1994: Briefly outline CSF function, formation and absorption transcellular fluid Function Formation

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1 1994: Briefly outline CSF function, formation and absorption General: Cerebrospinal fluid bathes brain and spinal cord - Part of body s transcellular fluid Function - Mechanical protection: Low specific gravity protects brain from injury via a cushioning effect o prevents deformation and damage caused by acceleration / deceleration forces with head movement o Water bath effect effective weight of brain 1400g 50g - Buffering ICP: CSF can be translocated from intracranial to extracranial (spinal cord) minimises rapid ICP associated with eg acute space occupying lesion o Once this is exhausted rapid ICP (Monroe Kellie Doctrine) - Constant ionic environment: neurons sensitive to ionic changes o Active transport: Ca 2+ / K + / Mg 2+ o 2 active transport: H + / Cl - - Return of interstitial protein to circulation: Nil lymphatics in brain interstitial protein returned via absorption with CSF into circulation - Acid-Base: Acid-base status important for control of respiration o Min protein in CSF ph changes greater for given PCO 2 cf plasma - Metabolism: Active transport of sugars, amino acids; simple diffusion of gases; removal of waste - Communication: Neuropeptide transport to different regions of brain Formation - Total vol: 150ml o Turned over 3 4 x daily (500ml / day) - Formed in the choroid plexus (>67%) and ependymal cells in walls of the lateral ventricles (33%) - Plasma ultrafiltrate via fenestrated capillary endothelium o Promoted by bulk flow and hydrostatic pressure - Formation not affected by ICP o Dependent on CPP (< 70mmHg perfusion choroid plexus production) - Active transport of electrolytes o Na + at apical membrane of ependymal cells - Passive diffusion o HCO 3 - formed within cells (H 2 O and CO 2 with CA) buffering capacity o Cl - - H 2 O moves down osmotic gradient Differences b/n CSF and plasma - pco 2 (50mmHg) ph (7.33) - protein (20mg/100ml) low buffering capacity

2 - Glucose - Electrolytes Cl - (15%) K + (40%) - cholesterol Absorption - Once formed in lateral ventricles third ventricle aqueduct of Sylvius 4 th ventricle exits foramina of Luscke and Magendie cisterna magna subarachnoid spaces of brain and spinal cord o Absorbed by arachnoid villi (90%) or directly into cerebral venules (10%) - Pressure gradient favouring absorption into venous circulation o CSF pressure absorption - Normally, production = absorption

3 1994: Draw a nerve action potential. Outline its physiological basis RMP: -70mV Threshold: -10mV Depolarisation: to +35mV Nerve axon contains - open ion channels maintain RMP (K and Na channels) - voltage-gated ion channels required to generate action potential RMP: 2 K conductance cf Na (relatively impermeable in resting state) - Arrival of a current membrane potential o Once reaches threshold opening of fast Na channels - Rapid Na influx depolarisation of membrane (action potential) - Na channels close / opening of voltage-gated K channels (slower to open) repolarisation of membrane o Overshoot (after hyperpolarisation) 2 delayed closing of K channels once closed RMP restored - Depolarisation of membrane acts as a current sink for surrounding axonal membrane o Causes membrane potential once reaches threshold depolarisation propagation of action potential - Propagation is unidirectional 2 refractory periods of axonal membrane o Absolute refractory period during depolarisation (1ms) fast Na channels move from open to closed inactive state No further depolarisation can occur o Relative refractory period depolarisation can occur but requires supramaximal stimulus Properties speed of conduction - Axonal diameter diameter = velocity - Myelin insulator with small gaps (Nodes of Ranvier) velocity

4 1996b(1): Explain briefly the physiological mechanisms whereby an action potential arriving at a synapse might not be conducted General: APs are electronic signals conducted along neuronal axons which arrive at a synapse - Synapse is the anatomical site where nerve cells communicate with other nerves, muscle, glands o Consists of pre-synaptic terminal, synaptic cleft and postsynaptic membrane - Mechanisms preventing the conduction may involve any of these Pre-Synaptic Terminal - Arrival of the AP vesicles containing NT released by exocytosis o Via opening of voltage-gated Ca channels - Release of neurotransmitter can be blocked by: o Depletion of neurotransmitter stored in vesicles (eg NA uptake into vesicles by NSRI) o Ca conduction (eg GABA) neurotransmitter release from pre-synaptic terminal o Failure of action potential to propagate to synapse (LA) o Activation of inhibitory interneuron leads to membrane hyperpolarisation failure to propagate AP Synaptic Cleft - Normally: Neurotransmitter diffuses across the synaptic cleft to the postsynaptic membrane where it interacts with receptors - Neurotransmitter diffusion can be impaired by: o breakdown of NT in cleft (eg AChE will break down ACh) o diffusion of neurotransmitter away from the cleft o Reuptake into presynaptic terminal Post-synaptic Membrane - Normally: Binding of neurotransmitter activates receptor leading to o Excitatory post synaptic potentials (EPSP) o Inhibitory PSP (IPSP) - Failure of conduction occurs: o Absolute / Relative refractory periods Activation of post-synaptic membrane AP (1ms) Fast Na channels open : unable to be activated during this time absolute refractory period move to closed inactive state closed active : during transition AP may be generated but only with supramaximal stimulus = relative refractory period o Failure of post-synaptic membrane to reach threshold potential for AP generation inadequate receptor occupancy failure of summation Concurrent IPSP generation (cancel each other out) o Inhibition of conduction Cell hyperpolarisation (eg GABA A R activation Cl - conductance)

5 1997a(5): What is saltatory conduction and what are the advantages of this type of conduction? Many PNS / CNS nerve fibres are coated with a layer of myelin (produced by Schwann cells of PNS; oligodendrocytes of CNS ) lipoprotein complex - Myelin is interrupted at regular intervals where nerve axon is exposed: Nodes of Ranvier (1μm space) concentration of ion channels here Saltatory conduction: Propagation of action potential in a myelinated nerve fibre where the action potential jumps from node to node - Advantages: o Very fast conduction of action potential cf unmyelinated fibres (50 x velocity of unmyelinated conduction) o axonal size for given conduction velocity o Less ionic flux (only at NOR) less energy required to restore RMP Unmyelinated nerve conduction - RMP: -70mV - Membrane exposed to current: once reaches threshold (~-10mV) opening of fast Na channels membrane depolarisation o Membrane depolarises to +35mV o Opening of K + channels, and closing of fast Na channels repolarisation - Membrane depolarisation (local effect) acts as a current sink and causes a rise in membrane potential of membrane ahead o Once reaches threshold membrane depolarisation and conduction of the action potential o Occurs in one direction due to absolute and relative refractory periods of tissue once it has depolarised Myelinated nerve conduction - Once local depolarisation has occurred at Node of Ranvier myelin insulates immediately surrounding membrane ( resistance / capacitance) distance which current sink operates (to next node) nodal depolarisation

6 2000b(6): Briefly outline the physiological control of intra-ocular pressure General: IOP is the pressure within the globe of the eye Normal Range:10 20 mmhg - Exhibits diurnal variation IOP dependent on: - Aqueous vol balance b/n production and absorption - Choroidal blood vol sclera non-compliant blood vol rapid IOP - External pressure (eg extraocular mm tone) Aqueous Humour - Transparent acellular fluid which circulates in anterior and posterior chambers - Produced by ciliary body (66%) and filtration from anterior surface of iris (33%) o Ciliary body production is active process which requires CA - Absorbed into circulation via trabecular meshwork through to Canal of Schlemm o Resistance to absorption in trabecular meshwork is the major factor in IOP Physiological control IOP Aqueous Humour - Drainage (impaired venous drainage): venous pressure / dilatation of episcleral veins (cough, strain); Madriasis (closes the angle b/n iris and trabecular meshwork) - drainage (via venous pressure): intrathoracic pressure; head tilt up; miosis Choroidal Blood vol: - blood vol: PaCO 2 (vasodilation); large MAP; PaO 2 (large) vasodilation - blood vol: PaCO 2 (vasoconstricts) Extraocular pressure: - Blinking: IOP by 10 20mmHg - Pressure (eg Hg prior to surgery) IOP 2 globe vol when removed Pharmacological control - Mannitol: rapid aqueous humour production / absorption - Amiloride (CA inhibitor): rate production aqueous humour

7 2003b(15)/1998a(8): Briefly describe the NMDA receptor and its physiological role in the CNS General: N-methyl D-aspartate receptor (NMDA) is a ligand gated receptor with an intrinsic ion channel - Ligand: glutamate o Requires glycine as a co-agonist to displace Mg 2+ which blocks the cation channel - Receptor: Ligand gated, voltage dependent GPCR receptor - Structure: transmembrane spanning multi-unit receptor with a central ionophore o Resting state Mg 2+ blocks ionophore o Activation leads DAG / IP 3 Ca 2+ conductance through opening of a Ca channel generation of EPSPs Summation reaching of threshold potential generation of AP - Location: NMDA receptors present through brain and spinal cord especially dorsal horn, hippocampus, cortex o Post-synaptic neurons 1. Wind up - C fibres synapse in Lamina II of dorsal horn repeat stimulation multiple partial depolarisations glutamate release NMDAR activation o Allodynia, hyperalgesia, recruitment of non-painful transmission as painful o NMDAR activation expression proto-oncogenes (c-fos) change cell structure and function Role in chronic pain states 2. Memory - Hippocampus / cortex - Early effects via receptor stimulation - C-fos expressions allows long-lasting neuronal behaviour 3. Cell death - Ca influx with NMDA receptor activation trigger apoptosis (seen post CVA)

8 2004a(15)/1997b(3)/1996a(8)/1996b(6): List the physiological factors that determine ICP. Explain briefly how ICP is regulated General: ICP is the pressure within the cranium - Hydrostatic pressure - Normal range: 5 15 mmhg Monroe-Kellie Doctrine - Skull is a rigid container fixed volume - Within the skull o Brain (85%) o Blood (5%) o CSF (10%) - volume of any of these components ICP o Pressure changes initially are buffered by translocation of CSF from intracranial to extracranial sites, may also get brain mass, CBF When exhausted rapid ICP as predicted by MKD Relationship of pressure change per unit vol is compliance (technically elastance) Brain - mass tumour, space occupying lesion (haemorrhage) CSF - CSF production ~500ml/day - Dependent on CPP o CPP (2 ICP) <70mmHg CSF production o ICP up to 30cmH 2 O (22.5mmHg) linear reabsorption CSF o ICP < 7mmHg (9cmH 2 O) min reabsorption CSF - Obstruction of drainage CSF vol ICP - Initially, translocation can compensate for acute ICP Blood - CBF = CPP where CPP= cerebral perfusion pressure, CVR CVR = cerebrovascular resistance - CPP = MAP CVP BUT If ICP > CVP behaves like a Starling Resistor CPP CBF - PaCO 2 CBF by 2-4% per mmhg (b/n 20-80mmHg) o Vasodilatation - PaO 2 nil effect within physiological limits ( CBF <50mmHg PaO 2 ) - T C every 1 C brain metabolic rate by 7% o Metabolism and CBF tightly coupled system - Changes in ICP 2 respiration, cough, strain 2 transient CBF o Can by 60cmH 2 O

9 2005a(10): Write brief notes on the physiological changes associated with sleep Sleep: state of awareness and reactivity to surroundings whilst being easily roused Non-REM sleep: EEG has 4 stages System REM sleep Non-REM Sleep CNS Rapid, low volt irregular EEG, resembles awake Active dreaming CMRO 2 matches awake 4 stages: 1-β & α waves replaced by θ waves 2-Sleep spindles α-like waves) 3-δ waves 4-Sychronised δ waves CMRO 2 Resp CVS RR: irregular, variable TV / MV: more than nonrem pco 2 : clockwise rotation MV v pco 2 curve. po 2 : response hypoxia Upper airway: profound loss of tone AWR: FRC OSA: highly likely HR: irregular, variable BP: varies RR: unchanged MV: ( TV) progressive Blunted, not as much as REM sleep Blunted, not as much as REM sleep Upper airway: progressive loss of tone AWR: FRC OSA: can also occur HR: 10-30% BP: in line 2 loss of muscle pump (venous pooling) Muscle Marked muscle tone hypotonia Some muscle tone Metabolic T C Release ADH Cortisol / sex hormones metabolic rate T C Release ADH Cortisol / sex hormones metabolic rate

10 2005a(10): Write brief notes on the physiological changes associated with sleep General: Sleep is a state associated with loss of reactivity to surroundings and reflexes and awareness but from which individual can be roused - 2 different kinds of sleep: o Slow-wave (non-rem) sleep o REM (rapid eye movement) sleep Slow wave (non-rem) sleep - inhibition of pontine and medullary nuclei - EEG: synchronised low-frequency waves - 4 stages: o Stage 1: going to sleep β- & α-waves replaced by low voltage θ-waves (4-6Hz) o Stage 2: Bursts of high frequency α-like waves sleep spindles o Stage 3: High voltage δ-waves (1-2 Hz) with bursts of rapid waves (Kcomplexes) superimposed on top o Stage 4: Large δ-waves become synchronised REM Sleep - Rapid, low voltage irregular EEG - Similar to EEG in alert state Cardiovascular - Heart is a demand pump - During sleep tissue metabolic demands are minimal o Resting CO ~5l/min o 750ml/min to brain - SNS activation / PNS activity to heart o SVR low ( MAP) Cerebrovascular resistance is low hydrostatic pressure 2 gravity (head is in line with heart) o HR (especially during slow-wave sleep) More irregular during REM sleep - Metabolic requirements of heart minimal (250ml/min) - Venous pooling of blood o Dependent areas (lungs, periphery) o tendency for venous return Respiratory - Airway tone: tone of upper airways during slow-wave sleep (especially tongue, pharynx) caliber of upper airway o Worse in men can lead to closure of upper airway during inspiration Intermittent snoring Complete sleep apnoea

11 - FRC: 2 recumbent position ( rib movement, diaphragm rises into thorax), venous pooling within thorax - Dependent atelectasis: compared to erect position (posterior lung) - MV o tidal vol o RR (1 during slow-wave sleep) Irregular during REM sleep Neurological - CMRO 2 Renal - urine production ( ADH secretion) Musculoskeletal - Overall muscle tone 1 during REM sleep o venous pooling o SVR Hormones - ADH - glucocorticoid production (especially during REM sleep) Body Temp - 2 metabolic rate

12 PAIN - Unpleasant sensory / emotional experience associated with actual or perceived potential tissue damage, or described in terms of such damage DETECTION - Nociceptors afferents made of myelinated Aδ and unmyelinated C fibre (more prolific) SYNAPSE - Laminae I and II (substantia gelatinosa) NORMAL PAIN - Depolarisation release of glutamate (excitatory) acts on AMPA (central cation pore) - Result: brief localised pain PRIMARY HYPERALGESIA: sensitivity to area of tissue injury - sensitivity within area of injury 2 peripheral mechanisms (inflammatory soup) WIND-UP - Summation of repeated C fibre inputs depolarisation postsynaptic membrane removal of Mg block in NMDA R o Mediated by glutamate action on metabotropic NMDA / substance P on neurokinin-1 receptors - Result: responsiveness during course of train of inputs SECONDARY HYPERALGESIA: Also known as central sensitisation. - sensitivity spreads beyond area of tissue injury - ongoing stimuli further excitability of dorsal horn neurons central sensitisation - Ca 2 NMDA R activation activate intracellular protein cascades - Result: receptor number, alterations activity efficacy synaptic transmission o o INHIBITION OF PAIN PATHWAYS - Non-nociceptive peripheral inputs (vibration, light touch) - GABAergic / glycinergic interneurons - Descending tracts - Higher centres threshold for activation ALLODYNIA pain in response to low intensity previously non-painful stimuli