of the hypothalamus (section along the plane shown in part B). B. A medial view shows most of the main nuclei. The hypothalamus is often divided analytically into three areas in a rostocaudal direction: the preoptic area, the tuberal level, and the posterior level. Reproduced with permission from Kandel E, Schwartz JH, and Jessell TM (2000). Principles of Neural Science, 4th edn. © The McGraw-Hill Companies Inc.

Another component of the limbic system, the amygdala, also has direct projections to the hypothalamus and this region has been implicated in learning, particularly tasks that might involve associating stimuli with an emotional response. Efferent hypothalamic connections and function The hypothalamus exerts a major influence over the pituitary gland thereby regulating metabolism, feeding, water homeostasis, and the circadian timing of physiology and behaviour. Connected to the hypothalamus by the infundibulum, the anterior pituitary is controlled by substances secreted primarily from small, peptidereleasing neurones found in the basal part of the middle region of the hypothalamus. Parvocellular (small) neurones located primarily in the PVN, but also the periventricular region and the preoptic nucleus, release peptides into the local plexus of blood vessels that drain into the vasculature of the anterior pituitary. These hormones then act to promote or inhibit the production of anterior pituitary hormones. For example, corticotropinreleasing hormone (CRH) promotes the release of adrenocorticotrophic hormone (ACTH) from the anterior pituitary and this induces cortisol release by the adrenal cortex—an important mediator of the stress response. Other hypothalamic hormones that act on the pituitary in this way include thyrotropin-releasing hormone (TRH), leading to thyrotropin production and regulation of growth and metabolism gonadotropinhormone releasing hormone (GnRH), stimulating follicle-stimulating hormone (FSH) and luteinizing hormone (LH) release and, thus, controlling gametogenesis; growth hormone-releasing hormone (GRH); somatostatin; and dopamine. In addition to this indirect pathway, magnocellular (large) neurones located in the PVN and supraoptic nucleus project to the posterior pituitary and directly release hormones into the circulation. In this way, water homeostasis is maintained by releasing the peptide, vasopressin, while the release of another peptide, oxytocin, controls uterine contraction and milk ejection. The temporal organization of hormonal release and behavioural patterns is dictated by the suprachiasmatic nucleus (SCN). This nucleus generates an endogenous circadian pattern that entrains many physiological processes to the light-dark cycle. Unidirectional input to the SCN from the visual system synchronizes the circadian clock to day length. The SCN itself has minimal projections, mainly to other parts of the hypothalamus. Thus, temporal synchronization of biological processes involves intrahypothalamic interactions and output from other hypothalamic nuclei. P.749
Other functions of the hypothalamus

  • Direct connections from the PVN to sympathetic preganglionic neurones in the intermediolateral cell columns of the thoracic and lumbar spinal cord as well as projections to parasympathetic nuclei in the brainstem indicate direct neuronal control of the autonomic motor nervous system. This control is regulated by the sensitivity of the hypothalamus to stimuli in the blood such as glucose and insulin
  • Visceral sensory information from the major organs is directed to the paraventricular and lateral hypothalamic nuclei via brainstem sensory nuclei, including the nucleus of the solitary tract
  • Hypothalamic involvement in sleep appears to involve at least three nuclei. Histamine-releasing neurones of the tuberomammillary nuclei that project to the cortex are inhibited during sleep by ventrolateral preoptic neurones, thereby reducing histamine release, a neurotransmitter implicated in arousal. Other hypothalamic nuclei are involved in wider serotonergic and noradrenergic pathways that regulate arousal. In addition, the circadian timekeeping associated with the SCN (see above) is also implicated in the timing and modulation of sleep patterns
  • Sexual dimorphisms in the hypothalamus of animals implicate a role in sexual behaviour as well as gametogenesis. Although well established in animals, evidence for similar dimorphisms in the human hypothalamus is less secure. Nevertheless, structural differences between the male and female hypothalamus, particularly in the preoptic nucleus, have been identified.

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Higher Function Sleep (Fig. 11.61) The passive electroencephalogram reveals rhythms of activity at four different frequencies:

  • Alpha rhythm (8-13Hz) characterizes the awake but resting EEG
  • Faster beta waves are associated with mental activity (>13Hz)
  • Higher frequency gamma rhythm (35-45Hz) may be a signature of the waking state
  • Slower rhythms, theta (4-7Hz) and delta (< 3.5Hz), are more common during reduced arousal in adults.

Two types of sleep can be defined using electrophysiological features detected with electroencephalography (EEG), electroculography (EOG), and electromyography (EMG)—rapid eye movement (REM, paradoxical) and non-REM (NREM, slow wave sleep, SWS), see Fig. 11.61. NREM sleep

  • NREM sleep occupies ~75% of sleep time and is predominantly associated with delta activity, while activity more like that seen during the waking state characterizes REM sleep. This is despite the individual being difficult to arouse at this point—hence the alternative term of paradoxical sleep
  • In general, NREM sleep is characterized by synchronized activity in the brain, while activity during waking and REM sleep is desynchronized
  • Four stages of NREM sleep have been defined, related to the depth of sleep and the increasing dominance of low-frequency synchronized wave activity in the EEG:
    • Stage 1 shows a slowing of the frequency of wave activity
    • In stage 2, the EEG displays distinctive bursts of high-frequency activity (spindles)—thought to be of thalamic origin (p.744)
    • In stages 3 and 4 (SWS), low-frequency, synchronized wave activity dominates the EEG.

REM sleep REM sleep is characterized by ‘wake-like’ EEG activity (low-amplitude, high-frequency gamma waves, 30-80Hz), clusters of eye movements in the EOG, and low muscle tone (atonia) in the EMG. Processes

  • Neuronal networks in the pons, midbrain, thalamus, hypothalamus, and basal forebrain (all of which regulate the rostral cerebral hemispheres) control wakefulness, NREM, and REM sleep
  • The areas of the brain implicated in arousal lie predominantly, but not exclusively, in the reticulum of the brainstem and midbrain (mesopontine junction—a region of the rostral brainstem containing the laterodorsal tegmental nucleus, pedunculopontine nucleus, dorsal raphe nucleus, and the locus coeruleus). An increase in activity in this ascending reticular activating system (ARAS) is suggested to underlie arousal
    Fig. 11.61 Behavioural states in humans. States of waking, NREM sleep and REM sleep have behavioural, polygraphic and psychological manifestations. In the row labelled behaviour, changes in position (detectable by time-lapse photography or video) can occur during waking and in concert with phase changes of the sleep cycle. Two different mechanisms account for sleep imobility. The first is disfacilitation (during stages I–IV of NREM sleep). The second is inhibition (during REM sleep). During dreams, we imagine that we move, but we do not. Sample tracings of three variables used to distinguish the state are shown: an electromyogram (EMG), an electroencephalogram (EEG) and electrooculogram (EOG). The EMG tracings are highest during waking, intermediate during NREM sleep and lowest during REM sleep. The EEG and EOG are both activated during waking and inactivated during NREM sleep. Each sample shown is approximately 20 seconds long. The three bottom rows describe other subjective and objective state variables. Reproduced with permission from Hobson JA (2005). Nature, 437, 1254–6. © Macmillan Publishers Ltd.
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  • The neurotransmitter systems that are prominently involved include the noradrenergic (locus coeruleus), serotonergic (5-HT, dorsal raphe) histaminergic (hypothalamus), cholinergic (pons/midbrain), and orexin/hypocretin (hypothalamus)
  • In general, the release of these neurotransmitters is under the control of both circadian (light-dark cycle—SCN in the hypothalamus) and homeostatic (fatigue) influences
  • The major projection of the ARAS is the thalamus—a critical relay for sensory and intra-cerebral pathways (p.740). In the absence of activity in the ARAS, the thalamus and the cortex tend towards slow wave activity and unconsciousness
  • The transfer into NREM sleep is associated with a reduction in activity of these networks
  • The length of the NREM/REM cycle is also determined by signals from cholinergic and aminergic neurones. During NREM sleep, aminergic signalling dominates. However, the transition to REM sleep involves reduced activity of aminergic systems and an increase in cholinergic activity. During REM sleep, aminergic signalling is silent and cholinergic excitatory activity is dominant
  • The termination of REM sleep is driven by increased noradrenergic and serotonergic system activity
  • NREM and REM activity alternate in each of four or five ~90-minute cycles each night. NREM is deeper and longer early in the night while, in later cycles, REM sleep occupies progressively longer periods of the cycle (p.750)
  • NREM sleep appears associated with conservation of energy and repair mechanisms, thereby suggesting a restorative function, though it has also been suggested to function in the iteration of information
  • The brain activity associated with REM sleep may be important in brain development and plasticity. A widely supported idea is that memory consolidation is a major function of REM sleep.
  • The disruption of metabolic homeostasis that results from severe sleep deprivation can lead to death emphasizing the crucial role of sleep.

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Consciousness

  • In healthy individuals, three main states of consciousness are recognized-wakefulness, NREM sleep, and REM sleep
  • Awareness might also be regarded as an aspect of consciousness, as we are aware, whether awake or dreaming. Nevertheless, analysis is difficult because someone other than the ‘aware’ individual interprets awareness on the basis of objective parameters such as behavioural or neuronal activity
  • The conscious state can be usefully assessed using objective criteria such as those in the Glasgow Coma Scale (p.755)—though it may be limited if the patient is prevented from making the usual responses to consciousness (e.g. by paralysis). The Glasgow Coma Scale includes numerically graded assessment of three parameters—eye opening, motor function, and verbal responsivity
  • Altered consciousness states, as a result of some pathology, range from coma, vegetative state, to brainstem death:
    • Coma is a state of continuous unconsciousness in the absence of a sleep-wake cycle. The degree to which an individual responds varies significantly, as does the level of cerebral metabolism. Coma may represent a transitional state between full recovery, re-establishment of the sleep-wake cycle with impaired awareness, or brainstem death
    • Brainstem death is associated with irreversible loss of all brainstem functions
    • The vegetative state illustrates distinctions between the underlying brain systems for wakefulness and awareness. In this state, several behaviours suggest wakefulness but any sense of purpose or attempts to communicate are absent. The vegetative state is often the result of severe brain injury (trauma/hypoxia/ischaemia) yet, while autopsies reveal damage to any or all of the cortical mantle, cerebral white matter, and thalamus, the brainstem networks associated with wakefulness are unaffected.

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The Glasgow coma scale (GCS) (OHCM6 p.776) This gives a reliable, objective way of recording the conscious state of a person. It can be used by medical and nursing staff for initial and continuing assessment. It has value in predicting ultimate outcome. 3 types of response are assessed: Best motor response This has 6 grades: 6 Carrying out request (‘obeying command’): The patient does simple things you ask (beware of accepting a grasp reflex in this category). 5 Localizing response to pain: Put pressure on the patient’s fingernail bed with a pencil then try supraorbital and sternal pressure: purposeful movements towards changing painful stimuli is a ‘localizing’ response. 4 Withdraws to pain: Pulls limb away from painful stimulus. 3 Flexor response to pain: Pressure on the nail bed causes abnormal flexion of limbs—decorticate posture. 2 Extensor posturing to pain: The stimulus causes limb extension (adduction, internal rotation of shoulder, pronation of forearm)—decerebrate posture. 1 No response to pain. Note that it is the best response of any limb which should be recorded. Best verbal response This has 5 grades: 5 Oriented: The patient knows who he is, where he is and why, the year, season, and month. 4 Confused conversation: The patient responds to questions in a conversational manner but there is some disorientation and confusion. 3 Inappropriate speech: Random or exclamatory articulated speech, but no conversational exchange. 2 Incomprehensible speech: Moaning but no words. 1 None. Record level of best speech. Eye opening This has 4 grades: 4 Spontaneous eye opening. 3 Eye opening in response to speech: Any speech, or shout, not necessarily request to open eyes. 2 Eye opening in response to pain: Pain to limbs as above. 1 No eye opening. An overall score is made by summing the score in the 3 areas assessed. Eg: no response to pain + no verbalization + no eye opening = 3. Severe injury, GCS ≤8; moderate injury, GCS 9-12; minor injury, GCS 13-15. NB: An abbreviated coma scale, AVPU, is sometimes used in the initial assessment (‘primary survey’) of the critically ill:

  • A = alert
  • V = responds to vocal stimuli
  • P = responds to pain
  • U = unresponsive

Some centres score GCS out of 14, not 15, omitting ‘withdrawal to pain’. NB: The GCS scoring is different in young children. P.756
The limbic system The limbic system functions as an integrator of information from the external world and from within the body. Its proposed role is in the generation of emotional experience. Anatomically, the limbic system consists of the limbic lobe, a ring of cortex around the brainstem comprising the parahippocampal gyrus, the cingulate gyrus, and the subcallosal gyrus (Fig. 11.62). In addition, the deeper lying hippocampal formation (including the hippocampus, dentate gyrus, and subiculum), the amygdala, parts of the hypothalamus, the septal area, the nucleus accumbens, and parts of the orbitofrontal cortex also contribute to the limbic system. Pathways between the association cortex, entorhinal cortex, the hippocampus, and amygdala provide a link between the neocortex and the limbic system. Thus, connections between the limbic system and higher cortical areas enable the integration of emotional processing with cognitive functions such as attention, memory, and reasoning. In addition, it is well established that the hippocampus is involved in processes of memory storage, while the amygdala has also been implicated in learning, particularly tasks that might involve the association of stimulus and emotional response. Both the amygdala and the hippocampus have direct, reciprocal connections with the hypothalamus. Pathways between the cortical cingulate gyrus, hippocampus, and hypothalamus extend the influence of the cortex over the hypothalamic expression of emotional behaviour. The amygdala has two major projections

  • The stria terminalis that innervates the hypothalamus and nucleus accumbens
  • The ventral amygdalofugal pathway that innervates the hypothalamus, dorsal medial nucleus of the thalamus, and the cingulate gyrus.

The connections between the limbic system and the hypothalamus regulate autonomic and visceral responses associated with motivational drives (food, water, sex) and emotional expression; they exert control over the endocrine system through its regulation of the secretion of hypothalamic hormones; and, through extensive connections with the sympathetic and parasympathetic nuclei of the brainstem and spinal cord, they exert influence over the autonomic motor system.

Fig. 11.62 The limbic system consists of the limbic lobe and deep-lying structures. (Adapted from Nieuwenhuys et al. 1988.) This medial view of the brain shows the prefrontal limbic cortex and the limbic lobe. The limbic lobe consists of primitive cortical tissue that encircles the upper brain stem as well as underlying cortical structures (hippocampus and amygdala). Reproduced with permission from Kandel E, Schwartz JH, and Jessell TM (2000). Principles of Neural Science, 4th edn. © The McGraw-Hill Companies Inc.

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Memory Much of our understanding of memory systems and their neurological basis originates from observations of patient H.M. who, after undergoing bilateral medial temporal lobe resection (including the hippocampal formation) in an attempt to cure intractable epilepsy, displayed an inability to learn or retain memories of events after the transection (anterograde amnesia) along with impaired recollection of memories in the few years preceding transection (retrograde amnesia). Nevertheless, longerterm memories could be retrieved and were intact. Interestingly, H.M. could learn some motor tasks and was able to retain some immediate and short-term information indicating a distinction between short- and long-term memory systems. Memory has been categorized into two types—declarative and nondeclarative. Declarative memory The formation and retrieval of explicit memories of facts and events specific to an individual and involving the conscious recollection of past experiences.

  • Episodic memory is the recollection of specific events occurring at a particular time and place. As seen in patient H.M., the medial temporal lobe, including the hippocampus, perirhinal cortex, and parahippocampal cortex, is involved in both the formation and retrieval of this form of memory. Also involved is the prefrontal cortex. Damage in these regions can impair the ability to:
    • Retrieve the time and place at which an event occurred
    • Distinguish temporally, two or more events
    • Recollect where or when a new task was learned.
  • Semantic memory involves the recollection of information not associated with time or place but relating more to meaning and function (e.g. of objects, words). It is also dependent on the medial temporal lobes, particularly the anterior and lateral regions of the left hemisphere—a localization that, despite its close relationship to episodic memory, clearly distinguishes semantic memory.

Non-declarative memory

  • Procedural memory relates to the acquisition of skills or habits. An intact cortico-striatal system, motor cortex, and cerebellum all appear important mediators of different types of procedural memory. Damage to the striatum, such as that seen in Huntington’s disease, impairs motor task learning without affecting declarative memory
  • The perceptual representation system is important in the recognition of objects by their structure or form. This is distinct from the meaning or function that can be attributed to semantic memory. This form of memory also includes priming, or the ability to recognize a partial object as a result of prior exposure to the whole object. The posterior cortical regions that are activated during this form of memory are also distinct from those involved in semantic memory. Thus, visual object form involves the extrastriate occipital cortex, while global object P.759
    structure involves areas at the interface between temporal and occipital cortices
  • Working memory, a form of memory used for the short-term retention of information important for problem solving or reasoning, can be severely disrupted by damage to the orbital frontal and medial frontal cortex, suggesting involvement of these regions in memory processes. Two sub-systems appear to operate in the transfer of working memory into long-term memory:
    • A phonological loop that allows rehearsal of speech-based information
    • A visuo-spatial map, located in the visual association cortex, inferior parietal lobule, and prefrontal cortex of the right hemisphere, that retains the visual and spatial information.

Associative and non-associative learning in non-declarative memory

  • Associative learning describes the linking of two events, whereas non-associative learning involves the influence of a single event on the probability that it elicits a response. Associative learning is typified by the classical conditioning experiments of Pavlov. Repeated pairing of a neutral (unconditioned) stimulus (bell ring) preceding one that evokes a response (conditioned stimulus, food) eventually leads to salivation in response to the bell ring—a conditioned response
  • The motor component of procedural associative memory, typified by the example of an eye-blink in response to a conditioned stimulus, is dependent on the cerebellum, even though the reflex eye-blink to an unconditioned stimulus is independent of cerebellar involvement. The hippocampus and amygdala, on the other hand, are both involved in storing the learning experience but not the acquisition of the motor response
  • Associative learning involving an unpleasant conditioned stimulus invokes mechanisms associated with fear and links emotion with memory. The amygdala plays a major role in emotional associative memory, along with the hippocampus and medial prefrontal cortex (p.762)
  • Non-associative learning, often expressed through reflex pathways, can involve a reduction in response (habituation), enhancement of a response (sensitization), or the removal of habituation by another, more powerful, stimulus (dishabituation).

Molecular and cellular mechanisms of learning and memory Current ideas of the cellular basis of learning and memory revolve around mechanisms that lead to the selective strengthening or weakening of synaptic connections between neurones. Experimentally induced cellular mechanisms such as long-term potentiation (LTP) and long-term depression (LTD), involving the strengthening or weakening of synapses, respectively, have been proposed as cellular correlates for learning and memory. The changes in synaptic strength in LTP and LTD are mediated by alterations in transmitter release and/or the insertion or removal of post-synaptic receptors. Both types of molecular event have been observed at synapses in pathways involved in the acquisition of particular tasks. P.760
Ageing With normal ageing (senescence), most individuals suffer some form of cognitive impairment that, while being short of dementia, can be problematic for quality of life. Mental capabilities most likely to show agerelated impairment include aspects of memory, executive functions, and reasoning. It is significant that when one of these mental functions declines, so do the others. The impairment of these mental functions can be at least partially accounted for by a reduced speed of information processing that can be first detected in the the third decade. In addition, sleep, motor, and sensory systems and brain circulation and metabolism may be affected. Interconnectivity between temporal, prefrontal, and parietal cortical areas and the pathways between the entorhinal cortex, dentate gyrus (hippocampal formation), and the principal neurones of the hippocampus (all forming the hippocampal formation) play prominent roles in cognitive function (p.756). As people grow older, there is a gradual decrease in brain volume. Traditionally, neuronal death spread across the cortex was proposed to underlie the reduced brain volume and, thus, explain cognitive impairment with ageing. This hypothesis was apparently supported by the large cortical cell loss seen in age-related disorders, such as dementia and Alzheimer’s disease (AD, OHCM6 p.376), that are also characterized by dramatic cognitive decline. More recent studies, however, indicate that the cognitive symptoms of normal ageing are not associated with significant neuronal death. Rather, the decrease in brain volume is thought to be due to shrinkage of neuronal cell bodies and dendrites and a progressive loss of myelin integrity. A reduction in synapse number, without accompanying neuronal death, is suspected of underlying impaired cognitive function during senescence. The loss of synapses is associated with a reduction in dendritic spine number and density (the sites of synapses) on cortical neurones that may be as much as 50% in individuals over 50. Also accompanying synaptic loss, degeneration of myelinated axons in the cortex and white matter has been reported. As white matter represents the major connective pathways within the central nervous system (CNS), it is likely that the damage to this cortical connectivity underlies the synaptic loss. This myelin damage is manifest as white matter lesions (small scars in the brain’s white matter) that can be detected using magnetic resonance brain imaging (MRI). They are found in healthy old people and accumulate with age. Neuronal death with ageing may, however, be more significant in subcortical areas. Modulatory inputs to the hippocampus and cortex from cholinergic neurones in the basal forebrain and from brainstem monoaminergic neurones are reduced during senescence. Correlations exist between the degree of cholinergic cell loss and behavioural change, suggesting that the reduction of these neuromodulatory systems is likely to contribute to the impaired integrative function of the cortex with age. P.761
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Disorders and Treatments Emotion Emotions of anger, fear, pleasure, and contentment are expressed as behavioural patterns that include facial expressions, bodily demeanour, and autonomic arousal. Conscious recognition of the physiological reactions to emotion-inducing stimuli can be described as ‘feelings’. In general, emotions influence all aspects of cognitive function (attention, memory, reasoning), yet we have restricted intentional control over them. Key brain regions and their interactions that influence the processing of emotions include the prefrontal cortex, the amygdala, the hypothalamus, and the anterior cingulate cortex (Fig. 11.63). Connectivity between these and other brain areas enables the integration of emotional and cognitive processes. The hypothalamus integrates and co-ordinates the motor and endocrine responses that constitute the behavioural expression of emotional states. Aggression is associated with neural activity in the medial hypothalamus. On the other hand, the lateral hypothalamus is active during expression of anger. Indeed, stimulating this region induces the behavioural profile associated with anger, though not the conscious experience of the emotion. Expressions of anger are also associated with activity in other parts of the limbic system, particularly the cingulate cortex. Reciprocal connections between the cortex and the hypothalamus perform several functions:

  • They allow the conscious experience of emotions in the form of feelings
  • They activate appropriate bodily mechanisms in response to external stimuli
  • They direct appropriate motor behaviour (e.g. avoidance) in response to the stimulus.

In addition, neocortical involvement may suppress emotional responses to minor stimuli. The amygdala is critical for the processing of emotional signals that are expressed through changes in hypothalamic function. Fear, for example, is associated with autonomic (heart rate and blood pressure), endocrine (stress hormones), and motor behaviour changes, along with analgesia and potentiated somatic reflexes like the startle response. Fear conditioning describes the ability of a neutral stimulus to acquire fear-inducing properties when paired closely in time with a threatening event. Damage to the amygdala can impair the processing of signals of fear such as facial and vocal expressions. From a clinical point of view, such a mechanism may relate to the pathophysiology of phobic anxiety and post-traumatic stress disorders. The amygdala also plays important roles in emotional conditioning, the consolidation of emotional memories, and associative learning involving reward and appetite. Modulation through β-adrenoceptors is essential for the enhancement of emotional memory. The amygdala processes emotion-inducing stimuli through two pathways:

  • Basic sensory input is received by the amygdala via a direct route from the thalamus and hippocampus. This elicits short-latency emotional responses, possibly without cortical (cognitive) involvement. This P.763
    direct input may also prepare the amygdala for the reception of more complex information from cortical areas
  • The prefrontal cortex receives processed sensory signals from the thalamus, as well as information concerning the output of the amygdala and homeostatic feedback concerning the rest of the body. A second pathway to the amygdala thus carries integrated cortical output, resulting in a slower response that also includes conscious awareness of the emotional experience.

The ventromedial prefrontal cortex is proposed to integrate signals originating within the body with other forms of cognitive information to modulate emotional intensity. This may enable decision making in situations where the possible choices have subtly different emotional values. In this respect, earlier significant emotional events may be linked with patterns of physiological reactions. Alternatively, the role of the prefrontal cortex is suggested to modulate emotional decision making in favour of longer-term adaptive rather than immediate gains. Homeostatic inputs from autonomic, visceral, and musculoskeletal sources via the brainstem, hypothalamus, and somatosensory and cingulate cortices are integrated into the generation of feelings. Likewise, the recall of feelings associated with emotional experience recruits similar brain areas including brainstem nuclei, hypothalamus, and somatosensory and orbitofrontal cortices. The anterior cingulate cortex is implicated in processing of emotional information with respect to the regulation of mood. The distinction between emotion and its mental representation as feelings suggests separate systems exist for the perception of emotion and feeling states. The involvement of the amygdala in emotional perception, but not in the pathways associated with the expression of feelings, supports at least partial distinction in the mechanisms underlying these two aspects of emotion.

Fig. 11.63 Key structures in the human brain associated with emotion. (Reproduced with permission from Dalgleish T (2004) Nature Reviews: Neuroscience 5, 583–9.)

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Depression (OHCM6 p.15, 60) Depression and mania are disorders of affect characterized by changes in mood. Two forms of depressive syndrome have been categorized:

  • Bipolar depressive syndrome reflects oscillation between depression and mania, perhaps suggesting a biochemical imbalance. There is good evidence for a hereditary link to this form of depression.
  • Unipolar depressive syndrome or depression without associated mania. This is more common in older patients and can be associated with anxiety and agitation.

Symptoms associated with depression include:

  • General feeling of apathy, misery, and pessimism
  • Low self-esteem including guilt, inadequacy, ugliness
  • Indecisiveness and loss of motivation
  • Retardation of thought and actions
  • Sleep disturbance
  • Loss of appetite.

Mania is associated with symptoms of excessive exuberance, self-confidence, enthusiasm, physical activity, irritability, impatience, and anger. Abnormal function of brain regions associated with emotion is implicated in mood disorders. The cognitive aspects of depression such as memory impairment, feelings of worthlessness, guilt, and suicidality may be mediated by the neocortex and hippocampus. The involvement of the amygdala, striatum, and nucleus accumbens in emotional memory suggests these regions may be involved in decreased drive for pleasurable activity, reduced motivation, and anxiety. The hypothalamus may also be involved in the disruption of sleep (circadian rhythm) as well as drives for food or sex. Drug treatment

  • Most drug treatments that alleviate the symptoms of depression have known effects on brain serotonin (5-HT) and noradrenaline (NA) systems
  • Tricyclic antidepressants (TCAs) (e.g. amitriptyline) are non-selective inhibitors of monoamine transporters that remove these transmitters from the extracellular space after synaptic release
  • Monoamine oxidase inhibitors (MAOI) (e.g. phenelzine) inhibit the breakdown of monoamine neurotransmitters
  • Selective serotonin (5-HT) re-uptake inhibitors (SSRI) (e.g. fluoxetine) selectively inhibit 5-HT transporters
  • Lithium is mainly used to control the manic phase of bipolar depression through mechanisms that may involve disruption of intracellular signalling pathways
  • The actions of these drugs led to the monoamine theory of depression that suggests depression is due to a functional deficit of monoamine (5-HT, NA, and dopamine (DA)) neurotransmission. Mania is thus regarded as being due to the opposite mechanism (i.e. a functional excess of these neurotransmitters)
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  • The monoamine hypothesis may have some basic validity in explaining the mechanism of action of antidepressant drugs. However, a unifying biochemical theory of affective disorders cannot be substantiated. The main problem is that the primary biochemical actions of drugs are very rapid but antidepressant effects usually take 2-4 weeks to develop. In addition, a proportion (~20%) of individuals do not respond to these treatments. This suggests that affective disorders are more than just a malfunction of monoamine neurotransmission. It is likely that antidepressant drugs promote secondary adaptive changes, probably through gene activation, that account for their therapeutic efficacy
  • Dysregulation of the hippocampus and the hypothalamic-pituitary-adrenal (HPA) axis, leading to increased levels of circulating stress hormones (cortisol), can promote many symptoms of depression. The ability of antidepressant drugs to stimulate, through genomic mechanisms, the production of growth factors (e.g. brain-derived neurotrophic factor, BDNF) that can promote synapse formation in the brain and normalize HPA axis function has been suggested to account for their delayed therapeutic effects.

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Schizophrenia Schizophrenia is a highly debilitating but common disorder with a lifetime risk in the general population of ~1%. A further 2-3% of the population suffers from the related schizotypal personality disorder. Schizophrenia is classified as a neurodevelopmental disorder that epidemiological studies suggest is predominantly, but not completely, attributable to genetic causes. Studies of identical (monzygotic) and non-identical (dizygotic) twins indicate ~50% and ~10% concordance, respectively-both considerably higher than the incidence in the general population. Two types of symptoms characterize the disorder:

  • Positive (type I) symptoms are manifest as psychotic episodes of the disorder and include auditory hallucinations, delusions and incoherent or disordered cognitive processes
  • Negative (type II or residual) symptoms characterize non-psychotic periods and represent the most unmanageable aspects of the disorder in that drug therapy is commonly ineffective. They include social isolation and withdrawal, decreased emotions, loss of drive, apathy, poverty of speech, and affective flattening.

The progression of the clinical signs of schizophrenia can be divided into four stages:

  • During childhood, no obvious symptoms of the disorder are apparent (premorbid phase)
  • During adolescence, non-specific behavioural changes appear, related to the development of negative symptoms (prodromal phase)
  • The onset of the disorder, characterized by the first psychotic episode, occurs typically during the late teens to early twenties. Left untreated, the disorder will continue, with psychotic episodes interspersed by phases displaying negative symptoms, throughout adulthood (progressive phase). Also associated with disease progression are mood disorders and impaired cognitive function
  • These symptoms persist during later life in the final residual stage of the disorder. Many sufferers never recover.

Neuroleptics

  • Drugs used in the treatment of schizophrenia are known as neuroleptics. Recurrence of psychotic episodes can be effectively controlled by chronic treatment. However, they are not useful for controlling the negative symptoms
  • ~40% of cases are poorly controlled by classical neuroleptics, though newer atypical drugs may be useful in some of these refractory cases
  • Classical or typical neuroleptics such as the phenothiazines (e.g. chlorpromazine), the thioxanthines (e.g. flupentixol), and the butyrophenones (e.g. haloperidol) show a preference for antagonism at D2 receptors but also block 5-HT2, α-adrenergic, and muscarinic acetylcholine receptors.
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  • Atypical neuroleptics show some effectiveness against negative as well as positive symptoms and, generally, have fewer ‘extrapyramidal’ side-effects. Examples include the dibenzazepine, clozapine, and the benzamide, sulpiride
  • As well as being effective blockers of D2 receptors (though D4 and presynaptic D1 receptors may also be blocked), their higher potency block of 5-HT2A receptors is regarded as an important factor in their different therapeutic and side-effect profile.

The dopamine theory of schizophrenia Based on the strong correlation between the potency with which neuroleptic drugs antagonize dopamine D2 receptors, and their effective therapeutic dose, the dominant hypothesis is that hyperactivity of brain dopaminergic pathways underlies the positive symptoms of schizophrenia. Nevertheless, while neuroleptic drugs occupy D2 receptors very quickly after oral administration, a delay of one to two weeks is needed before an overall decrease in dopaminergic activity is obtained and therapeutic effects are seen. This suggests that while the dopaminergic system may be integral to the mechanism of neuroleptic action, indirect actions of these drugs are also likely to be involved. There are four major dopaminergic pathways in the brain (Fig. 11.64):

  • Dopaminergic neurones originating in the ventral tegmental area (VTA), and projecting to nuclei of the limbic system, form the mesolimbic dopamine pathway. Projections to the nucleus accumbens, amygdala, hippocampus, anterior cingulate, and entorhinal cortex—areas intimately involved in emotional function and memory—support the idea that hyperexcitability of this pathway mediates the positive symptoms of the disorder
    Fig. 11.64 Dopamine pathways and schizophrenia.
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  • Dopaminergic neurones also originating in the VTA but projecting to the neocortex (in particular the prefrontal cortex) form the mesocortical dopamine pathway. These cortical areas are important in motivational planning, attention, and social behaviour. It is possible that abnormalities in these regions are important in the negative symptoms. Damage to cortical connections in these areas can result in similar symptoms. Thus, it is possible that reduced activity of this dopaminergic pathway is responsible for negative symptoms and this may explain their refractoriness to typical neuroleptic drugs
  • Two additional dopaminergic pathways in the brain are of importance relative to unwanted effects of neuroleptic drugs:
    • The nigrostriatal dopamine system is found in the basal ganglia and projects from the substantia nigra compacta to the striatum (Parkinson’s disease). Neuroleptic drugs acting on this pathway can induce unwanted extrapyramidal effects (movement disorders)
      • Acute dystonias are reversible effects associated with Parkinsonism-type symptoms of muscle rigidity, tremor, and loss of mobility. Onset is dose-dependent and the severity often declines with progressive treatment
      • Tardive dyskinesia is a chronic, irreversible effect involving involuntary movement of particularly the face and tongue, but also the trunk and limbs. These unwanted effects arise in 20-40% of cases and have a delayed appearance after prolonged neuroleptic treatment for months to years. Their underlying cause is unknown but changes in D2 receptor sensitivity in the striatum and neuronal death in cortical motor areas may both contribute
    • The tuberoinfundibular dopamine system projects from the hypothalamus to the pituitary (p.746). Neuroleptic treatment can cause endocrine disturbances, notably lactation, due to increased prolactin production.

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Addiction

  • Addiction or dependence is a compulsion to perform an action (e.g. take a drug) with a loss of control in limiting that behaviour. This compulsion or craving is a form of psychological dependence
  • Intimately associated with the concept of addiction is tolerance, a reduction in effect with repeated execution of the action, and withdrawal (also known as physical dependence) or the appearance of symptoms associated with the termination of chronic expression of the behaviour
  • Anxiety, depression, and dysphoria are symptoms common to withdrawal from a wide range of addictive behaviours. It is possible that these symptoms may also be motivating factors for perpetuating addictive behaviour
  • The development of addiction is associated with positive reinforcement (i.e. an increased probability of a response to a given stimulus). In the context of drug use, reinforcement could be through direct effects on the probability of self-administration or indirect effects such as the drugs’ ability to enable reinforcing effects of associated but neutral stimuli
  • While most frequently associated with drug use, other disorders such as impulse control disorders also display symptoms characteristic of addiction-namely, compulsion to perform the action, repeated performance, and withdrawal symptoms of dysphoria and depression. Such disorders are often associated with eating, exercise, gambling, sex, and shopping.

Brain pathways and addiction (Fig. 11.65)

  • The development of addiction has been associated with midbrain and forebrain systems that mediate motivated behaviour and natural reward mechanisms
  • Ascending and descending pathways through the median forebrain bundle, particularly monoamine pathways, link several regions associated with motivated behaviour. Of particular importance are the ventral tegmental area (VTA) and the basal forebrain, including the nucleus accumbens, olfactory tubercle, frontal cortex, and amygdala
  • Neurochemically, the mesolimbic dopamine pathway (p.767), linking the VTA and the basal forebrain, is seen as an integral component in linking dependence and natural reward systems
  • In addition, opioid, GABA, and 5-HT systems modulate the function of the VTA and basal forebrain during natural and drug reward related behaviours indicating the convergence of several neurochemical systems in positive reinforcement mechanisms
  • During withdrawal, monoamine levels, particularly dopamine in the VTA and 5-HT, decrease dramatically, suggesting that addiction involves neuroadaptive mechanisms that contribute to both dependence and withdrawal symptoms.
Fig. 11.65 Neural circuitry implicated in addictive mechanisms. Dashed lines indicate limbic input to the N. accumbens; the wavy connection represents the mesolimbic dopaminergic pathway believed to be important in reward mechanisms, as is the pathway from N. accumbens to VTA, represented by the broken grey connection. Various neurotransmitter systems indicated in white modulate VTA dopaminergic activity.

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Drug addiction mechanisms Cocaine and amphetamine Cocaine and ampetamine are psychomotor stimulants that induce euphoria and act as reinforcers for drug self-administration. Although they increase levels of all monoamines the reinforcing effects crucially depend on dopamine release. Impairing the mesolimbic dopamine pathway, particularly in the region of the nucleus accumbens and central nucleus of the amygdala, abolishes the reinforcing effects of cocaine and ampetamine. Opiates The reinforcing effects of opiates such as morphine and heroin involve actions at a specific receptor subtype, the µ-opioid receptor, found on neurones in the VTA and the nucleus accumbens. Blocking these receptors blocks positive reinforcement by opiates. This does not, however, involve the mesolimbic dopamine pathway as opiate addiction is unaffected by its pharmacological or anatomical disruption. Weak, long-acting µ-opioid receptor agonists, such as methadone, are used to alleviate physical dependence during drug withdrawal. Nicotine Nicotine has a direct reinforcing effect that involves activation of both the mesolimbic dopamine and opioid pathways through its agonistic actions at nicotinic acetylcholine receptors. Nicotine replacement, to alleviate withdrawal symptoms and psychological dependence, in conjunction with counselling, is the primary treatment used to help smokers give up. The A2-adreoceptor agonist, clonidine, may also be used. It acts presynaptically to reduce neurotransmitter release that may reduce the efficacy of the reward pathways. Alcohol The pathways associated with alcohol dependence are more complex. Alcohol shares sedative and anxiolytic properties with benzodiazepines and these may contribute to the reinforcing properties of both drugs. Alcohol and benzodiazepines potentiate GABA systems and this effect, in the central nucleus of the amygdala, is considered important for the development of dependence. Activity in the mesolimbic dopamine pathway may also contribute to alcohol reinforcement, though this is not essential. Glutamate, serotonin, and opioid systems have all been implicated in alcohol dependence. Benzodiazepines are commonly used to alleviate withdrawal symptoms during the acute drying-out period, presumably because of their shared action on GABA systems. Disulfiram, an inhibitor of aldehyde dehydrogenase, promotes increased plasma acetaldehyde levels if alcohol is taken. This causes unpleasant symptoms (flushing, hyperventilation, tachycardia, panic) that can act as a form of aversion therapy. Acamprosate, a taurine analogue, reduces craving through an unknown mechanism, though it may be related to interactions with amino acid neurotransmission. P.773
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Degenerative diseases Neurones in the central nervous system are post-mitotic cells and the potential for replacement is, in general, limited. As such, pathological neuronal loss is likely to have serious consequences for brain function. Neuronal death is a common feature of a group of disorders termed neurodegenerative disorders. Neuronal death in neurodegenerative disease can occur by one of two processes:

  • Necrosis (usually induced by acute injury) involves cell swelling, vacuolization, and lysis and is often associated with an inflammatory response
  • Apoptosis (or programmed cell death) can be triggered by extracellular signals that occur normally during development but can also be triggered pathologically during neurodegenerative disease. Apoptosis is characterized by cell shrinkage, nuclear chromatin and DNA damage, and by the activation of caspases that break down certain intracellular proteins. Macrophages remove dead cells without inducing inflammatory responses.

Two mechanisms known to induce necrosis as well as to trigger apoptosis, and hence implicated in neuronal death associated with neurodegenerative disease, are oxidative stress and excitotoxicity.

  • Oxidative stress refers to the excessive production of reactive oxygen species (ROS) including O2-, hydroxyl free radicals, and H2O2 when mitochondrial oxidative phosphorylation, and hence ATP production, is compromised. ROS damage important intracellular components including enzymes, DNA, and membrane lipids
  • Glutamate-induced excitotoxicity involves excessive stimulation of calcium-permeable NMDA receptors and a catastrophic increase in intracellular calcium that further promotes glutamate release, activates membrane-damaging proteases and lipases, and also induces the production of ROS
  • The importance of efficient mitochondrial ATP production and endogenous safety mechanisms to protect against ROS-such as enzymes like superoxide dismutase (SOD) and catalase, and antioxidants such as glutathione, ascorbate, and α-tocopherol (vitamin E)-has led to the suggestion that compromising any of these mechanisms may underlie several neurodegenerative diseases.

In many neurodegenerative disorders, the causes of cell death can be attributed to inherited traits. However, many sporadic cases are idiopathic, suggesting non-genomic mechanisms may also be important. Thus, specific genetic mechanisms account for all cases of Huntington’s disease (HD, OHCM6 p.726). Genetic mutations also account for some cases of motorneurone disease (OHCM6 p.394), Parkinson’s disease (OHCM6 p.382), and Alzheimer’s disease (AD, OHCM6 p.376). New variant Creutzfeldt-Jakob disease (nvCJD, OHCM6 p.720, 721), on the other hand, is attributable to a transmissible infective agent. P.775
Alzheimer’s disease (AD) (OHCM6 p.376)

  • In AD, neurones projecting from the entorhinal cortex to the dentate gyrus (hippocampal formation) and the principal neurones in the CA1 region of the hippocampus appear particularly vulnerable to death. This explains the usual course of the disease in which episodic memory is impaired early on (p.758)
  • Pyramidal neurones in the cortical circuitry that link temporal, prefrontal, and parietal cortical areas also display vulnerability in AD and the involvement of these areas in cognitive function may explain the later decline in cognition with disease progression
  • A characteristic of AD is a relatively selective loss of cholinergic neurones in the basal forebrain, leading to a reduction in the cholinergic innervation of the cortex and hippocampus. Attempts to alleviate this cholinergic loss using the cholinesterase inhibitors, tacrine or donepezil, has resulted in modest improvement in cognitive function in some patients
  • Abnormal processing of amyloid precursor protein (APP) is regarded as a key step in AD pathogenesis, leading to extracellular accumulation of β-amyloid protein in the form of amyloid plaques
  • Another characteristic of AD is intraneuronal deposition of the phosphorylated microtubule associated protein, tau. When neurones die, phosphorylated tau filaments aggregate to form extracellular neurofibrillary tangles (NFT)
  • Neurones die by apoptosis and necrosis in AD. However, it remains to be established whether amyloid plaques and NFTs mediate neurotoxicity.

Parkinson’s disease (PD) (OHCM6 p.382)

  • PD is manifest primarily as a disease of motor control resulting from the degeneration of nigrostriatal dopaminergic neurones in the basal ganglia
  • Both apoptotic cell death and death induced by ROS and mitochondrial dysfunction have been implicated in PD
  • Major treatment involves increasing brain dopamine levels by oral administration of the metabolic precursor, L-dopa. Dopamine itself cannot cross the blood-brain barrier. Brain levels of L-dopa are increased by the use of inhibitors of dopa decarboxylase (e.g. carbidopa) in the periphery
  • Intraneuronal protein deposits, called Lewy bodies, are characteristic of PD
  • A central role for Lewy bodies in PD neuropathology is suspected because mutations in genes encoding for their constituent proteins (e.g. α-synuclein) have been linked to some familial forms of the disease.

Motor neurone disease (OHCM6 p.394) Mutations in the SOD-1 gene have been causally linked to amyotrophic lateral sclerosis, a form of motor neurone disease that results in the degeneration of motor neurones in the spinal cord, brainstem, and motor cortex. P.776
Huntington’s disease (HD) (OHCM6 p.726)

  • HD is characterized by involuntary jerky movements that result from GABAergic cell death in the striatum. It is thought this leads to hyperactivity of the nigrostriatal dopamine pathway. Treatment of the symptoms is through dopamine D2 antagonists (p.766) or GABA agonists such as baclofen
  • HD is inherited and attributable to the presence of high repeats of the DNA nucleotide sequence, CAG, in the huntington gene (that encodes for a protein implicated in regulating apoptosis and other cell death mechanisms).

New variant Creutzfeldt-Jakob disease (NvCJD) (OHCM6 p.720, 721)

  • NvCJD is a type of spongiform encephalopathy characterized by a vacuolated appearance of the postmortem brain and associated with dementia and loss of motor co-ordination
  • It is postulated that an infective agent—an abnormal form of a protein called a prion-triggers the disease. The abnormal prion is thought to lead to accumulation of insoluble prion protein in the brain, triggering neurotoxic processes.

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