NeuroscienceThese notes were made by Hadley Wickham, hadley@technologist.com and are licensed under theCreative Commons No...
Table of ContentsTable of Contents...........................................................................................
EEG/Sleep/Epilepsy...........................................................................................................
Brain Introduction • average of 20g brain per kg of body mass     • male brain slightly larger than female brain because o...
• occiptal love: behind line between pre-occiptal notch and parieto-occiptal sulcus            •        input from one sid...
• alongside each pyramid an oval surface swelling contains the inferior olivary nucleus                 (where various cer...
Forebrain Cerebral Cortex • thin layer of grey matter, deeply folded to maximise surface area • basic common pattern of fo...
• complex function not well understond      Frontal Association Cortex       • huge area, involved with intelligence, mood...
Thalamus • two thalami form the largest part of the diencephalon     • extend ant-post on each side from the interventricu...
• has a short anterior limb, a genu, and a longer posteior limb • consists of motor and sensory cortical projection fibres...
Hindbrain Cerebellum  •    well delineated structure attached to the pons  •    10% of total volume of brain, but 50% of n...
Pars Basilaris       •   efferent (motor) fibres of the neocortex       •   corticospinal pathway (from motor cortex to th...
Efferent                                                                                                                  ...
Spinal CordExternal Anatomy •   extends from the foramen magnum to lower border of L1 in adults (L3 in children) •   cervi...
Other tracts                 • indirect spinocerebellar tracts: spino-olivary tract supplies integrated information from  ...
Intrinsic Control • many small cells with short axons known as internuncial neurons lie between dorsal and ventral     hor...
Sensation Detection • two main sensory pathways:     • dorsal column medial lemniscal pathway (discrimination sensation)  ...
Quality • adequate stimulus is the stimulus that requires the least amount of energy to stimulate the receptor     • eg. 1...
• 1 million nerve fibres from eye • very sensitive to movement, especially on periphery     • reflex action draws eyes tow...
Movement Motor UnitsSymptoms/Terms • paralysis = no voluntary movement     • monoplegia = one limb paralysed     • hemiple...
Axon diameter          +            +++             Terminals              +            +++             Tetanic contractio...
• poliomyelitis         • acute viral infection leading to muscle paralysisExamples      Myotonic Muscular Dystrophy      ...
• joint receptorsStretch (Tendon) Reflex • evoked from muscle spindle by a stretch of vibration of the muscle • only monos...
• monoplegia and hypereflexia ipsilateral and below lesion         • loss of pain and temperature sensation contralateral ...
• vascular occlusion (80%) atherosclerosis or thrombosis       • haemorrhage (20%) more destructive • symptoms occur withi...
Neuroradiology Introduction • historically it has been very difficult to figure out what’s going on in the brain, because ...
Subdural       • between dura and arachnoid       • often due to torn bridging veins especially sup sagittal sinus       •...
Clinical Myotatic (Muscle Stretch) Reflex • 2 components     • phasic (rapid, brief, eg. tendon jerk)     • tonic (weak, l...
Characteristics       • velocity dependent (slow: rigidity, fast: spasticity)       • different response in different musc...
•   pain        •   ANS dysfunction        •   depression        •   dementia • caused by the degeneration of dopamine cel...
• intention tremor in both hands and feet (worse in feet) • other signs that may be visible: nausea, vomiting, visual symp...
• prevalence equal in males and females but females may have a better outcome and males have           an early onset (15-...
Analgesia/Drug Abuse History • In 1965, Wall & Melzack proposed the gate control theory of (ie. there is maximum amount of...
Non-Opioids      Para-aminophenol Derivatives       • paracetamol is the only drug currently used in this category       •...
Problems            • gastric irritation and ulceration (especially duodenal) (PG play important role in                 m...
• anxiolysis (anxiety↓)            • cough depression           Side effects            • euphoria            • sedation  ...
• any use of mind-altering drugs is based on complicated theory involving     • user     • setting (availability, social t...
• positive reinforcement         (gain positive ability)            • negative reinforcement         (avoid negative exper...
• pharmacological methods use long acting benzodiazapines and slowly reducing dose (10-15%           per week)      Stimul...
Neurotransmission Voltage-Gated Ion ChannelsIntroduction • RMP determined by relative permeability’s of membrane to variou...
• inactivation: some channel inactivate, channel opens, N terminal forms a plug and blocks channel    shortly after it ope...
• activation of voltage-dependent Ca2+ channels       • presynaptic Ca2+ ↑          • Ca2+ binds with intracellular recept...
• diisopropyl fluorophosphate (nerve gas), a long-lasting anticholinesterase            • neostigmine, short lasting antic...
EEG/Sleep/Epilepsy EEG and Physiology of SleepEEG • non-invasive test of brain function • records spontaneous electrical a...
• Stage 3 sleep defined as presence of high voltage δ-activity 30-70% of the time       • Stage 4 sleep defined as presenc...
Introduction
Introduction
Introduction
Introduction
Introduction
Introduction
Introduction
Introduction
Introduction
Upcoming SlideShare
Loading in …5
×

Introduction

772 views
743 views

Published on

0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total views
772
On SlideShare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
8
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide

Introduction

  1. 1. NeuroscienceThese notes were made by Hadley Wickham, hadley@technologist.com and are licensed under theCreative Commons NonCommercial-ShareAlike License. To view a copy of this license, visithttp://creativecommons.org/licenses/nc-sa/1.0/ or send a letter to Creative Commons, 559 Nathan AbbottWay, Stanford, California 94305, USA.
  2. 2. Table of ContentsTable of Contents..............................................................................................................................2Brain.................................................................................................................................................4 Introduction................................................................................................................................4Forebrain..........................................................................................................................................7 Cerebral Cortex..........................................................................................................................7 Basal Ganglia.............................................................................................................................8 Thalamus....................................................................................................................................9 Internal Capsule.........................................................................................................................9Hindbrain........................................................................................................................................11 Cerebellum...............................................................................................................................11 Brainstem.................................................................................................................................11Spinal Cord.....................................................................................................................................14Sensation........................................................................................................................................17 Detection..................................................................................................................................17 Somatosensory System............................................................................................................17 Visual System..........................................................................................................................18Movement.......................................................................................................................................20 Motor Units..............................................................................................................................20 Muscle Reflexes.......................................................................................................................22 Injuries of Spinal Cord/Brainstem...........................................................................................23 Injuries to Brain.......................................................................................................................24Neuroradiology...............................................................................................................................26 Introduction..............................................................................................................................26Clinical...........................................................................................................................................28 Myotatic (Muscle Stretch) Reflex............................................................................................28 Sensation..................................................................................................................................29 Parkinson’s...............................................................................................................................29 Cerebellar.................................................................................................................................30 Pathways of Vision..................................................................................................................31 Stroke.......................................................................................................................................31 Psychotic Disorders.................................................................................................................31Analgesia/Drug Abuse....................................................................................................................33 History.....................................................................................................................................33 Analgesics................................................................................................................................33 Miscellaneous..........................................................................................................................36 Drug Abuse..............................................................................................................................36 Drugs of Abuse........................................................................................................................37Neurotransmission..........................................................................................................................40 Voltage-Gated Ion Channels....................................................................................................40 Synaptic Transmission.............................................................................................................41Hadley Wickham 2 08/12/10
  3. 3. EEG/Sleep/Epilepsy........................................................................................................................44 EEG and Physiology of Sleep..................................................................................................44 Epilepsy...................................................................................................................................46Neuropharmacology........................................................................................................................49 Neurodegeneration...................................................................................................................49 Schizophrenia...........................................................................................................................50 Antidepressants........................................................................................................................52Anaesthesia.....................................................................................................................................54 Anaesthetics.............................................................................................................................54Hadley Wickham 3 08/12/10
  4. 4. Brain Introduction • average of 20g brain per kg of body mass • male brain slightly larger than female brain because of greater body mass • much higher than any other animal • central nervous system (CNS) comprises the brain and spinal cord • peripheral nervous system (PNS) comprises the cranial and spinal nerves and their ramificationsPeripheral Nervous System • 12 paired cranial and 31 paired spinal nerves • innervate somatic or autonomic (visceral) structures and convey afferent or efferent motor impulses • somatic efferent: pass directly from cell bodies in CNS to skeletal muscle • visceral efferent: preganglionic fibres from CNS synapse in peripheral ganglia with neurons that supply smooth muscle and glands • somatic and visceral afferents: pass from peripheral receptors to cells of origin in spinal dorsal root ganglia • autonomic nervous system has sympathetic and parasympathetic divisions • sympathetic outflow is from thoracolumbar region • parasympathetic outflow is from craniosacral region • generally have opposing actions: sympathetic associated with expenditure of energy (eg “fight-or-flight”), parasympathetic with conservation and restoration of energyCentral Nervous System • topographically CNS can be divided into forebrain, midbrain, hindbrain and spinal cord • midbrain, pons and medulla oblongata are collectively known as the brainstem Forebrain • paired cerebral hemispheres have external grey cortex and white centre (containing deep grey masses the basal ganglia) • two hemispheres separated by median longitudinal fissure, and joined by a massive bridge, the corpus callosum • cerebral cortex convoluted by gyri and furrowed by sulci (very deep sulci are called fissures) • insular cortex is buried in the lateral fissure (LF) (of Sylvius) • central sulcus (CS) extends from sup-med border of hemisphere to its mid point down and forwards towards the lateral fissure, surrounded on both sides by gyri • central sulcus and lateral fissure divide the brain into four lobes: • frontal lobe: ant to CS, sup to LF • parietal lobe: post to CS, sup to LF • temporal lobe: inf to LFHadley Wickham 4 08/12/10
  5. 5. • occiptal love: behind line between pre-occiptal notch and parieto-occiptal sulcus • input from one side of the body projects to the contralateral hemisphere • the diencephalon (lying between hemispheres and brainstem) consists of the thalamus, hypothalamus, and epithalamus • each thalamus is a major relay centre for information going into the brain • hypothalamus regulates visceral activity through ANS and hormones • epithalamus includes pineal gland and habenular nuclei • basal ganglia comprise the grey mass of corpus striatum within each hemisphere • related to subthalamic nuclei (diencephalon) and substantia nigra (midbrain) • mass of fibres in internal capsule partially divides corpus striatum into caudate and lenticulate nuclei • between the internal capsule and cortex nerve fibres diverge to form corona radiata Grey Matter • cerebral cortex • thalami • basal ganglia White matter • corpus callosum (connection between hemispheres) • internal capsule (to/from cerebral cortex) Midbrain • the mesencephalon is traversed by the cerebral aqueduct • four little hillocks called corpora quadrigemina lie dorsal to this roof (tectum) • ventral to the aqueduct a central tegmentum is separated from two crura cerebri (cortico- spinal, -pontine and -bulbar tracts) by the substantia nigra • a interpeduncular fossa lies between the two crura • two large, oval, pinkish masses are located in the tegmentum, these are known as the red nuclei • two superior cerebellar peduncles enter the lower midbrain and decussate (→ thalamus & red nuclei) Hindbrain • the rhombencephalon consists of pons, medulla oblongata and cerebellum • pons continuous above with midbrain and below with medulla • broad bridge-like structure on ventral aspect • ventral medial sulcus contains the basilar artery • numerous pontine nuclei (ventral) give rise to transverse fibres which decussate into the opposite middle cerebellar peduncle • bundles of fibres run from crura of midbrain to pyramids of medulla • medulla oblongata continuous with spinal cord and pons • bilateral ventral surface elevations, pyramids, contain cortico-spinal fibres which cross in a pyramidal decussation to descend contralaterallyHadley Wickham 5 08/12/10
  6. 6. • alongside each pyramid an oval surface swelling contains the inferior olivary nucleus (where various cerebellar afferents converge) • on each side of dorsal surface of lower medulla are gracile and cuneate tubercules produced by nuclei of the same name, these project to the spinal cord via the medial lemniscus • cerebellum lies dorsal to the pons and medulla • has two lateral hemispheres and a midline vermis • cortex has narrow transverse folia separated by deep fissures, white medullary centre contains intracerebellar nuclei • is close to the roof of the fourth ventricle, formed by superior and inferior medullary vela • inf. medullary vela is invaginated by choroid pleuxus and perforated post. by median aperture • connections between cerebellum and spinal cord are mainly ipsilateralHadley Wickham 6 08/12/10
  7. 7. Forebrain Cerebral Cortex • thin layer of grey matter, deeply folded to maximise surface area • basic common pattern of folding in all humans (see page 18)Sensory Areas Primary Sensory Cortex (Somato-sensory) • location: located in the post central gyrus • organisation: somatotopically organised (eg. homunculus) • information received: touch, pressure and joint position from contralateral side of body Primary Visual Cortex • location: folded around the calcarine sulcus • organisation: visuotopically and retintropiicaly organised • information received: receives information from the contra-lateral visual field (not eye!), most peripheral information goes to the deepest part of the visual cortex Primary Auditory Cortex • location: mainly in the two transverse/superior temporal gyrus (of Heschl), into the lateral fissure • organisation: tonotopically organised • information received: sound information from contralateral ear Secondary Areas • information from primary sensory areas is passed to secondary areas for further processing • these areas are involved in the interpretation of the information • are different on opposite hemispheres, eg. left usually the verbal hemisphere • Wernicke’s speech area: sounds → meaning (speech recognition) • Broca’s speech area: words → sounds (speech production) • arcuate fasciculus: Broca’s area ←→ Wernicke’s area Language • inferior parietal lobe (IPL) is the major reading and writing area of the brain, especially the angular gyrus and supramarginal gyrus) • primary visual cortex (reading) and Wernicke’s area (internal auditory response to word) both have major connections • writing aided by Exner’s area (located close to hand motor cortex, thought to have learned coordination of writing skills) • non-dominant hemisphere ares concerned with non-verbal language (body language, emotions, spatial skills, conceptual understanding, mathematical and musical abilities)Association Areas • frontal lobes, superior parietal lobe, middle temporal gyrusHadley Wickham 7 08/12/10
  8. 8. • complex function not well understond Frontal Association Cortex • huge area, involved with intelligence, mood, personality, behaviour and cognitive function • tumour in frontal lobe may lead to personality changes • relatively huge compared with other animals Parietal Association Cortex • mainly superior, but also some inferior • spatial skills, 3D recognition (shapes and faces), abstract perception, concepts, recognition of written word Temporal Association Cortex • memory, mood, aggression, intelligence • affected in AlzheimersCerebral Arteries • middle cerebral a. commonly associated with strokes (doesn’t supply leg/foot area) Basal Ganglia • lie in the base of the forebrain, deep to the cortex • consists of the: • caudate nucleus + putamen • globus pallidus (= paleostriatum) • subthalamic nuclei • substantia nigra (SNC = pars compacta, SNR = pars reticulari) • putamen + globus pallidus = lenticulate nucleus • caudate nucleus and lenticulate nucleus are essentially the same, but partially separated by the internal capsule • lecticulate nucleus + caudate nucleus = corpus striatum (= neostriatum) • globus pallidus + caudate nucleus = striatum • globus pallidus consists of two parts: inner and outer • substantia nigra lies in the midbrain and is a very important part of the basal ganglia, major function is control of movementFunction • mood and movement • give the ability to express mood via mobility (most of movement is concerned with conveying inner emotional status) • initiation and direction of voluntary movement • play large part in programming and memory of movementsHadley Wickham 8 08/12/10
  9. 9. Thalamus • two thalami form the largest part of the diencephalon • extend ant-post on each side from the interventricular foramen to posterior commissure • extend transversely from internal capsule to 3rd ventricle • ovoid mass of grey matter, ~40 mm long • usually attached across midline by narrow interthalamic connexus of grey matter • receives all incoming information and preprocesses it • mass of grey matter, divided into nuclei • internal medullary lamina (IML), an oblique sheet of myelinated fibres, divides the thalamus into three parts • anterior (afferents from hypothalamic and limbic system, efferents to limbic) • lateral/ventral • medial (afferents from other thalamic nuclei, connections to association areas, associated with mood and emotional balance) • lateral nucleus is further subdivided on the basis of cell characteristics • dorsal (afferents from ventral tier, connections to association areas) • ventral anterior (afferents from basal ganglia, efferents to motor cortex) • ventral lateral (afferents from cerebellum, efferents to motor cortex) • ventral posterior (somatic sensory, VPL receives medial lemniscus, VPM receives trigeminothalamic input, efferents to somatosensory cortex) • caudal part of the lateral nucleus forms the pulvinar • medial (auditory) and lateral (visual) geniculate nuclei occupy two small swellings on ventroposterior surface • each nucleus is related to a specific functional region of the cortex • thalamus gives instructions to the cortex • cortex also feed information about the processing it’s done back to the thalamus • cortex can control information being sent to (eg. listening to one conversation out of many) • summary of functions • sensory integration and relay (all sensory inputs, except olfaction, converge on thalamus) • motor integration and relay (basal ganglia and cerebellum exert effects on motor via thalamus) • awareness of nocioceptive input (non-discriminative) • emotional and subjective responses (sensory input interpreted as good or bad) • memory and instinctive behaviour (anterior nucleus part of limbic system) • activation and arousal Internal Capsule • in horizontal section internal capsule is a compact aggregation of fibres sited between thalamus and lenticulate nucleusHadley Wickham 9 08/12/10
  10. 10. • has a short anterior limb, a genu, and a longer posteior limb • consists of motor and sensory cortical projection fibres, fan out between cortex and internal capsule as the corona radiataHadley Wickham 10 08/12/10
  11. 11. Hindbrain Cerebellum • well delineated structure attached to the pons • 10% of total volume of brain, but 50% of neurons • divided into two hemispheres which control ipsilateral side of the body • major role is the coordination of voluntary movements • three precise functions • coordination of muscles involved with equilibrium (axial musculature) • maintenance of muscle tone • control of rate, timing and force of voluntary movements (appendicular muscles) • correspondingly, diseases of the cerebellum have three major symptoms • upset of equilibrium (fall to side of lesion) • intention tremor (disorder of control of muscle tone) • ataxia (uncoordinated control of movement) • connected to the midbrain via three cerebellar peduncles: • inf cerebellar peduncle: carries vestibulo-cerebellar, olivo-cerebellar and DSCT fibres • mid cerebellar peduncle: carries ponto-cerebellar fibres • sup cerebellar peduncle: carries VSCT and efferent thalamic fibresMechanism • can be divided into three area, receiving three inputs (olivary nucleus supplies all three) Name Phylgenetics Information Afferent Input Location Efferent OutputArchicerebellum oldest (vertebrates) balance information vestibular nuclei flocculonodular lobe fastigial nucleus (reticular)Paleocerebellum newer (land animals) proprioceptive input brainstem and CN nuclei vermis, med zone globose & emboliform nuclei (→ red nucleus)Neocerebellum newest (mammals) cortical input pontine nuclei lat zone dentate nucleus (red nucleus) • cortex is three-layered: molecular layer (axons), pyramidal layer (Purkinje cells, axons run perpendicular to folia), granular layer (axons run parallel to folia) • receives afferent input in two fashions • climbing fibres: from olivary nuclei, supply one Purkinje cell • mossy fibres: all other inputs, supply many thousands of Purkinje cells BrainstemSubdivision and General Organisation • can be divided up in two different fashions • horizontally – midbrain/pons/medulla • vertically – pars basilaris/tegmentum/roof plateHadley Wickham 11 08/12/10
  12. 12. Pars Basilaris • efferent (motor) fibres of the neocortex • corticospinal pathway (from motor cortex to the LMNs) • cortibulbar (corticonuclear) pathway (to “LMN”s of motor cranial nerve nuclei) • corticopontine pathway Tegmentum • cranial nerve nuclei • suprasegmental nuclei • fibre tracts Reticular formation • present throughout pontine tegmentum, rostral extension of interneuronal network present in spinal cord • divided into nuclear groups along a med-to-lat axis • raphe nuclei produce serotonin, composed of small midline aggregations, involved with slow wave sleep • mesostriatal and mesolimbic & mesocortical nuclei produce dopamine, important role in controlling voluntary movement, though to be site of action of anti-psychotics and stimulants • locus ceruleus and lateral tegmental neurons source of NA, widespread projections throughout CNS yet little afferent input, have a role in attending to sudden contrasting or novel stimuli • function include activation of brain for behaviour arousal, modulation of segmental stretch reflexes, control of breathing and cardiac function, modulation of sense of pain • asc. reticulospinal tracts involved with arousal, alerting reactions and heightening perceptions • desc. reticulospinal tracts involved with stereotyped movement and are significant in control of posture and muscle tone Roof Plate • contains the superior and inferior colliculi (aka corpora quadrigemina) • superior colliculi: have complex six-layered structure (reflect derivation from optic lobes of lower vertebrates), concerned with visual reflexes and eye movements, integrate afferents from diverse sources, descending fibres form the tectospinal and tectobulbar tracts • inferior colliculi: relay station on the auditory pathway, lateral lemniscus passes intoCranial Nerve Nuclei • organised into seven longitudinal nuclei on basis of embryological origin and nature of structure innervated • functional significance two-fold • neurons with similar functions brought into proximity • different function affected by local damaged in the brain steam Classification Functions Structures InnervatedHadley Wickham 12 08/12/10
  13. 13. Efferent medial General somatic control of skeletal muscle extraocular and tongue muscles General visceral control of autonomic effectors tear glands, sweat glands, gut Special visceral control of skeletal muscles muscles of facial expression, jaw, neck, pharynx and larynx → Afferent General somatic touch, pain, temperature, proprioception skin, skeletal muscles of head and neck, mucous membrane of mouth, teeth lateral Special somatic hearing, vision, balance cochlea, vestibular organ General visceral mechanical, pain, temperature, proprioception pharynx, larynx, gut Special visceral olfaction, taste taste buds, olfactory epitheliumHadley Wickham 13 08/12/10
  14. 14. Spinal CordExternal Anatomy • extends from the foramen magnum to lower border of L1 in adults (L3 in children) • cervical and lumbar enlargements (nerve cell bodies controlling limb muscles) • segmental arrangement, 31 pairs of spinal nerves (8C, 12T, 5L, 5S & 1Co) • total length ~45cm, weight 38gWhite Matter • divided into three columns or funiculi • ventral (located between ventral median fissure and ventral spinal roots) • lateral (located between dorsal and ventral spinal roots) • dorsal (located between dorsal spinal roots and dorsal median fissure) • gracile fasciculus: dermatomes below T5 (eg. legs) • cuneate fasciculus: dermatomes above T5 (eg. arms) • organised somatotopically (S medial, C lateral) • further subdivided into fasciculi • amount of white matter decreases with increasing distance from the brain Ascending Tracts Pathways to cortex via thalamus • three-neuron chain: primary neurons in dorsal root ganglion, secondary in spinal dorsal grey matter of dorsal medulla, tertiary in thalamus • provide contralateral information to cortex • highly myelinated fibres enter medially, ascend dorsal columns, relay in medulla, conveying information about proprioception, vibration, touch and pressure • non-myelinated fibres enter laterally, relay in dorsal grey horn, cross midline to form ventrolateral spinothalamic system, conveying information about pain and temperature • Pain pathway: fibres enter dorsolateral tract, ascend or descend 1 or 2 segments, terminate in lamina I,II or V, axons from 20 neurons located in nucleus proprius cross white commuissure, ascending by one segment as they do so and enter the spinothalamic tract • Touch, pressure, position: fibres enter medially, accumulate in either cuneate (above mid-thoracic level) or gracilis (below mid-thoracic level) fasciculus, ascend to cuneate and gracilis nuclei where they synapse, and 20 axons cross over, then travel in the medial lemniscus Pathways to cerebellum • two-neuron chain, provides ipsilateral information to cerebellum • dorsal spinocerebellar and cuneocerebellar tracts: relay propioceptive input from muscle spindles and joint receptors • ventral (upper limb) and rostral (lower limb) spinocerebellar tracts: conveys pre- integrated information about spinal motor activity and reflexesHadley Wickham 14 08/12/10
  15. 15. Other tracts • indirect spinocerebellar tracts: spino-olivary tract supplies integrated information from higher centres, spinoreticular fibres • spinotectal tract: supplementary pain pathway, concerned with reflex head movements • propriospinal tracts: fasciculus proprius Descending Tracts • pyramidal tract extends from cerebral cortex to ventral horn cells (corticospinal) and some cranial nerve nuclei in the brainstem (corticobulbar) • vestibulospinal tracts facilitate extensor muscle control in anti-gravity maintenance of posture and in locomotion • reticulospinal tracts involved in control of muscle tone, posture, locomotion and other stereotyped limb movements • rubrospinal tract is a rudimentary, phylogenetically old pathway • tectospinal tract is involved in reflex head movements in response to visual, auditory and painful stimuliGrey Matter • grey matter has a variable butterfly profile • roughly divided into two horns, ventral (sensory) and dorsal (motor) • grey commissure encloses a small central canal • intermediate area has a small lateral horn in thoracic sections (contain cell bodies of visceral efferents) • amount increased in the cervical and sacral enlargements Dorsal Horn • Rexed defined 10 layers of grey matter based on cell characteristics, have functional significance Lamina Name Notes CellsI posteromarginal nucleus largeII substantia gelatinosa small, unmyelinatedIII nucleus proprius large, thick myelinatedIVV sympathetic preganglionic Only present in enlargementsVI muscle spindleVII intermediolaternal nucleus dorsal nucleus of ClarkeVIII medial motor nucleusIX lateral motor nucleus group of interneurons surrounding VIIIX small neurons around central canal Lamina FunctionI nocioceptorsII cutaneous afferentIII mechanoreceptorsIVV superf. laminaVI neurons activated by joint movementVII interneuronsVIIIIX α & γ LMN’sX part of grey commissureHadley Wickham 15 08/12/10
  16. 16. Intrinsic Control • many small cells with short axons known as internuncial neurons lie between dorsal and ventral horns, commonly interposed between ascending and descending fibres and may form part of a reflex arc • association neurons are restricted to one side of the cord, axons of commissural neurons cross the midline • interneurons may be intersegmental or limited to one spinal cord segment • Renshaw interneurons are sited between an axon collateral and cell body of motor neurons, being inhibitory they limit the duration of the discharge • when directed towards adjacent neurons their surround inhibition tends to sharpen signals • intrinsic spinal mechanisms include stereotyped simple motor programs such as steppingHadley Wickham 16 08/12/10
  17. 17. Sensation Detection • two main sensory pathways: • dorsal column medial lemniscal pathway (discrimination sensation) • anterolateral pathway (pain & temperature)Sense Detectors • two types • encapsulated (thick (~20 μm), well myelinated axons, fast) • free nerve endings (thin, poorly myelinated, slow) Encapsulated • often terminate into lamina III & IV, dorsal nucleus of Clarke, or intermediate area • often have direct link with α-motor neuron to give monosynaptic reflex arc • 25% send a collateral up the spinal forming the dorsal columns, which terminate in the dorsal column nuclei in the medulla Free Nerve Endings • terminate in lamina I – III • 20 neurons have an oblique projection across the spinal (1-2 segments) and cross at the ventral white commisure Somatosensory System • “somatic sensation allows our bodies to fell, to ache, to chill and to know what its parts are doing” • How does it differ from the other sensory systems? • receptors are distributed throughout the body • system is a group of four senses • touch • temperature (innocuous) • body position • pain/nociception (pain = meaning given to nociception) • Which functional tasks does it have to perform? • for each stimulus it must encode: • quality (what?) • magnitude (how much?) • location (where?) • temporal pattern (when?)Hadley Wickham 17 08/12/10
  18. 18. Quality • adequate stimulus is the stimulus that requires the least amount of energy to stimulate the receptor • eg. 1-2 photons or pressing on the eyeball triggers receptor • energy contained in 1 or 2 photon much less than the mechanical energy of pressing on the eyeball, so light is the adequate stimulus • receptors often received different stimului but usually most are most sensitive to one, determined by the non-neural components • eg. Pacinian corpuscle, layered like an onion with many mechanoreceptive Na+ channels, triggered by both application and removal of a mechanical stimulus • slow and rapidly activating receptors • slow good at determining duration • rapid good at determining positionMagnitude • digital encoding: magnitude ↑, AP frequency ↑ • temporal summation: if stimulus frequency ↑, AP frequency ↑ • spatial summation: magnitude ↑, receptors recruited ↑ (can cut mesentry without pain, but very painful if dragged)Location • receptive field: one neuron may receive input from many receptors, activation of any of these receptors will lead to the same response • two-point discrimination: requires stimulus of two different (even if overlapping) receptive fields • somotatopy: map of the surface of the body in the brain (related to receptor density, not surface area)Temporal • can tell much more about a surface by moving your hand over it, compared with resting your hand on it • in the brain the 10 sensory area shows no recognisable pattern in response to a vibrational stimulus • however, the 20 sensory area shows a clearly phasic response • ensemble encoding: the 20 sensory area assembles information from several lines of receptors Visual System • visual system has a number of functions, including: • object identification • localisation • composed of perception for action and perception for analysisClassical View • involved with the appreciated of form and pattern • retina specialised outgrowth of nervous system, very high resolving power (perhaps better than any other) • 125 million rods, 6-7 million coneHadley Wickham 18 08/12/10
  19. 19. • 1 million nerve fibres from eye • very sensitive to movement, especially on periphery • reflex action draws eyes towards movement • locates and identifies movement • highly foveating animals have eyes that are always moving with intent • detection of brightness is active over a very wide range • basic function is the detection of contrast • detection of distance (absolute and relative) • specialised cells detect disparities between the two eyes • many monocular clues but diocular is the most important for accurate localisation • many parallel pathways between eyes and cortexHadley Wickham 19 08/12/10
  20. 20. Movement Motor UnitsSymptoms/Terms • paralysis = no voluntary movement • monoplegia = one limb paralysed • hemiplegia = left or side of body paralysed • paraplegia = both lower limbs paralysed • tetraplegia = all limbs paralysed • paresis = weakness • ataxia = incoordination • decomposition of movement • dysmetric (finger-nose-finger test) • involuntary movements (eg. epileptic fit, rest tremor, intention tremor) • abnormalities of muscle tone (eg. hypotonia/hypertonia, spasticity, rigidity) • apraxia/dyspraxia (loss or impairment of acquired motor skills)Motoneurons • motoneurons and muscles form the final pathway for these disorders • located in motor nuclei in the spinal cord and brainstem (all CN except for I, II & VIII) • two types: • α-motoneurons: innervate extrafusal muscle fibres, directly responsible for generation of muscle force, containing fast and slow firing elements • γ-motoneurons: innervate intrafusal muscle fibres, responsible for controlling excitability of stretch receptors in muscle spindlesMotor Units • motor units are functional elements of the motor system • components are: • cell body of an α-motoneuron • axon • all NMJ’s formed by a single motoneuron • all muscle fibres innervated a single motoneuron • innervation ratio varies from 5 to 2000 muscle fibres per motoneuron Classification • motor unit vary not only in size but also in biochemical and physiological properties S Type FF type (Type I or (type II or slow) fast) Units +++ +Hadley Wickham 20 08/12/10
  21. 21. Axon diameter + +++ Terminals + +++ Tetanic contraction + +++ Speed of contraction + +++ Fatigue 0 +++ Metabloism aerobic anaerobic Mygolbin +++ + Glycogen + +++ Mitochondria +++ + Capillaries +++ + Muscle fibres small, red large, pale Recruitment early lateDisease of Motor units Disorders of Muscles • eg. myotonic muscular dystrophy Disorders of Motoneurons Myopathies • inherited (eg. Duchenne muscular dystrophy) • acquired (eg. secondary to endocrine, toxic or metabolic disturbances) Axotomy • injury to axons results in changes both proximal (chromatolysis) and distal (Wallerian degeneration, terminal degeneration, myelin debris, microglial macrophage infiltration) to lesion • loss of synaptic transmission within hours • degeneration of distal part of axon follows 4-5 days after injury, presynaptic boutons degrading first • chromatolysis (breakdown of rER) signals that cell is preparing for regrowth • axon regeneration (1-4 mm/day) is facilitated by Schwann cells • reinnervation of some muscle fibres and partial recovery of function • Schwann (ie. PNS) cells secrete growth factor, oligodendrocytes (ie. CNS) secrete inhibitory substance Peripheral neuropathies • demyelinating disorders reduce AP speed, increase interference and can block conduction • myelinated sections of axons have specific membrane modifications (ie R↑, C↓, K+ channels↑, Na+ channels↓) so dysfunction occurs in myelination is removed • eg. Guillan-Barre syndrome, adrenoleucodystrophy Disorders affecting cell bodies of motoneurons • amylotrophic lateral sclerosis • degeneration of anterior horn cells, motor nuclei in medulla and corticospinal tract • aetiology is unknown, possibly due to excitotoxicity mediated by GLU • combination of muscle wasting and spasticity • syringomyelia • large cavities form in the spinal cord and compress anterior horn cells (LMN signs) • unknown aetiologyHadley Wickham 21 08/12/10
  22. 22. • poliomyelitis • acute viral infection leading to muscle paralysisExamples Myotonic Muscular Dystrophy • myotonia (stiffness ↑, don’t relax immediately after contraction), wasting and weakness of muscle • theory: failure of Ca2+ uptake • autosomal dominant trinucleotide repeat disorder Duchenne Muscular Dystrophy • muscle weakness (can head to respiratory or cardiac failure) • becomes evident in early life • x-linked recessive disorder (frame-shift deletion) Myasthenia Gravis • Ach receptors ↓, EPP ↓, safety factor ↓↓ • usually auto-immune disorder Botulism • food poisoning (toxin from Clostridium botulinim) • impairs release of Ach at peripheral synapses and ANS ganglia • leads to weakness of striated and smooth muscles (+ ANS dysfunctions) Muscle ReflexesFinal Common Path • α-motoneurones are the final common path for a number of inputs: • descending tracts (cortico-spinal, rubro-spinal, vestibulo-spinal, tecto-spinal, reticulo-spinal) • segmental interneurons • propriospinal neurons • muscle receptorsSpinal Reflexes • roles of receptors in control of movements: • to more a part of the body the motor control system must first have information about the current position of that part of the body and length of the muscle that controls it • as the motor act progresses, it is aslo necessary to have continuous information about the state of the muscles, the position of that part of the body, and the velocity with which its relationship to the target is changing • to initiate a new movement through reflex actions • major grows of receptors which can control movemnts or initiate spinal reflexes are: • muscle spindles (in parallel to the extrafusal muscles fibres, monitors length) • golgi tendon organs (in series with extrafusal muscles fibres, monitors tension) • nocioceptive receptorsHadley Wickham 22 08/12/10
  23. 23. • joint receptorsStretch (Tendon) Reflex • evoked from muscle spindle by a stretch of vibration of the muscle • only monosynaptic reflex in the body • components • receptors: muscle spindles • afferents: 1a afferents (fastest, 100 m/s) • synaptic delay: GLU synapses on α-motoneurones • efferents: axons of α-motoneurons (40-80 m/s) • effectors: homonymous of synergistic muscle • latency of the knee jerk reflex is about 25 ms • other features of stretch reflexes include: • stimulus dependency • symmetry • non-fatigable (‘S’ motor units recruited first) • facilitated by voluntary movement (Jendrassik manoeuvre) • evoked by electrical stimulation of 1a afferents (H-reflex) • reciprocal inhibition ensures that complementary muscles relaxγ-Motoneurons • innervated intrafusal muscle fibres located in distal muscle spindle • activation of γ-motoneurons usually precede activation of α-motoneurons but does not occur in isolation • activation of intrafusal muscle fibres leads to stretching of the central zone of spindles and activation of 1a afferentsGolgi Tendon Organ Reflexes • under physiological conditions, reflex plays role in adjusting tension among muscles during motor task • evoked through inhibition of tone in muscle whose tendon has been stretch (homonymous muscle) and excitation of antagonistic muscles • additional roles are to protect muscles from overloading and compensate for muscle fatigue • threshold higher in the disease of UMNs (clasp-knife reflex) Injuries of Spinal Cord/BrainstemInjuries of Spinal Cord • most frequent traumatic injuries of the CNS • can be caused by traffic accidents, malignant tumours, demyelination, posterior intervertebral disc protrusion, syringomyelia Hemisection (Brown-Séquard syndrome) • small area of LMN paralysis at level of lesionHadley Wickham 23 08/12/10
  24. 24. • monoplegia and hypereflexia ipsilateral and below lesion • loss of pain and temperature sensation contralateral and below lesion • loss of fine discrimination and proprioception ipsilateral and below lesion Acute Complete Transection (Spinal Shock) • Spinal shock – temporal period areflexia due to loss of facilitatory input from reticulospinal and vestibulospinal tracts • paraplegia, areflexia • anaesthesia • blood vessel dilation, thermal sweating absent (SNS ↓) • bladder and bowels atonic • dysfunction of sexual organs • partial recovery and additional symptoms • recovery of muscle tone • hyperactive muscle stretch reflexes • spontaneous emptying of bladder and rectum • BP↑ (autonomic dysreflexia) • flexor (withdrawal) reflex after many months • extensor plantar reflex • paraesthesia • mechanisms of recovery • sprouting of presynaptic terminals (synaptic plasticity, can be enhanced by neutralising myelin inhibitory protein, tissue bridges and giving certain growth factors) • dennervation supersensitivity • release from inhibitionBrainstem Lesions Decerebrate Rigidity • large increase in tone of extensor muscles after transection between sup and inf colliculi • persists indefinitely • involvement of brainstem reticular formation (loss of excitatory input via corticoreticulospinal tract to medial inhibitory area and lat vestibular nucleus) Other Brainstem Lesions • far more likely to be fatal as vital respiratory and cardiovascular centres lie in brainstem • produce widespread sensory and/or motor defects • motoneurones associated with cranial nerve nuclei are often affected Injuries to BrainStroke • sudden and focal impairment of and/or sensory functions resulting from disorders of blood vesselsHadley Wickham 24 08/12/10
  25. 25. • vascular occlusion (80%) atherosclerosis or thrombosis • haemorrhage (20%) more destructive • symptoms occur within seconds, irreversible damaged within minutes • stroke is third leading cause of death (following heart disease and cancer) • two milder forms occur: • transient ischaemic attack (TIA) symptoms last < 24 hours • reversible neurological deficit (RIND) symptoms last < 2 days • symptoms • arm (mid cerebral a.) • leg (ant cerebral a.) • impaired vision (post cerebral a.) Mechanisms of Neuronal Death • neuronal depolarisation (Na+↑, Cl-↑, intracellular oedema, ICP ↑) • intracellular Ca2+ accumulation • enhanced release of excitatory neurotransmitters → excitotoxicity • reperfusion damage involving free radicals Treatment • anticoagulants/thrombolitic agents • antagonists of Ca2+ or Na+ channels • antagonists of excitatory amino acidsHadley Wickham 25 08/12/10
  26. 26. Neuroradiology Introduction • historically it has been very difficult to figure out what’s going on in the brain, because you can’t operate • brain very unforgiving with almost no room for movement and very tightly packed • unable to make standard x-rays of the brain because of the skull (103 years ago) • if you could fill the ventricles with air, you’d be able to observe the brain (albeit indirectly) • lacrimal plate weak and easily broken, leading to a communication between the ventricles and the outside • injected air into lumbar CSF and tumbled patient to distribute it evenly around the ventricles • intensely painful, leading to vomiting and intense headaches • very useful because the only way to localise tumours (by observing displacement of ventricles) • 1920’s Portugese radiologist injected thorium into arteries to get an arteriogram of the brain • still done but with more innocuous contrast and through the femoral vein • can be used to detect tumours by observing arterial displacement • CT was the first technology to give actual views of the brain, though only in axial slices • MRI was the next revolution allowing axial, coronal and sagittal sections of the brainCSF • constantly made and destroyed (~500 ml/day) • made in the choroid plexuses (hanging in the lateral ventricles) and the lateral walls of the lateral ventricles • travels from the lateral ventricles to the 3rd ventricle then the 4th ventricle through the cerebral aqueduct • absorbed by the arachnoid granulations into the venous system • can become blocked between lateral and 3rd ventricles or 3rd and 4th ventricles (aqueductal stenosis) or in other places • may be caused by inflammation, infection, meduloblastoma, etc. • causes “water on the brain”, ie. hydrocephalus = CSF ↑Haemorrhages Extradural • extradural haemorrhage (between the skull and dura) will rip dura away from the bone, tearing meningeal vessels • tough connections between bone and dura will give a tamponade effect and a characteristic lens shape • often from middle meningealHadley Wickham 26 08/12/10
  27. 27. Subdural • between dura and arachnoid • often due to torn bridging veins especially sup sagittal sinus • tends to bleed quite freely Subarachnoid • sometimes blood can be found the in the CSF indicating a subarachnoid haemorrhage • 90% are due to a ruptured berry aneurism (most commonly in the ant. & post. communicating aa. and the 1st branch of the middle cerebral) or trauma • DIAGNOSTIC: blood in fissuresHadley Wickham 27 08/12/10
  28. 28. Clinical Myotatic (Muscle Stretch) Reflex • 2 components • phasic (rapid, brief, eg. tendon jerk) • tonic (weak, long lasting, eg. tone)Tendon Jerk • stretch reflex (eg. knee jerk) is monosynaptic • elicited by tapping tendon with a tendon hammer • tap tendon → muscle stretched → intrafusal muscle spindles depolarise → signal along 1a neurons • monosynaptic reflex with α-motor neuron causes muscle contraction (synapses with all ant. horn neurons for that muscle) • synapses (via inhibitor interneuron) with ant. horn cells of antagonistic muscle • γ-motor neuron supplies intrafusal muscle fibres, acting to keep muscle spindle fibres taut and responsive to stretch Characteristics • involuntary • stereotyped • stimulus depend • non-fatiguing • stimulus strength proportional to response amplitude Affected By • underlying muscle activation (Jendrassik effect, contraction in higher level muscles increases amplitude and sensitivity, contraction in same muscle causes decreased response, variable between people) • anxiety • sleep Clinical • reduced: lesion in sensory axon, ant horn cell, motor axon, muscle • increased: lesion in inhibitory desc. tractsTone • force with which muscle resists being lengthened • two components • muscle • neural (tonic stretch reflex)Hadley Wickham 28 08/12/10
  29. 29. Characteristics • velocity dependent (slow: rigidity, fast: spasticity) • different response in different muscle groups (eg. UMN spasticity in arm flexor and leg extensors) Clinical • clonus (rapid, sudden muscle stretch leader to repeated contraction and relaxation) (UMN) • rigidity: diseases of basal ganglia (eg. Parkinsons), non-selected, non-velocity dependent • spasticity: enhanced stretch reflexes, selective, velocity dependent (test by pulling knee up when patient lying flat on back) Sensation • most difficult and unreliable part of examination, leave until you know what you’re looking for General Rules • demonstrate stimulus over a part where you know sensation will be normal (eg. over sternum) • most of the examination should be done with the patients eyes closed • apply stimuli at irregular intervals so patient can’t anticipate them • don’t slant your questions towards the abnormal • move from area of decreased to normal sensation • draw a diagram to show sensory abnormalities Modalities • light touch • pinprick • temperature (shouldn’t need to do if pinprick tested properly) • vibration (no physiological basis, but reliable and convenient) • deep pain • discriminative sensation: • two point discrimination • stereognosis • graphthaesia • bilateral simultaneous sensation (sensory inattention) Parkinson’s • three major symptoms: • rest tremor (“pill-rolling”) (asymmetric) • hypo/bradykinesia • rigidity • non-motor symptoms include: • sensoryHadley Wickham 29 08/12/10
  30. 30. • pain • ANS dysfunction • depression • dementia • caused by the degeneration of dopamine cells in the SNC • aetiology unknown but may involve • genetic susceptibility (gene mutation on chr 4 causes early onset form of Parkinson’s) • toxins: MTPT-Parkinsonism (narcotic analogue, used in animal models) • infection: Von Economo’s encephalitis • 80% on one side must die before any effects become apparent • always starts on one side only, but may eventually progress to involve both • leads to decreased activity of all cells in the motor cortex • treatment • drugs • L-Dopa (dopamine precursor) + dopa decarboxylase inhibitor • dopamine agonists (side effects tend to be worse than L-dopa) • anticholinergics • monoamine oxidise B inhibitors • catechol-o-methyltransferase inhibitors • kill cells in the globus pallidus (tremor↓, rigidity↓), 75% cure rate • kill cells in the thalamus • transplantation of dopamine producing tissue • deep brain stimulation Cerebellar • six years ago couldn’t walk straight (like a drunken walk), about six months later saw her GP who referred her to a neurologist • started using a stick, mainly for use outside, walking to letter box etc. • finds it very easy to loose balance (especially when turning quickly) and has some problems getting her left foot started • both father and sister had the same problemSigns • slight dysarthria • normal muscle tone, reflexes and proprioception • rapid alternating movements slightly slowed • finger-nose-finger test jerky and slightly inaccurate • has trouble standing with feet together • walking jerky, with lateral displacement of feet (better centre of gravity), stride length unevenHadley Wickham 30 08/12/10
  31. 31. • intention tremor in both hands and feet (worse in feet) • other signs that may be visible: nausea, vomiting, visual symptoms (eg. nystagmus, oscillopsia) Scans • widened cerebellar folia • general degenerationDiagnosis • spinocerebellar ataxia – a slow, progressive, genetic disorder • to achieve a diagnosis you must determine the location (from exam) and cause (from history and others) of the lesion • the time course of the disease can also be very revealing Pathways of Vision Stroke Psychotic Disorders • experiences qualitatively different to normal experience eg. hallucinations • involve whole of personality • usually associated with loss of reality testing (ie. loss of “insight”) • behaviour may be conspicuously disorderedSchizophrenia • person sees an event and attributes it to a reality that shouldn’t be (delusions of reference) • remember: a person may have a disorder but it is not them (you may have schizophrenia but you aren’t a schizophrenic) Diagnosis • positive symptoms – delusions, hallucinations, disorganised speech/behaviour • false beliefs out of character for persons cultural and social background • structured in an unusual way and very compelling • common feeling of external control • negative symptoms – amotivation, restricted affect, poverty of speech • social/occupational dysfunction • at least six months in duration • not due to general medical condition Epidemiology/Aetiology • lifetime risk is 1% (annual incidence 1/10,000)Hadley Wickham 31 08/12/10
  32. 32. • prevalence equal in males and females but females may have a better outcome and males have an early onset (15-25 vs. 25-35 in females) • both genetic and environmental factors important (first degree relative 10-15% risk) • CT, MRI, etc. show abnormalities in brain structure and function in some subjects • stress, or drug use can precipitate relapses Clinical Features • prodromal phase – social withdrawal, loss of interest, irritability, poor self-care, vague unease • acute phase – delusions, hallucinations, disorganised speech • residual phase – amotivation, social withdrawal, restricted affect, poverty of speech • subtypes – paranoid, disorganised, catatonic, undifferentiated, residual Treatment • must establish a good relationship with the patient • early intervention (ie. 1st episode) improves outcome • antipsychotic drugs block dopamine and are good for positive symptoms but have side effects • new drugs (clozapine, risperidone) reported to have greater effect on negative symptoms • education • decrease interpersonal stress (problem solving, communication skills etc.) • decrease social stress (help with accommodation, work, etc)Bipolar Mood Disorder (manic-depressive psychosis) • cyclic changes in mood from mania (elation, happiness, euphoria) to depression • two poles: • mania: motor activity ↑, euphoric, excited, less sleep, delusions of grandeur, appetites ↑, feeling of omnipotence → may destroy life very rapidly • depression: lower mood, extremely sad, lack energy, slow thinking (can’t make sense of anything), difficult of function, guilt, deserve punishment, suicide • cycles take about 4-5 months at the minimumHadley Wickham 32 08/12/10
  33. 33. Analgesia/Drug Abuse History • In 1965, Wall & Melzack proposed the gate control theory of (ie. there is maximum amount of information that can flow into the spinal cord) • Actually more complicated (inhibitory interneurons are stimulated by tactile feedback) than this, but essentially their theory was correct • Nocioception (the pain stimulus) can be measured, but pain itself can’t, because it passes through the “black box” of the CNS • in 1979 a new definition of pain was made, including the following statements • pain is an unpleasant sensation • involves both sensory and emotion components • usually associated with tissue damage, or described in the context of tissue damage • always subjective • pain is sometimes felt in the absence of nocioception (eg. phantom pain from amputated limbs) • nocioceptive input is processed mainly in the dorsal horn of the spinal cord, influenced by: • transmitters • inhibitory descending pathways (from brain stem and cortex) • sensory pathways (eg. tactile input) • it is then transmitted to the brainstem (arousal, respiration, and hypertension), thalamus (emotions) and cortex (somatosensory) • nocioception can be caused by mechanical, chemical (acids, K+) and temperature (>420C) • first reaction to pain is the spinal reflex (withdrawal), to minimise any further damage • amount of pain control required is proportional to the amount of descending inhibition Analgesics • can block pain at any of the sites between the nocioception and the brain, these include: • free nerve endings (NSAIDs inhibit PG formation and prevent nocioceptor activation) • nerve transmission (local anaesthetics prevent development of electric potential, distance to spinal cord↓, amount required ↓↓, effect ↑↑) • increased interneuron inhibition (TENS) • increased desc. pathway inhibition (hypnosis, relaxation and amitripyline) • spinal cord to brain/brainstem (systemic opioids) • separation between peripherally and centrally acting drugs neither correct nor useful • generally classified as either opioid or non-opioid, but this isn’t terribly usefulHadley Wickham 33 08/12/10
  34. 34. Non-Opioids Para-aminophenol Derivatives • paracetamol is the only drug currently used in this category • phenacetin (a paracetamol pro-drug, was used up until the 1950’s, but was withdrawn because of a side reaction which produce a highly nephrotoxic substance) Benefits • extremely harmless, except in large doses • very little gastric irritation, and no effect on clotting times • minimum toxicity (except at doses greater than 6g/day) • nearly complete bioavailability Problems • image problem, seen by public as of little use for serious pain, generally under utilised • induction of methaemoglobin and haemolytic anaemia in patients with a rare genetic disorder (glucose-6-phosphatase deficiency) • extremely dangerous is taken in sufficient quantity (or with alcohol or severely malnourished), due to centrilobular liver necrosis caused by the production of N-acetyl-p- benzoquinone (formed with insufficient supply of glutathione in the liver) (treated with acetylcystein, which replenishes supply) Conclusions • + very rare side effects • + high patient acceptance • + high patient bioavailability • - limited efficacy • - no parenteral formulation • (- hepatotoxicity) NSAIDs • oldest NSAID is aspirin, but now over 55 are available (in principle almost completely interchangeable) • inhibit COX (arachidonic acid → PGs), PG production ↓ • PG are the main mediators of inflammation, pain and fever • should only be used when anti-inflammatory effect also necessary • selective COX inhibitors look very promising by only reducing the PG (inducible) produced in inflammation, not constitutional PGs Benefits • have a central antipyretic effect by prevention of pyrogen-induced PG release in the hypothalamus • unbeatable (even better than morphine) in situation of pain and inflammation (eg. wisdom tooth extraction) • very good for joint and soft-tissue pain • not effective for neurogenic painHadley Wickham 34 08/12/10
  35. 35. Problems • gastric irritation and ulceration (especially duodenal) (PG play important role in maintenance of gastric mucus) • renal dysfunction (PG important in rescue perfusion of kidney in situations of hypovolaemic/hypotension) • prolongation of bleeding time (production of thromboxane A2, important in clotting, inhibited) • allergic reaction (asthma induction because LK production ↑) Conclusions • + proven analgesic effect • + useful anti-inflammatory effect • - adverse effects limit use • - renal problems in clinical setting ↑Opioids • longest used analgesic (from 3000BC, when it was used in the treatment of diarrhoea) • reacts in humans like a receptor binding drug: • only L-isomers display bio-activity • dose/effect curve shows plateau • antagonism (eg. by naloxone) reverses all effects • endogenous opioids = endorphins and enkephalins, produced by the body to moderate pain • have very short half life compared to morphine Sites of Action • supraspinal (activates desc. pathways of pain control) • periaqueductal grey (IV ventricle) • periventricular grey (IV ventricle) • area postrema (also causes vomiting) • spinal (can target spinal receptors and avoid system effects) • substantia gelatinosa • peripheral (may be useful in the future, currently used only in arthroscopy) • expressed only after injury Function • opioids are the 10 messenger • triggers the release of two 20 messengers: • cAMP ↓ (G protein activation) • Ca2+ ↓ • triggers 30 messenger, resulting in changes in gene expression (early intermediate genes) Effects Useful • analgesiaHadley Wickham 35 08/12/10
  36. 36. • anxiolysis (anxiety↓) • cough depression Side effects • euphoria • sedation • constipation Side effects – harmful • respiratory depression (increased threshold and decreased sensitivity to CO2) • nausea/vomiting • visceral spasms • dysphoria Long Term • tolerance (very rare) • physical dependence (occurs in most patients using for more than 10 days, weaning off prevents withdrawal) • addiction (doesn’t occur when used to treat pain) Opiophobia • opiophobia = customary under utilisation of opioids • based on irrational fear that appropriate use will lead patients to become addicts • patient perception is that it is for severe pain/terminal cases Miscellaneous Definitions • narcotic = addictive drug (used by law enforcement agencies) • opiate = drug that has plant origin and binds to opiod receptor • opioid = drug that binds to opiod receptor Relevant Drug Properties • receptor specificity (opioids should bind only to the μ subtype) • receptor affinity/potency (“extrinsic affinity”, receptor binding) (not important) • efficacy/maximum effect (“intrinsic activity”, receptor activation) • active campaign by regulatory agencies to increase use around the world Drug Abuse • drug misuse = taking drug for wrong indication at wrong dosage for too long • drug abuse = any use of drug for non medical purposes almost always to alter consciousness • in common use connotes social disapproval • different meaning to different people and cultures • eg. alcohol, caffeine and nicotine are all drugs used for non-medical purposesHadley Wickham 36 08/12/10
  37. 37. • any use of mind-altering drugs is based on complicated theory involving • user • setting (availability, social tolerance, experience) • drug • eg. experience of Vietnam airforce staff: high use of heroine in Vietnam, but returned to normal when they returned • simple exposure to drug not sufficient to provoke abuse • prohibitive measures don’t seem to reduce incidence of abuse (about 5% regardless of drug) Tolerance • pharmacological term • with repeated administration increased doses required for same effect • tolerance development impairs return to normal, but does not equal addiction • different types of tolerance include • metabolic/pharmacometric (eg. barbiturates induce enzymes) • pharmacodynamic – receptor changes (number ↑, effect ↓) (eg. β-agonists) • behavioural (eg. alcohol, stay sober for longer but same doses still kill) • don’t get tolerance to opioids if used for pain relief (maybe related to endogenous endorphins) Physical Dependence • pharmacological process • occurrence of withdrawal symptoms after abrupt discontinuation of drug or administration of antagonist • not addicted, receptor system merely adapted to higher doses • non-addictive drugs (eg. clonidine and β-blockers) so physical dependence • addictive drugs (eg. cocaine) may have little physical dependence • more than 7-10 days on morphine leads to physical dependence, but withdrawal effects can be limited if the drug is withdrawn gradually • withdrawal effect rebounds in the opposite effect to the drug Addiction • behavioural pattern of drug use, characterised by overwhelming involvement with use of drug (compulsive use), securing of its supply and high tendency to relapse after withdrawal (WHO) Pseudo Addiction • behaviour perceived as drug seeking but representing, in reality, an attempt to get appropriate pain relief in the face of previous undertreatment of pain Drugs of AbusePharmacological Properties Pharmacodynamics • mind altering • rewardHadley Wickham 37 08/12/10
  38. 38. • positive reinforcement (gain positive ability) • negative reinforcement (avoid negative experience) • (social reinforcement) (eg. cigarettes) Pharmacokinetics • rapid onset (eg. heroine vs morphine, crack vs. cocaine) • short duration (more highs per day, eg. cocaine vs. methadone)Dopamine – Molecular Basis for Reward? • dopamine system reinforces behaviours • antagonists generate withdrawal effects • drugs of abuse interfere with dopaminergic system • cocaine induces dopamine receptor down regulation • increase concentrations of dopamine induces “high”-like behaviour and indifference towards abuseSpecific Types Opioids • was widely practised habit (especially in China and Asia) • after civil war 4% of Americans used opium regularly, last boom was in 1964 • now ~600,000 are dependent (but 6,000,000 are alcoholics!) • get high immediately after use, leading to euphoria, happiness and complete satisfaction with life • problems: don’t know what you’re buying (concentration, purity, etc) • withdrawal within 8 hours with shivering, goose bumps, nausea, vomiting ,pain, involuntary movements, insomnia, hypertension and hyperventilation • lasts 7-10 days • can be reduced by reducing sympathetic overdrive (eg. with clonadine) • don’t usually die but still suffer craving • methadone substitution programs work quite well (60-70% successful) • no craving, clean drug, very few health risks • drop out rate still high, and some seek cocaine (uses different receptors) • opposite treatment is to give opioid antagonist (naltrexone) with a long half life Alcohol/Sedatives • striking similarity in patterns of abuse lead to alcohol and sedatives being grouped together • increasing relevance of benzodiazapines because of increasing addiction, but better than barbiturates which tend to be fatal • often use both agents, leading to very high risk of death/severe injury • probably most relevant abuse pattern in our society • alcohol withdrawal leads to delirium, hallucinations, fear, nausea, vomiting and convulsions (dangerous) • best treatment option seems to be group psychotherapy, counselling and complete abstinenceHadley Wickham 38 08/12/10
  39. 39. • pharmacological methods use long acting benzodiazapines and slowly reducing dose (10-15% per week) Stimulants • include caffeine, cocaine and amphetamines • cocaine use common for at least 1,200 years in chewing coca leaves (especially in South America) • in Europe since the 1860’s • strongest reinforcing agent in animal experiments, but questionable physical dependence • amphetamines used during WWII by American airforce pilots because they reduce fatigue • stimulants often used in combination • can develop psychosis and paranoid schizophrenia, interfere with bodily function (eg. water intoxication with ectasy; malignant hyperthermia) Hallucinogens • include mescalin, psycolobin, LSD, PCP and ketamine • Amerindian used for many years (eg. cactus buttons, magic mushrooms) • close resemblance to major neurotransmitters (eg. NA, serotonin, dopamine) • LSD extremely potent (1 μg/kg), effect very dependent on personality • give nightmares, impair ability to judge situations correctly, panic reactions, psychotic crises • may give flashbacks long after use has ceased • lead to severe psychiatric disease (psychotherapy only treatment available) Marijuana • used for thousands of years • now one of most used drugs, estimated 300,000,000 use it • leads to impairment of psychological function, • limited tolerance and physical dependence • hazards controversial and ambiguous, with no definite evidence • decreases testosterone, narrows airways and can lead to angina pectoris Inhalants • includes NO, amyl nitrate, industrial solvents • factors: peer influence, low cost, readily available, convenient packaging, quick intoxication, short duration, “mood enhancement” • mainly hallogenated hydrocarbons • multiple toxicity problems (including sudden death) caused by numerous toxic ingredientsHadley Wickham 39 08/12/10
  40. 40. Neurotransmission Voltage-Gated Ion ChannelsIntroduction • RMP determined by relative permeability’s of membrane to various ionic species, and the relative concentration of ions inside and outside cell • Nernst potential: ion movement determined by interaction between two main forces, electrical and chemical • when two forces are balanced and there is no net movement of ions across membrane, membrane is at equilibrium, or Nernst potential for that ion • under resting conditions membrane is permeable to more than one species of ion so RMP represents interaction between variety of ions • membrane is much more permeable to K+ than Na+ so RMP sits much closer to EK than ENa • with small changes in membrane potential voltage-dependent ion selective channels open, drastically altering relative permeability of membrane • change in permeability, along with large electrochemical gradients set up for many ions, underlies current flow and ultimately changes in membrane potential Ion Selectivity: How do ion channels conducts ions at high rates and remain selective? • ions become surrounded by electrostatically bound water called “waters of hydration” • ion can’t easily shed associated H2O and must move through aqueous pore to enter cell • structure of ion channels provides hydrophilic domain spanning cell membrane • within lumen, interaction with charged amino acids provides ion selection, biasing population of ions than can pass • regions between S5 and S6 forms this filterStructure Voltage-gated Na+ channels basic repeating structure S4 is voltage sensor 2+ 6 membrane spaning regions S6 lines pore Ca channels 4 subunits region between S5 and S6 K+ N and C terminals intracellular forms selectivity filter Inward rectifiers 2 membrane spanning regions NAchR and relatives 4 membrane spanning regions Ligand-gated ion 5 subunits N terminal extracellular, C terminal intracellular Ligand binding on N-terminal Glutamate 3 membrane spanning regions (M2 goes in and out) 5 subunits ligand binding on N terminalChannel Gating • activation: voltage sensor in S4 detects change in transmembrane voltage, triggers conformational change in channel and pore opensHadley Wickham 40 08/12/10
  41. 41. • inactivation: some channel inactivate, channel opens, N terminal forms a plug and blocks channel shortly after it opens, repolarisation of membrane removes plug so that channel can reopenChannelopathies • channelopathies are relatively rare but often serious Channel Channelopathy Cl- cystic fibrosis: most common fatal genetic disease in people of northern European descent, 1/20 carry mutant form, gene encodes cystic fibrosis transmebrane conductance regulator (CFTR), channel functions properly, but not transferred to cell membrane Ca2+ different mutations in brain specific gene encoding P/Q Ca2+ channel shown to be involved in three different episodic disorders: familial hemiplegic migraine episodic ataxia (type 2) chronic spincerebellar ataxia (type 6) + K episodic ataxia (type 1) long QT syndromes (conditions where repolarisation of cardiac action potential delayed, can result in sudden cardiac death) familial inherited neonatal epilepsies Na+ long QT syndromes • as researchers gain more information about role of ion channel in disease and precise nature of defect associated with disease, new therapeutic targets are emerging • of especial interest in first x-ray crystallography of an ion channelIon Channel Diversity Channel K+ most diverse Ca2+ at least 5 types (L, N, P/Q, R and T) current drugs only on L-type channels, preventing opening, wide application in CV disease for arrhythmia’s, HT and angina Na+ action potential in many tissues appears stereotyped however, cloning studies have revealed at least 9 separate isoforms of channel for skeletal muscle, heath, neurons and glial cells of special interest is one channel found only on small nociceptive neurons Synaptic TransmissionIntroduction • majority of neuron-to-neuron communication occurs at synapses via diffusion of NT from presynaptic neurons, across synaptic cleft, and on to interaction with receptors of postsynaptic membrane • unlike situation at NMJ where single transmitter substance is responsible for communication, very large variety of compounds are employed in CNS • at present, at least 50 substances are known or suspected to act as NT in brain Acetylcholine Amino acids (eg. ASP, GLU, GABA) Biogenic amines (eg. dopamine, A, NA, histamine) Neuropeptides (eg. AgII, ADP, ANP, CCK, endorphins) • Table 1 - Known and suspected NTs • each NT can bind to many receptor types, each producing a different effect • NT’s can have excitatory, inhibitory or modulatory effects • some transmitters actions are rapid and transient while others are slow and long-actingMechanism of Synaptic Transmission Events underlying transmitter release • presynaptic action potentialHadley Wickham 41 08/12/10
  42. 42. • activation of voltage-dependent Ca2+ channels • presynaptic Ca2+ ↑ • Ca2+ binds with intracellular receptors which cooperatively control release of vesicles from terminal • mobilisation of vesicles: release of synaptic vesicles from reserve to release pool (unphosphorylated synapsin binds and keeps in reserve pool, Ca2+ activates kinases which phosphorylate synapsin) • attachment to docking sites • fusion with membrane: synaptophysin (Ca2+-BP, high numbers in vesicles) possibly involved • release of NT by exocytosis • reaction of NT with postsynaptic receptor • activation of ligand-gated channels Role of Voltage-gated Ion Channels • Hodgin-Huxley Na+/K+ channels necessary for AP generation and transmission • LVA (T-type) and HVA (N-type) Ca2+ channels responsible for increase in presynaptic Ca2+ Mechanism for NT Action Ionotropic Receptors • in directly gated transmission, single molecule acts act both receptor and effector • ligand-gated ion channels mediating EPSPs are primarily permeable to Na+ and K+, although Ca2+ can also be involved • channels mediated IPSPs are usually Cl- permeable Metabotropic Receptors • with G-protein coupled receptor, recognition of transmitter and activation of effect are carried out by different molecules • time course of actions is much slower (>10,000x) and usually longer lasting • may different second messenger pathways but share many common features • ultimate action on cellular function is produced through: • direct action of G-protein on channel • ion channel phosphorylation • changes in gene regulation (through phosphorylation of transcriptional regulatory proteins) Removal of NT After Release • rapid removal is critical if cell is to respond to high frequency inputs • there are three main mechanisms of removal: • diffusion: all NTs removed to some degree by diffusion • enzymatic degradation: eg. acetylcholinesterases remove Ach very rapidly (<1 ms) • reuptake: most common mechanism • importance of transmitter removal demonstrated byHadley Wickham 42 08/12/10
  43. 43. • diisopropyl fluorophosphate (nerve gas), a long-lasting anticholinesterase • neostigmine, short lasting anticholinesterase used in treatment of myasthenia gravisNeurotransmitters Definitions and criteria • NT can be defined as substance that is released at synapse by one cell and affects another cell in specific manner • in order for substance to recognised as NT it must meet the following criteria: • be found and be able to be synthesised at presynaptic terminals • be released from presynaptic neuron at appropriate stimulation • microapplication at postsynaptic terminal must have same effect as stimulation of presynaptic neuron • specific mechanism must exist to remove it from synaptic cleft Classification • strength • sign (inhibitory or excitatory) • time course of action Postsynaptic response to NT • determined by NT released and receptor present on membrane • important considerations: • multiple NTs: many neurons synthesise, store and secrete more than one NT allowing for greater potential complexity • multiple receptor subtypes: many NTs bind to more than one type of receptor and response varies according to type of receptor Modulation of Synaptic Efficacy • neuromodulators modulate synaptic transmission by altering amount of NT transmitter release or response • presynaptic: hyper- or depolarisation of terminal, activation of 2nd messenger systems, • postsynaptic: alteration of Ileak, activation of 2nd messenger systems • by binding to different receptors some NTs function as both NTs and neuromodulatorsHadley Wickham 43 08/12/10
  44. 44. EEG/Sleep/Epilepsy EEG and Physiology of SleepEEG • non-invasive test of brain function • records spontaneous electrical activity of cortex, detects changing potential differences between difference scalp locations • potential differences usually in order of 10-100 μV • represent fluctuating sum of excitatory and inhibitory post-synaptic potentials in apical dendrites perpendicular to surface • amplitude and rhythmicity varies with state of arousal and brain pathology • waking state is characterised by: • α (8-13 Hz) and β (14-20 Hz) waves • α-activity is suppressed during mental tasks and by eye opening • in adult activity in θ (4-7 Hz) and δ (1-4 Hz) ranges may signify encephalopathy • major clinical role of EEG is in diagnosis and management of epilepsy • seizures characterised by stereotyped sequence of events beginning with suppression of ongoing rhythmical activity and appearance of low voltage fast activity • role of EEG in epilepsy enhanced by common occurrence of specific EEG discharges interictally • have form of spikes or sharp waves that stand out from background rhythms Evoked Potentials • consist of change in CNS activity in response to visual, auditory or somatosensory stimulus • some are relatively large (eg. flashing bright light) and can be distinguished from background activity, used to detect lesions in sensory pathways • others (such as auditory) require computer summation of thousands of response, used to detect brainstem pathology and screen for hearing lossPhysiology of Waking and Sleep • in adult waking state defined by purposeful quality of response to environment and be presence of intact memory • sleep is temporary suspension of this • amnesia for events that take place between onset of sleep and time of awakening • exact point of transition difficult to apply in practice and usually defined by EEG • drowsiness (Stage 1 sleep) characterised by: • loss of visual fixation, and appearance of slow eye movements • reduction in level of α-activity and intrusion of θ-activity • specific EEG transients, spindles and K-complexes define onset of true sleep (Stage 2) • if sleep maintained high voltage δ-activity becomes increasingly prominentHadley Wickham 44 08/12/10
  45. 45. • Stage 3 sleep defined as presence of high voltage δ-activity 30-70% of the time • Stage 4 sleep defined as presence of high voltage δ-activity >70% of the time • quality and duration of δ sleep somewhat dependent on time of day but mostly influenced by sleep history • behaviourally, sleep stage 2, 3 and 4 categorised as non-REM • postural (tonic) muscle tone is high, especially in anti-gravity muscles of jaw and neck • phasic muscle activity (eg. eye and limb movement) is absent • when sleep maintained for >90 minutes transition to REM may occur, especially during night sleep episodes • transition often heralded by isolated REM • at onset body movement is followed by sudden fall in postural muscle tone • burst of REM then become prominent • EEG reverts to low voltage pattern resembling that seen in drowsy state • REM sleeps persist for up to 40 minutes before tonic muscle activity is restored following a body movement and stage 2 sleep transients reappear • both propensity for REM sleep and duration are determined by endogenous circadian rhythm and are linked to nadir of body temperature cycle • individual entrained to day-night environment and sleeping 7-9 hours experiences most δ sleep in first 2-4 hours and most REM sleep in early morning hours, just prior to waking • circadian rhythm of sleep propensity is demonstrated by human subject studied in constant environment • also demonstrated by individuals on ultradian (eg. 30 minutes) sleep-wake schedule • nocturnal and mid-afternoon peaks in sleep propensity • mid-afternoon peak followed by period of wake maintenance followed by ‘gate’ that marks nocturnal increase in sleepinessBiological Rhythms • paired SCN located in ant hypothalamus identified as site of circadian rhythm pacemaker in mammalian species • SCN contains several cell groups defined by cytoarchitecture and expression of peptides • project to and receive projections from ant hypothalamus, retrochiasmatic area and ventromedial area of tuber cinereum • entrainment to light-dark cycle mediated by retina and neural pathways from retina to brain (retinohypothalamic tracts, terminating in SCN) • retinal illumination also causes reduction in NA release at post-ganglionic nerve endings in pineal resulting in inaction of melatonin syntheses • melatonin synthesis in pineal regulated by SCN output in turn modulated by melatonin in feedback loop • may serve function of synchronising SCN circadian close to time of night-fall and contribute seasonal adjustments • administration of melatonin in evening lowers body temperature, promotes sleep and advances timing of body clockHadley Wickham 45 08/12/10

×