Mbchb3 Physiology


Pain – Def
• An unpleasant sensory and emoal experience assoc w actual or potential tis damage
• Subjective eg cultural ceremonies involving pain, giving birth (positive experiences)
• All pain is in the brain
• But – pain can exist without tis damage (eg back pain where no tis damage can be seen), emoal pain has no tis damage either and tissue damage can occur without pain (eg where analgesia has been given)
• Hypnosis – can provide total analgesia
Nociception – the sensation of pain
Suffering – converts nociception into pain
Nociception + Suffering = the experience of pain
Nociceptive pain (involving nociceptors) – usu is responsive to opoids
Neuropathic pain – ha its origin in nerve damage is generally resistant to opoids
Chronic pain – pain which persists 6 months or more

Physiology of nociception and pain
• Peripheral factors – receptors and inflame compounds released in response to damage
• Transmission from periphery to spinal cord
• Interactions betw incoming neurons and asc and desc pways
• Activity within and betw brain centers and the asc and desc pways
Emoal overlay – converts nociception into pain

Org of Sensation
• Receptor → 1’ (1st order) afferent nerves with cell bodies in dorsal root ganglion → synapses in dorsal horn of spinal cord → 2’ nerves → cross to contralateral side and ascend →nuclei in brain or brain stem → 3’ neurons which project to the cortex → conscious awareness of the sensation

• Nociception – 2nd order neurons asc typically in the contralateral spinothalamic tract and synapse typically with 3rd order neurons in the thalamus
• 2 categories of 2nd order neurons – nociception-specific and wide dynamic range (WDR) neurons

Nociception-specific neurons 2nd order neurons
• nociceptors
• unspecialized naked nerve endings
• lie adjacent to small blood vessels and mast cells – forming a structural triad which responds to injury by an inflame response involving degranulation of the mast cell
• primary afferents – predom unmyelinated sensory C fibers but lightly myelinated delta fibers may also be involvd
• rate of nociception conduction is <10% of motor impulse conduction
• specific nociceptive 2nd order neurons carry these signals to the thalamus
• conscious awareness of pain may occur pre-cortically in the thalamus
• it is thought that delta fibers produce the initial sharp discreet sensation of pain and the C fibers are assoc w more diffuse, burning sensation the comes on later

WDR (wide dynamic range) 2nd order neurons
• transmit impulses arriving at the dorsal horn via 1st order polymodal delta fibers (high and low threshold) mechanical and thermal receptors responding to increasing stimulus intensities by ↑ firing freq
• in the dorsal horn – the connection betw 1st and 2nd order neurons may be modulated (inhibited or facilitated) by interneurons and by desc impulses from supraspinal centres via ipsiateral spinal tracts

Inflam response to tis injury
• tis injury – local release and accum of chem mediators which can strongly activate the nociceptive triads
phospholipase A2 releases arachidonic acid (arachidonate)
• prostaglandins, prostacyclins and thromboxanes are produced from this substrate via a clinically v impt enzymatic cascade involving cyclo-oxygenase
• inhibition of cyclo-oxygenase is the basis of NSAIDs
• 2 main types of cyclo-oxygenase – COX 1 and 2
• COX1 is constitutive (it is present and has a number of roles in normal physiol circumstances)
• COX2 is assoc w injury
Leukotrines – also produced from arachidonate via an alternative pway involving lipoxygenase
• Often they have opposing effects to prostaglandins
• Eg – they produce bronchospasm while certain prostaglandins produce bronchodilation
• Blocking prostaglandins w NSAID may result in a predominance of leukotrine effect → may manifest as bronchospasm (may explain why asthma is a contra-indication to NSAID use)
Bradykinin and Histamine
• Also impt in nociception and inflamm
• Mast cell degranulation also releases chemotactic agents that attract neutrophils, eosinophils and other inflame cells
• Platelets become activated and aggregate in the inflamed area
• Platelets release serotonin
• Edema fluid accumulates, pH drops, pres ↑ and the combined effect of pres, the numerous released chemicals and the increasingly acidic evt stimulates nociceptive nerve endings
C Fibers
• Contribute to the vicious cycle of inflame and nociceptive cascade
• Depol releases neuropeptides called tachykinins from vesicles in nerve endings, esp substance P (SP)
• These fibers also release and respond to glutamate
• They become sensitized and therefore more susceptible to further noxious events
Opioid Receptors and Endogenous opioids
• Analgesic action of opium (active ingredient morphine)
• Endogenous opioid peptides include enkephalins and endorphans
• The following types of opioid receptors may be impt
o Mu1 (analgesia)
o Mu2 (resp depr)
o Kappa (sedation and analgesia)
o sigma
• it should be theoretically possible to create an opioid which has analgesic properties without the other effects of morphine but this still hasn’t been achieved
• opioid receptors also in brain and spinal cord → spinally administered opioids
• eg fentanyl – administered via epidural space or directly into the CSF in order to obtain max analgesic effect w least central effect
• opioid receptors also in periphery – found on the small nociceptive fibers
• endogenous opioids are now thought to contribute to pain modulation at the periphery as well as centrally – by antagonizing the acute effects of SP and glutamate

Dorsal Horn of the Spinal Cord
• main site for integration of segmental nociceptive info from periphery w info from supraspinal sources and from other parts of the periphery
• uppermost (or outermost) lamina of dorsal horn – contains cells specialized to transmit pain info which receive input only from nociceptive fibers
• WDR neurons lie deeper and receive input from a variety of sources (nociceptive fibers, and fibers subserving pres, temp and touch)
• In dorsal horn – main nociception assoc NT is SP
• Glutamate is also involved and has a major role in transmission assoc w non-nociceptive fibers – these substances are excitatory
• Interneurons synapse w 1’ and both 2’ neurons
• Most interneurons are inhibitory
• Inhibition may be pre-synaptic or post-synaptic
• Pre-synaptic inhibition usu involves the release into the synapse of GABA, glycine and probably an opioid peptide
• Post-synaptic inhibition my inolve peptide opiois, glycine, nor-adr, serotonin and acetylcholine

• There is a variable rship betw the input into the spinal cord and the output from the spinal cord to the brain
• Net effect of modulation in the spinal cord is generally inhibitory
• But under certain circumstances – 2nd order neurons may start to fire at a freq out of proportion to the incoming signals bec of persistent partial depol – this is called windup
• Windup manifests mainly via WDR neurons – bec there is a greater range of inputs into these than the specific nociceptive 2nd order neurons
• Windup can occur when there is greatly ↑ afferent input from 1st order neurons that have been sensitized by inflame or when interneuronal inhib modulation is reduced
• Windup is assoc w ↑ release of neurokinins and glutamate
• Glutamate – activates nitric oxide synthetase with ↑ release of nitric oxide which in turn ↑ glutamate release
• SP acts at the N-methyl-D-aspartate (NMDA) receptor to ↑ sensitivity to glutamate
• Windup can be blocked centrally by SP inhibitors and by glutamate antagonists ex katamine which act via NMDA receptors
• Ketamine is an ex of a NMDA antagonist
• Opioids reduce the release of SP from nociceptive fibers and may ↓ the devt of windup
• Inhibitors of nitric oxide synthetase also block windup
• Once windup has become established, opioids are ineffective in reversing it, but NMDA antagonists continue to be effective analgesics in animal models

• Corticosteroids and NSAIDs also inhibit windup – presumably via their effect on inflame and hence 1st order neurons

Supraspinal Influences
• Areas in midbrain, pons and medulla → induce analgesia when electr stim
• These areas are rich in endogenous opioids and opioid receptors
• They give rise to fiber tracts that project to the dorsal horn – synapse w 1’ and 2’ order neurons → release serotonin, nor-adr and Ach
• Inhibitory action of serotonin is mediated by opioid releasing interneurons
• The effect of interspinal serotonin is blocked by naloxone (opioid antagonist)
• The action of nor-adr and alpha 2 receptors such as clonidine is not understood but these agents are not blocked by naloxone
• Tricyclic antidpreessant agents prolong the actions of nor-adr and serotonin
• These and selective serotonin uptake inhibitors may alleviate certain forms of chr pain

• Supraspinal influences may occasionally be facilitatory instead of inhibitory
• Central facilitation of nociception probably originates in structures in the ventral medulla where electr stim appears to induce pain
• Desc fibers may enhance pain transmission by releasing SP, cholecstokinin (CCK) and other excitatory AAs
• Conseq may be 2ndry hyperalgesia – often distant from the area of inflame
• There may also be ↓ in circ endogenous opioids which like windup may contribute to certain chr pain states which persist after injury and inflame have healed

Gate Control Theory of Pain
• Spinal cord and brain are active syss involved in filtering, selecting and modulating inputs

• Hyperalgesia - ↑ sensitivity to painful stimuli
• Hyperaesthesia - ↑ sensitivity to non-noxious stimuli
• Allodynia – misperception as pain of non-noxious stimuli
• WDR neurons – 2nd order neurons which transmit impulses from a range of 1st order receptors and respond to ↑ stimulus intensities by ↑ firing freq


Functions of CSF
1. maintains constant evt for neurons and glia – bbb and csf preserve homeostasis of CNS by facilitating entry of essential metabolites and removing or excl toxic and unnecessary metabolites
2. protects the brain from impact with the skull during mvment
3. may act as conduit for peptide hormones which are secr by hypothal and act at pituitary and other parts of brain
Anatomy of CSF pathways
• CSF located in ventricles and subaracnoid space
• Dura – thick periosteal and inner meningeal layer – these two layers split to form intracranial venous sinuses
• Leptomeninges – aracnoid and pia layers
• Virchow-robin spaces – as blood vessels enter or leave the brain or spinal cord, the pia is invaginated into the brain or spinal cord to form the outer surfaceof a perivascular space
• Ependyma – single layer of cells lining the ventricles
• CSF flow –
o most csf produced in lateral ventricles
o flows from lateral ventr through interventr foramina into third ventr and through the cerebral aquaduct (sylvian) to 4th ventr
o leaves 4th ventr via a midline and two lateral foramina entering the subaracnoid space
o within the subaracnoid space, csf flows down spinal canal and over the convexities of the brain
o it extends into the depths of the cerebral cortex in the verchow-robin spaces
CSF prodn
• most csf formed by the choroid plexus in the lateral ventricles
• choroid plexus – a capil network surrounded by a single row of epith cells
• the ventr surface of the epith cells has a brush border of microvilli
• choroid plexus is part of the bbb
• there are tight junctions joining adjacent epith cells in the choroid plexus
• formation of csf involves two processes in series
o filtration across the choroidal capil wal which depends on hydrostatic pres of capils
o active secret by choroidal epith
• endothelial and epithelial cells of choroid plexus have spec tport syss for a variety of compounds incl ions, vitamins, nucleosides, purines, glucose and AAs
CSF Volume
• normal rate of prodn is 0.35ml/min (500mL/day)
• entire CSF vol turned over 3-4 times a day
• total csf vol is 140 ml
CSF absorption
• major route is via aracnoid villi
• some solutes (esp lipophilic) disappear from csf by diffusion into adjacent brain and capils
• there is also active tport of spec solutes by choroid plexus
• aracnoid villi are herniations of the arachnoid membr through the dura into the lumen of the superior sagittal sinus and other cerebral veins
• flow across arachnoid villi unidirectional
CSF composition
• WBC 5*10(6)
• RBC absent
• Protein <0.45g/l
• Glucose >2.5mmol/l

• Along with csf, bbb preserves homeostasis of neurons and glia
• Bbb includes epithelial cells of the choroid plexus and endothelial cells
• Bbb depends on
o Morphological constraints to transfer solutes betw blood and brain or csf
o Biochem characteristics of solute
o Spec tport syss to facilitate entry of solutes essential for normal brain func
Morph feats of bbb
• Endothelial cells in the CNS differ from endothelial cells in other organs in several ways
• Most characteristic feat of endothelial cells in brain are tight junctions which allow little mvment of compounds betw cells and effectively separates plasma from ECF of brain
• Brain endothelial cells also have fewer pinocytotic vesicles, a thicker bment membr, more mitochondria and astrocytic foot processes
BBB – consists of specialized endothelial cells, thick bment membr, astrocyte processes on capil and a large number of mitoc
Transport across BBB
o Diffusion – small lipid sol (CO2, O2, alcohol)
o Receptor mediated – facilitated or en dep (glucose, some AAs, vitamins)
o Ion channels
Biochem characteristics of solute also determine bbb function –
• Molec weight
• Lipid sol – these compounds cross bbb readily while water sol polar compounds have difficulty in absence of spec tport syss
• Ionization at physiol pH
• Protein binding – this restricts entry into CSF and brain
What molecs normally enter the brain?
• Small lipophilic molecs
• Molecs w spec tporters – eg ions, glucose, some AAs, some vitamins, some nucleosides
Disorders of the BBB
• During bbb disruption, there is disruption of tight junctions leading to paracellular passage across tight junctions and ↑ vesicular tport across endothelial cells
• In addition, new blood vessels form in brain tumors – these vessels may have leaky capillaries without feats of the bbb
BBB Disease processes
o Brain tumors – abnormal cells with abnormal blood vessels, vessels can be leaky, interstitial fluid accumulates (edema)
o Meningitis (infection of sub-arachnoid space – inflame response causes BBB breakdown, WBCs and protein enters CSF
CSF alters in dis –
o Meningitis - ↑ wbc, ↓ glucose, ↑ protein
o Sub-arac hemorrhage - ↑ RBC, xanthochromia (yellow discol products of rbc breakdown)

Intracranial pressure – ICP
Intercranial Compliance and Elastance (pres/vol rships)
• Non-linear rship between ICP and ICVol
• Compliance – a measure of the distensibility of the intracranial cavity
• Compliance falls as ICP rises
• Elastance is the reciprocal of compliance
Maintenance of ICP
• Cranium and spinal cord are a closed sys
• Intracranial vol fixed
• It is vented through the foramen magnum into the spinal subarachnoid space
• Intracranial contents incl brain, blood and CSF
• These three components are all displaceable
• ↑ in vol of one component must be offset by a ↓ in another, or there will be an ↑ in ICP
• normally – intracranial vol of blood and csf vary reciprocally to maintain normal ICP
Factors affecting ICP
1. arterial bp
 icp maintenance depends on cardiac output
 an acute ↑ in arterial bp ↑ icp
 chr changes in arterial pres usu do not affect csf pres
2. venous pres
 csf pres is immediately affected by intracranial venous pre
 rapid compression of jugular veins causes an immediate rise in csf pres
3. thoracic pres
 ↑ intrathoracic pres ↑ central venous pres and icp
4. posture
 changes central venous pres
5. partial arterial pres co2
 hypercapnia causes cerebral vasodilation
 → ↑ cerebral blood flow and thus ↑ csf
6. partial arterial pres o2
 hypoxia causes arteriolar dilation → ↑ cerebral blood flow → ↑ icp
 these changes are probably mediated by alterations in hydrogen ion conc 2ndry to glycogenolysis and lactic acid prodn
7. temp
 hypothermia causes a fall in cerebral blood flow and thus icp
Compensatory mechanisms
• devt of a mass within the intracranial cavity, ↑ vol csf or an ↑ intracranial blood vol can be compensated by the following mechanisms
1. ↑ CSF absorpn causes a ↓ in csf vol
2. collapse of cerebral veins which reduces intracranial blood vol
3. distensibility of the lumbosacral dura has a slight compensatory affect
4. plasticity of the brain – tumor or other intracranial mass may cause extensive displacement of surrounding brain tis (herniation)
Causes of ↑ ICP -
1. mass lesion
2. cerebral edema
3. hydrocephalus
1. Intracranial HT due to mass lesion
• a mass lesion may cause a generalised ↑in icp if –
o it reaches a critical mass and compensatory mechanisms fail
o it obstructs the cerebral venous sys
o it obstructs the csf pways
• ↑ icp is harmful if it causes cerebral ischaemia or 2ndry tis displacements (herniations)
2. Brain Edema
• ↑ water content of the brain which accompanies a variety of diseases
• several types of edema –
1. vasogenic edema –
o most common form
o ↑ vol of extracellular fluid in brain
o caused by ↑ permeability of brain endothelial cells to albumin and other molecs that are normally excluded by the bbb
2. cellular (cytotoxic) edema –
o intracellular swelling of neurons, glia and endothelial cells caused by either energy depletion and failure of ATP dependent Na pumps allowing Na and water to accum in cells or acute plasma hypoosmolality
3. interstitial edema –
o ↑ water and Na content in periventricular white matter due to transependymal reabsorption of csf in hydrocephalus
3. Hydrocephalus
o dilated ventricles
o ↑ csf prodn, ↓ absorpn, obstruction to csf flow
o and brain cannot compensate
Cushings Triad – late signs of ↑ ICP
1. arterial HT
2. slow HR
3. slow resp rate
Mechanism - ↓ blood flow to medulla due to a direct distortion of medulla

Cerebral Blood Flow
• autoregulation is the intrinsic capacity of the brain to regulate its blood flow according to its metabolic needs
• by this way – cerebral blood flow is maintained at a constant level indep of changes in arterial bp (above shock levels)
• autoreg is effective with cerebral perfusion pressures of 60-150 mmHg
• mechanism of autoregulation include
o myogenic factor – intrinsic activity of smooth mus cells to changes in the tension of blood ves walls
o metabolic factor – cerebral blood flow is coupled to metabolic needs – achieved by control of the tone in small blood vessels by the local hydrogen ion conc
If there is loss of cerebral autoreg – cerebral blood flow and cerebral blood vol change passively w changes in systemic bp


Disorders of Movement
Diversity of Sx –
• Paralysis → monoplegia (one limb), hemiplegia (one side), paraplegia (legs) or quadraplegia
• Paresis – weakness (monoparesis, hemiparesis, paraparesis, quadraparesis)
• Abnormalities of mus tone – hypertonia (spasticity in stroke or rigidity) or hypotonia
• Ataxia – incoordination, decomposition of mvment and dysmetria (finger-nose test)
• Involuntary mvments – eg tremor and L-dopa induced dyskinesia in Parkinsons, epilepsy
Note – the lesions which cause many of these sx can be focal or diffuse/chronic or acute
Acute Chronic
Focal Trauma or Vascular Neoplasms
Diffuse Toxins or infections Degenerative

Motoneurons (motor neurons or LMNs)
• A neuron that passes from the CNS or a ganglion toward or to a muscle and conducts an impulse that causes movement
Location of Motoneurons
• Motor nuclei in spinal cord (ant horn cells)
• Motor nuclei in brainstem (cr nerves 3-7 and 9-12) – not 1,2 or 8
• Alpha motoneurons
o Innervate extrafusal fibers (extrafusal = situated outside a striated muscle spindle)
o Directly responsible for the generation of force by muscles
o Fast firing elements FF (type 11B) motor units
o Slow firing elements S (type 1) motor units
• Gamma motoneurons
o Located near alpha motor neurons
o Control excitability of stretch receptors in muscle spindles
o Innervate intrafusal muscle fibers (intrafusal = situated within a muscle spindle)
o Activation alpha and gamma motoneurons always occur together (alpha-gamma coactivation)
Muscle Spindle
• a sensory end organ in a muscle that is sensitive to stretch in the muscle – consists of small striated muscle fibers richly supplied with nerve fibers and enclosed in a CT sheath (aka stretch receptor)

Motor Units
• The functional elements of the motor system
• Vary not only in size (large vs small innervation ratio) but also according to biochem and physiological properties
• Two major types – FF type (fast twitch, fatiguable) and S type (slow twitch)
• Functional elements of the motor system – consist of 4 componenets
1. cell body of alpha motoneuron
2. axon
3. all neuromuscular junctions (synapses) formed by a single motoneuron
4. all muscle fibres (extrafusal mus fibers) innervated by a single motoneuron (each motoneuron can innervate from 5-2000 muscle fibers – innervation ratio)
Motor Unit Type FF S
Twitch time Short (-20ms) Long (>50ms)
Size (no. muscle fibres belong to motor unit) Large Small
Power Powerful Weak
Relative no. few Many
Glycogen much little
Fatigue rapid none or slow
• Muscles generally have both fibres
• Properties of muscles match the properties of the motoneurons which innervate the muscle (eg cross innervation experiment)
Size principle
• S type motor units always recruited first
• FF type units recruited only at relatively high levels of muscle force
• Physiological consequences of size principle
o Some S type motor units fire almost always (except during REM sleep)
o S type motor units best suited for carrying sustained but small loads
o Weak contractions can be graded with greater precision than strong contractions
o Necessity to exercise to prevent atrophy of FF units

Receptors which control movement –
• Muscle spindles – monitor muscle length (L) and speed of length change (dL/dt) – run in parallel to extrafusion fibers
• Golgi tendon organs – monitor muscle tension – in series with extrafusal fibres
• Nociceptive (pain) receptors in skin
• Joint receptors (monitor position)

Alpha Motoneurons and Motor Units
The final common path for –
• Descending tracts converging on alpha-motoneurons
o Corticospinal (pyramidal) tract
o Rubro-spinal tract
o Vestibule-spinal tract
o Tecto-spinal tract
o Reticulo-spinal tract
• Spinal (or brainstem) internenurons making synapses w alpha motoneurons (eg inhibitory interneurons)
• 1a afferents – from muscle spindles

Diseases of motor units
• Disorders of Muscles – myopathy
• Disorders of motoneurons - neuropathies
1. Myotonic Muscular Dystrophy
2. Myasthenia gravis
3. botulism
4. injury to axons
5. peripheral neuropathies

Myotonic Muscular Dystrophy (dystrophia myotonica)
• myotonia = muscle stiffness, hypertonia – failure of the muscles to relax immediately after contraction (slowness of relaxation)
• wasting and weakness of muscles
• inherited (dominant)
• males and females equally affected in early adult life (up to 2000 triple CTG repeats in chrom 19 coding for myotonin)
• occurs first in feet, face and hands (peripheral)
• muscle wasting also occurs in heart
Muscular Dystrophy
• group of inherited disorders
• progressive muscle wasting and weakness
• no primary structural abnormality in LMNs

Myasthenia Gravis
• autoimmune dis
• muscle weakness only – no wasting
• fewer Ach binding sites → smaller amplitude of EPPs (endplate potentials at NMJ) → safety factor for transmission reduced
• Tx – Edrophonium – blocks enzyme Acetylcholinesterase → ↑ Ach at synapse →↑ synaptic transmission (also used for dx of m.gravis)

• food poisoning and muscle paralysis caused by clostridium botulinum which ↓ Ach release
• the toxin impairs release of Ach at all peripheral cholinergic synapse
• the toxins bind to nerve terminal and are endocytosed → proteolysis of several membrane proteins involved in NT release eg SNAP-25/Syntaxin
• weakness of striated and smooth muscles (somatic and autonomic dysfunctions)
Applications of botulinum toxins
• dystonias – persistent ↑ in mus tone w co-contraction of antagonistic muscles and assumption of abnormal postures eg cerebral palsy
• hyperhydrosis – excessive sweating
• gastrointestinal and urionary d/os
• etc

Injury of Axons (axotomy)
• resulting from disc protrusion or plexus lesion
• changes in distal segment (wallerian degeneration)
o myelin surrounded by schwann cell
o lesion due to cut, fracture, tumor etc
o → myelin debris and schwann cell partial atrophy
• changes in the proximal segment (chromatolysis)
o nissel substance (ribosomes involved in protein synth) → moves peripherally
• axon regeneration and re-innervation of muscles
Wallarian Degeneration
• changes in distal part of axon → loss of synaptic transmission within hours
• degeneration within days
• changes in motoneuron cell body → chromotolysis
• → axon regeneration – 1-4mm/day facilitated by arrays of schwann cells
• → re-innervation of muscle spindles
• → re-myelination of axons (sometimes only partial)

Peripheral Neuropathies
• can cause both motor and sensory deficits/sx
• most common – demyelinating neuropathies eg diabetic neuropathy, guillian-barre syndr, ms
• demyelination means ↓ Na2+ channels and ↑ K+ channels → slowing or breaking of conduction and inability to conduct APs at a high freq


1. LMN Disease/Lesion
• General clinical term for motor disorders involving motoneurons (both alpha and gamma) in the spinal cord and brain stem and/or muscles eg muscle denervation
• Atrophy and muscle wasting/weakness or paralysis
• ↓ or abolished mus tone (flaccidity)
• depressed or abolished stretch (tendon) reflexes
• signs of muscle denervation
 fasciculations – course twitches due to activation of individual motor units
 fibrillations – EMG term, discharge of single mus fibers
• no spasticity
• no babinski reflex – flexor or absent plantar reflex
 spasticity and babinski reflex are the two principle signs of UMN dis lesion
 toe normally points down

2. Diseases affecting Cell bodies of LMN – alpha and gamma
• poliomyelitis
o acute viral infection (oral)
o bought under control since 1950s via vaccine
o causes degen of motoneurons and muscles
• syringomyelia
o syrinx = cyst
o formation of large cysts within central portion of spinal cord
o damage of pain and temp fibers (spinothalamic tract crosses near central canal) followed by damage of motoneuron cell bodies
o bilateral loss of pain and temp
o pathogenesis unknown

3. Amyotrophic Lateral Sclerosis (ALS, Lou Gehrigs, Motoneuron Dis)
• Amyotrophic = muscle wasting, lateral = referring to spinal cord, sclerosis = thickening
• Many neurological diseases cause weakness and wasting of skeletal muscles and can lead to a complete muscle paralysis
• These disorders are usu assoc w a lesion of parts of the brain outside the motor nuclei in the spinal cord and/or brainstem
• In contrast – ALS affects motoneurons themselves (as well as UMNs in the cerebral cortex) and leads to v severe weakness of various mus groups
• 5/100,000 with approx 200 affected in nz
• 90% have no family hx of the illness (sporadic form of dis)
• 10% approx have familial form – inherited autosomal dominant due to mutation affecting enzyme superoxide dismutase
• ave age onset – 5th decade of life
• death usu within 3-5 yrs (except in the rare benign form)
• progressive wasting, weakness and atrophy of muscles leading to paralysis
o legs, arms and hands
o difficulty with speech and swallowing
o respiration impairment → pulmonary infection
• muscle stretch reflexes exaggerated and muscle tone ↑ (spasticity)
• Signs of mus denervation
o Fibrillations – EMG recordings (denervation sensitivity = ↑ sensitivity to tiny amounts of Ach)
o Fasciculations – twitches which can be observed w naked eye (not all neurons degenerate at same time and this causes surviving fibers to largen)
• No involvement of extraocular muscles
• No involvement of anal and bladder sphincters
• No sensory or intellectual deficits
Causes of the Disease
• Progressive degen of –
1. Motoneurons (a and gamma) in spinal cord – ie ant horn cels (except those controlling sphincters)
2. Motoneurons in brain stem (but not the 3,4 and 6th nuclei) → hence eye mvment occurs
3. UMNs – cortico-spinal neurons in the motor cortex → spasticity
o 1+2=LMN dis (mus wasting and paralysis)
o 3 = UMN dis (↑stretch reflexes, babinski reflex and spasticity)
o Unusual combination of muscle wasting AND ↑ stretch reflexes – ie both LMN and UMN sx are present
o Babinski reflex – big toe normal goes down
Pathogenesis (unknown) – Theories
• Autoimmune Hypothesis
o Presence of antibodies against Ca2+ channels in some pts
o Intracellular Ca2+ conc ↑ → neuron damage
• Neurotrophic Hypothesis
o Reduction in the level of neurotrophic factors
o Ex BDNF or NT3
o Neurotrophic factors promote motoneuron survival
• Oxidative Stress Hypothesis
o Mutation of an anti-oxidant enzyme superoxide dismutase (SOD) in some (10%) of pts w familial form of dis
o Damage of motoneurons by free radicals (reactive oxygen and nitrogen species)
o Occurs when radical prodn exceeds detox capacity of specific enzymes such as superoxide dismutase, glutathione, catalase
• Excitotoxic Hypothesis – ↑ Glutamate (main excitatory NT)
o Excessive activation of AMPA and/or NMDA glutamate receptors by glutamate
o Nerve cells cant cope with excessive amounts of glutamate and become over stimulated/over excited
o Possibility 1
• Extracellular glutamate ↑
• Due to ↓ activity of glutamate transporter mainly in astrocytes surrounding motoneurons
• Eg GLT1
• Astrocytes ↓ glutamate levels by uptake
o Possibility 2
• ↓ expression of GluR2 subunit of AMPA glutamate receptor
• motoneurons which are typically involved in ALS have a lower abundance of GluR2 subunits in glutamate receptors
• this predisposes them to higher calcium fluxes and exitotoxic damage
• AMPA receptors usu contain GluR2 subunits and are therefore not permeable to Ca2+
• No effective drugs avail to arrest or alter course of dis
• Small beneficial effects of Riluzole – a blocker of glutamate release → can slow dis process by a few months
• Baclophen – agonist of GABA-B receptors → ↓ in spasticity
• Other symptomatic txs – eg control of excessive salivation
• Future directions – replacement therapy using genetically modified or stem cells


Drugs act on the brain and other organs by interacting with target molecules –
• Enzymes (involved in NT synth or degradation)
• Structural proteins
• Ion channels
• NT uptake proteins (transporters)
• NT receptors
• Transducer proteins (eg G proteins, 2nd and 3rd messngrs)

• Basic Unit of the nervous system is the nerve cell or neuron (there are over 10 (10)
• Unlike the peripheral nervous sys where neurons largely make contact with effector organs such as muscles, most neurons in the brain make contacts with other neurons
• These contact points are called synapses and a single neuron can have thousands of synaptic contacts
• A few of these synapses convey info from one to cell others by electr means but by far the majority use chemical messengers called NTs (first messengers) which are released from the pre-synaptic terminal (calcium dependent) and diffuse across the synaptic cleft and act on NT receptors on the post-synaptic target neuron
• Binding of the NT to the receptor then leads to some effect in the target neuron such as ion channel opening and/or generation of a cytoplasmic messenger called a second messenger
• If this results in excitation of the neuron, the NT is said to be excitatory and if inhibition results then the NT is said to be inhibitory
• Termination of transmitter action is achieved either by metabolism and/or reuptake into neurons and/or glial cells (astrocytes) by specific transporter proteins
o Astrocyte – supports neuron and contributes to the bbb
• Most drugs that act on the brain and spinal cord do so by interacting in some way with chemical NT
• Because the brain is a v complex organ composed of diff anatomical regions that serve diff functions the action of a drug will not only depend upon which NT sys it modulates or mimics, but also on the anatomical localization of the NT sys
• The study of anatomical localization of NT systems is known as chemical neuroanatomy

• Released from pre-synaptic terminal to act on post-synaptic neuron and produce relatively fast inhibitory or excitatory effects
1. monoamines – serotonin, nor-adr, dopamine
2. AAs and AA derivatives – GABA, glutamate, glycine
3. Acetylcholine
4. Neuropeptides – neuromodulators and co-transmitters
• Produce slower pre and post synaptic responses
• Released by nerve cells and astrocytes
• Eg adenosine
Neurotrophic factors
• Released by non-neuronal cells – astrocytes, microglia and neurons
• Work over long time scales
• Act on tyrosine-kinase type receptors to mediate growth, morphology, functional properties, survival promoting effects in the nervous sys
• Eg nerve growth factor, BDNF, IGF-1

• Fast acting - work via ion channels eg glycine, GABA, glutamate
• Slow acting – via G protein coupled receptors eg dopamine, neuropeptides, GABA, Ach
• NTs can have both fast and slow actions depending upon the receptor sub-type they act on

• Serotonin, nor-adr, dopamine
• Derived from dietary AAs eg tryptophan, tyrosine
• Three Distinct Properties –
o Axons arise from cell bodies in distinct subcortical nuclei of about a few hundred cells
o Axons ramify extensively to innervate most parts of the cortex and other brain regions
o They produce a mixture of inhibitory and excitatory effects which are generally neuromodulatory

• Main inhibitory transmitter in brain
• Major site of action for benzodiazepines
• GABAa receptors and GABAb receptors
• Main excitatory transmitter in brain
• Main inhibitory transmitter in spinal cord
• Styrychnine is a glycine antagonist
• Small (2-40AAs) peptides stored within vesicles in neurons in terminals
• They are released following activity → powerful biological effects
• Many isolated in the gut/enteric nervous sys and now also found in brain and spinal cord
• Chains of AAs therefore larger than the classical NTs (single AAs or derivatives)
• 40 discovered so far
• differ in many ways from classical NTs – v potent, present in small quantities, synthesis and inactivation diff
• but like classical NTs, their release is Ca2+ dependent
• NPs can act as NTs and also as co-transmitters
• Widely distributed in CNS
• Mediates many functions esp those involved in learning and mem formation
• Nicotinic and muscarinic receptors

GABA – Gamma-amino butyric acid
• Main inhibitory NT in brain
• Synthesis – Glutamate → GABA (“glutamatic acid decarboxylase”(GAD) and “pyridoxalphosphate”(Vit B6))
• GAD is found only in the cytoplasm of nerve terminals containing GABA – this is the rate limiting step in GABA synth
• Storage – in nerve terminals, vesicular and on-vesicular storage
• Release – Ca2+ dependent release
• Inactivation –
o Re-uptake (Na+ dependent)
 Into nerve terminals where GABA can be reused or metabolized
 Into astroctyes (glia) where GABA is metabolized
• Metabolism – 2 stages
o GABA → Succinic semialdehyde (“GABA transaminase”) succinate (“succinate semialdehyde dehydrogenase”)
o Succinate part of krebs cycle
• Receptors/second messengers –
o GABAa – receptor complex is a member of the ligand gated ion channel family that comprises a no. of binding sites (probably pentameric)
o The ion channel allows chloride influx
o GABA binding site produces chloride channel opening causing chloride influx and hyperpolarization (chloride Cl- flowing into cell decreases the conc gradient which is Na+ dependent)
o Muscimol – selective agonist
o Bicuculline – selective antagonist
o Allosteric modulatory sites –
 Benzodiazepine binding site – BZs ↑ the affinity of GABA for its receptor and also ↑ freq of channel opening in response to GABA thereby ↑ inhibition
 Barbiturate binding site - ↑ the duration of chloride channel opening in response to GABA producing an ↑ in inhibition
o Functions of the GABAa receptor – neuronal inhibition
 GABAa antagonists produce seizures and agonists produce anti-convulsant effects
 These receptors are important in epilepsy and anxiety
 Benzodiazepines and inverse agonists –
• Benzodiazepines bind to BZR to ↑ GABA action (agonists)
• Flumazenil binds to BZR to BZ effects (competitive antagonist) – used for benzo overdose
• B-carbolines bind to BZR to ↓ GABA action (inverse agonists) – powerful convulsants not used clinically
• GABAb Receptors
o Member of the G-protein receptor family and it opens a K+ channel which causes hyperpolarizaton and ↑ inhibition (K+ flows out of the cell) → inhibits NT release
o It is located mainly pre-synaptically but is also post-synaptic
o Baclofen (agonist) → used to tx spastic conditions (hyperexcitability of the spinal cord) and there are high levels of GABAb receptors in the spinal cord
o Phaclofen (antagonist)


Spinal cord injuries
• Most freq traumatic injuries of the CNS eg traffic incidents
• Other causes – malignant tumors, demyelination, posterior intervertebral disc protrusion, syringomyelia

1. Hemisection of Spinal Cord – Brown-Sequard Syndr
Ex – hemisection of L spinal cord at T8
• Motor Deficits
o Monoplegia (no voluntary motor functions in L leg)
 Loss of inputs to motoneurons from corticospinal tract and rubrospinal tract
o Hyperactive reflexes in L leg eg Babinski reflex, clonus
 Loss of inputs to motoneurons from the reticulospinal tract and vestibulospinal tract
• Sensory Deficits
o Loss of pain and temp below T8 on R – due to the fact that the spinothalamic tract is crossed at segmental levels
o Fine tactile perception and proprioception lost below T8 ipsilateral to the lesion (L) – due to the fact that the dorsal columns remain ipsilateral throughout their course in the spinal cord

2. Acute complete transaction of the spinal cord – Spinal Shock
• Spinal shock – a temporary period of areflexia due to loss of facilitatory inputs from the reticulospinal and vestibulospinal tract
• Ex – after complete lesion below cervical enlargement of spinal cord at T8
o Flaccid paralysis in both legs – paraplegia
o All conscious sensation lost (total anesthesia)
o No mus reflexes (areflexia)
o Blood vessel dilation (BP↓)
o Thermal sweating absent – red and hot skin
o Bladder and bowel mvments atonic – bladder distends w urinary overflow
o Dysfunction of sexual organs
• Recovery (partial) and additional Sx
o Recovery of mus tone (but vol mvements of leg remain absent)
o Hyperactive mus stretch reflexes (spasticity and clonus)
o Spontaneous (reflex) emptying of bladder and rectum
o BP ↑ (autonomic dysreflexia) - unstable
o Flexor (withdrawal) reflex
o Extensor plantar (babinski) reflex – toe dorsiflexion
o Paresthesia – abnormal sensations from the affected areas eg burning sensation – due to reorg of synapses in sensory pway
• Mechanism of Recovery
o Sprouting – of pre-synaptic terminals (synaptic plasticity)
o Denervation supersensitivity (fibrillations)

3. Aspects of mgt of pt after spinal cord injuries
• Quadriplegic pts – artificial ventilation or breathing pacemakers
• Paraplegic pts – parastep

4. Regeneration in the CNS (experimental animals)
• Neutralizing antibodies to a growth-inhibiting myelin-assoc glycoprotein (MAG)
o Peripheral nerves are supported and nourished by schwann cells
o In spinal cord, oligiodendrocytes perform the same function but release a chemical that doesn’t support nerve regrowth
o Hence – peripheral nerves can regrow
• Neurotrophin 3 (growth factor)
• Tissue bridges with fetal spinal cord (aborted fetus)
• Tissue bridges w peripheral nerves (nerve grafts), schwann cells, or olfactory ensheathing glia cells
• Injection of neural stem cells (embryonic or adult)

Sleep Physiology

Why Sleep???
• Body repair
• Energy replenishment
• Predator avoidance
• Thermoregulation
• Memory consolidation
• Neuronal integrity
• Resculpting of synaptic popns
Recent Research – Sleep and the Brain
• Sleep improves procedural mem tasks requiring practice and repetition
• Prob solving skills
• Pruning and strengthening of circuits that promotes learning new things and reinforcing old ones
• Refueling of brain
• More efficient use of glucose
• Detox of free radicals
Sleep Deprivation Effects
• Impaired performance tests on vigilance
• Impaired serial math calcs
• Verbal processing, complex prob solving
• ↓ in procedural skills
Common Complaints of Pts w poor quality sleep
• fatigue – low en – running on empty
• irritability – less tolerant
• tired but having a nervous buzz – feeling wired
• eye bags – raccoon eyes – heavy feeling around eyes
• poor mem


EEG = Electroencephalogram
• records cerebral activity detected by surface electrodes
• in standard array of scalp electrodes – most are named for the underlying cerebral lobe – odd numbered ones on the L, even on the R
Clinical Utility
• seizures
• other neurologic conditions – eg toxic metabolic encephalopathy and dementia
• sleep d/os – use of sleep EEG or polysomnogram
• polysomnography = simultaneous and continuous monitoring of relevant normal and abnormal phsyiologicla activity during sleep
Polysomnogram – physiologic sensor leads placed on pt and record -
• brain electrical activity – sleep EEG
• eye and jaw mus mvment
• leg mus mvment
• airflow
• respiratory effort (chest and abdo excursion)
• O2 saturation

• occur mostly during REM phase sleep
• REM occurs about 5* per night – totaling 2 hours
• Remember les than 5% of our dreams
• There is no logical dream
• Why Dream? Erasing theory, filing theory – ie recurrent dreams after stressful event

Tools in Dx of Sleep D/os
• Sleep hx
• Sleep diary – eg consuming products like alcohol
• Actigraph – wristwatch that records sleep patterns over 3-4 wks
• Polysomnogram – overnight sleep study

Sleep - Clinical

Sleep Disorders***
1. Insomnias
• Primary insomnia – no obvious reason for not sleeping eg learned beh
o Pts feel unrefreshed, awaken multiple times during night etc
o 50% due to anxiety/depr (classic sign of depr) – have to dip to a certain level of relaxation before going to sleep
o pt may often suddenly become wide awake in the middle of the night
• Secondary insomnia – due to substances, psychiatric, medical or neurological conditions
• Circadian rhythm probs – clocks shifting
• Jet lag
• Shift work
2. EDS (Excessive daytime sleepiness conditions)
• Narcolepsy/sleep attacks
• Sleep apnea – absence of breathing - severe snoring (3 rooms away)
• Idiopathic hypersomnia – excessive sleep during day despite sleeping normally at night – unknown why
3. Parasomnias
• Sleep walking/somnambulism
• Sleep talking
• REM beh d/os
• Periodic Limb mvments (PLMs)

Mgt of Sleep D/os
• Need to have correct dx first
• Cog-behal tx for insomnia – gold standard
• Light tx – seasonal and clock probs
• Melatonin – doesn’t work for insomnias but does work for clock probs
• CPAP – continuous pos airway pres – works for apnea
• Medications
• Surgical

Countermeasures for sleep deprivation fatigue or sleepiness
• Eg if driving and feel sleepy – pull over and have a 5-10 min nap
• Sleep!!
o 2-8 hr nap prior to 24 hour sleep loss
o 15 min naps ev 2-3 intervals
o stimes – more than 2 hour naps can worsen sleep inertia
• Caffeine – not that effective
• Modafinil – awakeful drug – no LT side effects

Enhancing Sleep
• Address underlying medical and psychiatric condition
• Basic Tips
o Avoiding stimulating substances – caffeine, nicotine, amphetamines
o Minimizing alcohol intake
o Physical aspects of sleeping (bed firmness, temp, noise)
o Minimize stimulating activities at night
o Going to bed only when really sleepy (yawning, nodding off, droopy eyelids) – fatigue not necessarily same as sleepy
o Consistent time in getting out of bed
o Avoid doing anything else in bed – just sleep and sex
• Calm and Focused mind
o Learning to un-clutter
o Learning mindfulness – focusing in present moment, full attention to current activity, not judging, just observing

Additional Notes on Sleep
• total sleep requirement = 8 hours average but considerable variability – ie a normal distbn
• most people need betw 7 and 9 hours but some people need more or less than this
• tossing and turning at night – possibly an indication that less sleep is reqd
• as we age – total sleep requirement ↓
• total sleep deprivation (REM and nonREM)
o death within 11-32 days (ave =20)
o disheveled fur/hair
o skin lesions
o ↑ food intake
o 20% weight loss
o ↑ en expenditure – 1.9* ↑ in energy use
o ↓ body temp terminally
• REM Sleep Deprivation
o Fatal after 37 days
o Same abnormalities as total sleep deprivation

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