530.302 – Medical Neurosciences Lecture Notes THE CEREBRAL CORTEX AND THALAMUS •

Overview of the Brain

The brain consists of forebrain (thalamus, basal ganglia, hypothalamus, cerebral cortex), midbrain and hindbrain (pons, medulla and cerebellum). The midbrain, pons and medulla are also known as the brain stem. The corpus callosum transmits information between each hemisphere. Contralateral control – the left side of the brain generally controls the right side of the body, and the right side of the brain controls the left side of the body. The human brain is very much dominated by the forebrain. The brain can be divided into lobes: Frontal – superior, middle and inferior frontal gyri Parietal – superior and inferior lobules, and supramarginal and angular gyri Occipital and temporal – superior, middle and inferior temporal gyri The central sulcus lies between the precentral and postcentral gyri; the lateral sulcus is really a fissure; the parietal-occipital fold is best seen from the medial aspect. The brain also contains conduit areas: Primary motor cortex – precentral gyrus (and supplementary area) Primary somatosensory cortex – postcentral gyrus (and supplementary area) Primary visual cortex – cortex lateral to the calcarine sulcus (big supplementary area) Primary auditory cortex – superior temporal gyrus (and transverse gyrus of Heschl) Note that the visual cortex is visuotopically (retinotopically) organised – the left half of the visual field of each eye is interpreted by the right side of the brain, and vice versa (note the optic chiasm). Other areas are specific to the dominant hemisphere of the brain (left for most people): Broca’s area (posterior 1/3 inferior frontal gyrus) – motor control of speech (engrams) Wernicke’s area (posterior 2/3 superior temporal gyrus) – recognition aspects Arcuate fasciculus – connects Broca’s and Wernicke’s areas Sensory/motor/conduction aphasias Note the association of right-sided hemiplegia with speech problems (in stroke cases) Inferior parietal lobule (especially the supramarginal/angular gyrus) – integration/interpretation of visual and auditory input for reading and writing Exner’s area (superoinferior 1/3 middle frontal gyrus) – motor aspects of reading and writing Functions of the non-dominant cortex include non-verbal language, emotional expression, spatial skills (3D), conceptual understanding and artistic/musical skills. Damage leads to spatial disorientation, inability to recognise familiar objects, and loss of musical appreciation. Note that the size of the superior temporal gyrus is larger in the dominant hemisphere – this means the lateral fissure is at a different angle on either side of the brain. Associational cortex has a number of functions, depending on localisation: Frontal lobe – intelligence, mood, personality, behaviour, cognitive function Parietal lobe – spatial skills, 3D recognition, shapes, faces, abstract perception Temporal lobe – memory, mood, aggression, intelligence Note 3 major neurotransmitters (monoamines) – noradrenaline, serotonin and dopamine The cerebral cortex is supplied by the circle of Willis (carotid and vertebral arteries): Anterior cerebral artery – superior, anterior of cortex, including medial surfaces Middle cerebral artery – most of the lateral aspect of the brain (common infarcts)

530.302 – Medical Neurosciences Lecture Notes Posterior cerebral artery – occipital lobe, medial aspect of the temporal lobe •

Cellular Organisation of the Cerebral Cortex

There are 14,000 x 106 neurons in the cerebral cortex, consisting of two basic types: Pyramidal cells (10-70μm) – apical/basal dendrites, long axon – efferent (Golgi type I) Granule/stellate cells (6-10μm) – round cells, short axons – local circuit (Golgi type II) The grey matter can be divided into allocortex (3 laminae) medial to the rhinal/collateral sulcus, and the neocortex more frontally (6 laminae): Supragranular Molecular (I) External granular (II) External pyramidal (III) Granular Internal granular (IV) Infragranular Internal pyramidal (V) Multiform VI Projection fibres (V) – cell bodies in the internal pyramidal lamina Æ subcortical structures Association and commissural (efferent) fibres (III) – cell bodies in the external pyramidal layer Specific afferent fibres (IV) – sensory data from outside of the cortex Æ layer IV (corticipetal) Associational and commissural afferents (I-III) – cortex/nervous system Æ layers I-III and VI Note that the cerebral cortex differs in composition depending on the local cortical function: Agranular cortex – predominant III, V and VI layers (pyramidal) – note giant (Betz) cells e.g. precentral gyrus (primary motor cortex) Granular (koniocortex) cortex – predominant II and IV layers (granular cells) e.g. primary sensory cortices Homotypical cortex – e.g. associational cortex (prefrontal, parietal associational, temporal) •

Thalamus and Internal Capsule

The thalamus is the ‘toll gate’ for the cerebral cortex, performing the preliminary analysis of all information. It consists of two hemispheres (connected by interthalamic adhesions) and has grey matter with a lamina of myelinated fibres that divides it into a number of compartments: Ventral nuclear group – anterior, lateral and posterior nuclei (VA, VL, VP) Geniculate bodies (metathalamus) – medial and lateral (MGB and LGB) Anterior, medial and lateral nuclear groups The VA-VL unit sends information to the motor cortex (anterior part Æ legs) – it receives input from the cerebellum and basal ganglia, and feedback from the cerebral cortex. The VP nucleus sends information to the primary somatosensory cortex (lateral part Æ legs). It analyses touch, pressure, pain and temperature information from the trigeminothalamic medial lemniscus and spinothalamic tracts. The LGB consists of six different cell layers – information from specific parts of the visual field is processed by specific parts of this nucleus. The MGB gets input from the auditory pathway and passes it to the primary auditory cortex. Medial dorsal nucleus Æ prefrontal cortex Lateral nuclear group Æ parietal and temporal cortex Anterior nuclear group Æ limbic system (cortex?)

530.302 – Medical Neurosciences Lecture Notes THE SPINAL CORD AND BRAIN STEM •

Spinal Cord

The spinal cord extends from the foramen magnum to the lower border of L1 vertebra. It terminates in the conus medullaris (and cauda equina), although the pia mater continues as the filum terminale (~20 cm in length) to the level of the posterior coccyx (passing through the termination of the arachnoid mater and dura mater, about 15 cm inferior to the conus medullaris). Note that CSF can be extracted from the subarachnoid space between L3 and L4 vertebrae. NB: the spinal cord is encased in a dural sac (note that the endosteal and meningeal dura fuse) that extends to (and fuses at) the level of S2 vertebrae. This sac is lined with arachnoid mater, and this also terminates at S2 vertebrae. There is a cervical enlargement (C3-T1) and a lumbrosacral enlargement (L1-S) associated with lower motor neurones (limb innervation). While there is no intrinsic segmentation in the structure of the spinal cord, paired spinal nerves can be divided as follows: 8 cervical nerves (note there are only 7 cervical vertebrae) 12 thoracic nerves 5 lumbar nerves 5 sacral nerves 1 coccygeal nerve The dorsal root fibres (6-8 rootlets) of each spinal nerve unite in the vertebral formation and join with ventral roots. They then enter the dorsolateral sulcus (medial and lateral bundles); the efferent fibres exit the ventrolateral sulcus. Structurally, a dorsal median sulcus and ventral median fissure are also present. White matter in the spinal cord is located peripherally, while grey matter is more central. Note that there is a large ventral grey horn in the cervical and lumbar regions, but not in the thoracic region (as there is no limb innervation here). There is also less white matter at the base of the spinal cord compared to the top. The grey matter in the spinal cord is divided into laminae: Dorsal horn: Posteromarginal nucleus (I) Substantia gelatinosa (II) Nucleus proprius (III and IV) Laminae V and VI Intermediate zone (VII): Intermediolateral nucleus (T1-T2) – preganglionic sympathetics Dorsolateral nucleus of Clarke (T1-L2) Ventral horn: Medial motor nucleus (VIII, some IX) Lateral motor nucleus (IX) The white matter is divided into funiculi: Dorsal funiculus: Gracile fasciculus – discriminative sensory fibres, lower limb Æ medulla Cuneate fasciculus – discriminative sensory fibres, upper limb Æ medulla Lateral funiculus: Lateral corticospinal motor column Anterior funiculus: Lateral spinothalamic (pain and temperature sensation) Propriospinal tract: Carries interspinal neurons (short are central; long are peripheral) •

Cerebrospinal Fluid and Intracranial Pressure

Functions of CSF: 1. Maintains constant environment for neurons and glia (metabolites, toxins) 2. Mechanical cushion for brain 3. May act as a conduit for peptide hormones

530.302 – Medical Neurosciences Lecture Notes CSF is located in the ventricles and subarachnoid space 1. Anatomy a. Dura mater – falx cerebri and tentorial notch are important clinical areas b. Leptomeninges (arachnoid and pia mater) c. Virchow-Robin spaces – perivascular space produced from invaginations of the pia mater where blood vessels enter/exit the brain and spinal cord d. Ependyma (single layer of cells lining the ventricles) 2. CSF flow – produced mainly in the lateral ventricles a. Æ 3rd ventricle via left and right interventricular foramina (Monro) b. Æ 4th ventricle via cerebral (Sylvian) aqueduct c. Æ subarachnoid via 1 midline (Magendie) and 2 lateral (Luschka) foramina 3. CSF production – most produced by the choroid plexus in the lateral ventricles, though secretion through the ependyma may also be involved a. Production involves filtration across the choroidal capillary wall, followed by active secretion by choroidal epithelium (microvillous, BB barrier) b. Figures i. 0.35mL/min (500mL/day) ii. Total volume is 140mL – complete turnover 3-4 times daily 4. CSF absorption a. Most by unidirectional bulk flow in arachnoid villi (Æ superior sagittal sinus) b. Some molecules (especially lipophilic) diffuse into brain and capillaries c. Active transport of some solutes by the choroid plexus 5. CSF composition a. White blood cells – 45°C) and high threshold mechanical stimuli b. C afferents respond to noxious cold ( 21%, adequate barometric pressure, clear airway, VT, frequency, CO. Pain can also be categorised to acute pain (illness/injury, gets better), chronic non-cancer pain (> 6 months or past the time of healing), and cancer pain. Reasons for pain relief: ‘Good’ – humanitarian Functional improvement Economic benefits (e.g. reducing admission period) Chronic pain – treatment and prevention aspects WHO classifies analgesic drugs as: Simple analgesics – paracetamol, NSAIDs, acupan Weak opiates – dextroproporyphene, codeine, tramadol Strong opiates – morphine, methadone, pethidine, fentanyls Other drugs may be used as adjuvants in atypical types of pain – tricyclic antidepressants, anticonvulsants, antiarrhymics, local anaesthetics Paracetamol is a non-opiod – it has minimal toxicity and nearly complete bioavailability. However, it can induce methemoglobinemia and haemolytic anaemia in patients with glucose6-phostphatase deficiency. Also, centrilobular liver necrosis occurs following overdose due to the formation of n-acetyl-p-benzoquinone (antidote is acetylcysteine). NSAIDs act by inhibition of cyclo-oxygenase, and are effective for pain caused by inflammation and distension of soft tissues, bones and joints; but are not effective in pain of a neurogenic nature. They have a central anti-pyretic effect by preventing pyrogen-induced release of prostaglandins in the hypothalamus. Note however that prostaglandins protect the stomach mucosa, and thromboxane A is required post-operatively to minimise bleeding. Leukotrienes are also produced in excess when the cyclo-oxygenase pathways are blocked. Selective COX inhibition does not constitutive COX1 (physiologically protective), but blocks COX2 (inflammatory). Opioids are drugs that bind to opioid receptors located supraspinally (periaqueductal grey, periventricular grey, area postrema), spinally (substantia gelatinosa of the dorsal horn), and peripherally after injury. Opioid Æ G protein (inhibits adenylate cyclase, lowers cAMP) Æ coupling to ion channels (increased intracellular Ca+2) Æ early intermediate genes Effects include analgesia, anxiolysis, cough suppression, euphoria, sedation and constipation. Opioids can also induce respiratory depression, nausea and vomiting, visceral spasms and dysphoria. Respiratory depression is typically only an issue after pain subsides – also note that in acute renal failure there can be residual opioid due to impaired clearance.

THE MOTOR SYSTEMS OF THE BRAIN •

Basal Ganglia and Movement Systems

The basal ganglia consist of several interconnected subcortical nuclei with major projections to the cerebral cortex, thalamus and certain brain stem nuclei. They receive input from the cerebral cortex and thalamus, and send their output to the cortex and brain stem. The striatum is a large bilateral structure consisting of the caudate nucleus, the putamen and the ventral striatum. Except at its most anterior pole, it is divided into the caudate nucleus

530.302 – Medical Neurosciences Lecture Notes and putamen by the internal capsule. It is the major recipient of inputs to the basal ganglia from the cerebral cortex, thalamus and brain stem. It projects to the globus pallidus and substantia nigra, which give rise to the major output projections of the basal ganglia. The globus pallidus lies medial to the putamen (lateral to the internal capsule) and is divided into external and internal segments. Note the claustrum, which function is unknown. The internal segment is related functionally to the pars reticulata of the substantia nigra, and has cells responsive to GABA. Note – putamen + globus pallidus = lenticular nucleus The substantia nigra consists of pars reticulata and pars compacta. The pars compacta is dorsal to the pars reticulata, and contains dopaminergic cells (with neuromelanin). The ventral-tegmental area (medial extension of the pars compacta) is also rich in neuromelanin. This substance is converted to melanin if too much dopamine is produced – in Parkinson’s the cells die and no pigmentation is visible. The subthalamic nucleus is closely connected anatomically with both segments of the globus pallidus and the substantia nigra – it is located below the thalamus and above the anterior part of the substantia nigra. The glutaminergic cells in this nucleus are the only excitatory projections in the basal ganglia – damage can lead to death by ballismus. The basal ganglia must communicate with the sensorimotor cortex (upper and lower motor neurons) to influence movement. This is achieved as follows: 1. Cells across the entire cortex project onto the striatum via the corticostriate projection, using glutamate as a transmitter 2. Striatopallidal and striatonigral projections are negative, and use GABA as a transmitter 3. Nigrostriatal and nigropallidal projections have receptor mediated inhibitory (D2) and excitatory (D1) effects. They use dopamine as a neurotransmitter. 4. There are also reciprocal connections: a. Globus pallidus ÅÆ subthalamic nucleus b. Globus pallidus ÅÆ reticular formation and thalamus c. Thalamus ÅÆ sensorimotor cortex Disease or damage to the basal ganglia results in mood/cognitive changes, difficulty initiating movements, involuntary movements and muscle tone defects. Parkinson’s disease is characterised by mood (emotionally flat), bradykinesia/hypokinesia, tremor at rest (‘pill-rolling’) and rigidity. The pathology is due to the death of cells in the pars compacta, resulting in a dopamine deficiency in the striatum – inactivating the nigrostriatal pathway. Symptoms tend to present first on one side (80% cell death) before spreading bilaterally. Treatment includes: 1. Dopamine replacement (requires L-dopa to cross the blood-brain barrier) 2. Cell transplantation of dopaminergic cells to the striatum (foetal cells) – note ‘frozen addicts’, stem cells in the hippocampus and striatum 3. Gene therapy 4. Pallidotomy (internal segment of globus pallidus – output pathways, note proximity of optic tract) or thalamotomy can help with tremors by reducing gabinergic activity. 5. A stimulator placed in the globus pallidus interna or the thalamus with a modulating frequency can also reduce the magnitude of tremors (deep brain stimulation) Huntington’s disease is a much more rare disease of the basal ganglia. It is inherited as a dominant gene (trinucleotide repeats) and causes behavioural/cognitive changes, hyperkinesia and involuntary movements. Pathologically, it is due to a loss of gabinergic projections in the striatum. Treatment is very symptom-dependent, and includes advances into gene therapy and neuron replacement.

530.302 – Medical Neurosciences Lecture Notes •

The Cerebellar and Pyramidal Systems

The cerebellum is divided into several distinct regions, each of which receives projections from different portions of the brain and spinal cord and projects to different motor systems. It influences the motor system by evaluating disparities between intention and action, and by adjusting the motor centres during motion. Functions of the cerebellum: 1. Rate, timing, force of contraction 2. Coordination of muscles of equilibrium 3. Tone of muscles This is mediated by three factors: 1. The cerebellum is provided with extensive information (goals, commands, feedback) associated with the programming and execution of movement. 2. The output projections of the cerebellum are focussed mainly on the pre-motor and motor systems of the cerebral cortex and brain stem (control spinal interneurons and motor neurons directly) 3. Synaptic transmission on the circuit modules can be modified Damage to the cerebellum disrupts the spatial accuracy and temporal coordination of movement (Æ intention tremor, ataxia). It impairs balance and reduces muscle tone, and markedly impairs motor learning and certain cognitive functions The cerebellum is comprised of an outer mantle of grey matter, internal white matter, and 3 pairs of deep nuclei – the fastigial, interposed (globose and emboliform) and dentate. It is connected to the dorsal aspect of the brain stem by three symmetrical pairs of tracts: 1. Inferior cerebellar peduncle – olivocerebellar fibres (related to initiation), vestibulocerebellar fibres, dorsal spinocerebellar tract 2. Middle cerebellar peduncle – pontocerebellar fibres 3. Superior cerebellar peduncle – efferents to thalamus/motor cortex, ventral spinocerebellar tract The three mediolateral regions of the body of the cerebellum and the flocculonodular node receive different afferent inputs, project to different parts of the motor systems, and represent distinct functional subdivisions. 1. Mediolateral regions – note that the vermis and intermediate hemisphere (spinocerebellum/palaecerebellum) are the only regions to receive somatosensory input from the spinal cord a. Vermis – receives visual, auditory and vestibular input, as well as somatic sensory input from the head and proximal parts of the body (Æ posture, locomotion, gait). It projects via the fastigial nucleus to cortical and brain stem regions associated with the medial descending systems. b. Intermediate part of the hemisphere – receives somatosensory information from the limbs. It projects via the interposed nucleus to lateral corticospinal and rubrospinal systems to control the distal muscles of the limbs and digits. c. Lateral part of the hemisphere (neocerebellum) – receives input exclusively from the cortex. Its output is mediated by the dentate nucleus, which projects to motor, pre-motor and prefrontal cortices. It is involved with planning and mental rehearsal of complex motor actions, and in the conscious assessment of movement errors. 2. Flocculonodular node (archicerebelluim/vestibulocerebellum) – receives input directly from primary vestibular afferents. It projects to the lateral vestibular nuclei, and is related to controlling balance and eye movement. The efferent projections of the cerebellar system can be summarised as follows: 1. Ascending projections via the thalamus to upper motor neurons in the motor cortex 2. Descending projections via the vestibular nuclei, reticular formation and red nucleus to the lower motor neurons in the spinal cord

530.302 – Medical Neurosciences Lecture Notes Disorders of the cerebellum result in distinctive signs and symptoms: 1. Truncal and gait ataxia 2. Limb ataxia 3. Dysarthria (loss of speech articulation) 4. Abnormal eye movements (nystagmus – rhythmic, oscillatory movements) 5. Vertigo and/or nausea and vomiting Tone may be normal or reduced. Power, tendon reflexes, plantar responses and sensation are normal. Note that many cerebellar diseases also affect other parts of the nervous system. Aetiology of cerebellar disease: 1. Congenital abnormalities 2. Inherited, degenerative diseases of the cerebellum 3. Inflammation, demyelination (e.g. multiple sclerosis, autoimmune disease) 4. Tumours (primary, metastatic) 5. Vascular disease (ischaemia, haemorrhage) 6. Infections (bacteria, virus, prions) 7. Metabolic disorders (hypoxia, ischaemia, hyperthermia, toxins, vitamin deficiency) The corticospinal tract is the means by which the brain controls voluntary movements. It passes from the motor cortex, through the posterior limb of the internal capsule and brain stem to terminate on lower motor neurons on the opposite side of the spinal cord. Note the prominence of the layer V pyramidal cells (Betz cells). The corticobulbar/corticonuclear tract is also part of the pyramidal system, but passes from the motor cortex, through the genu of the internal capsule. In the area of the midbrain and pons, it sends fibres to cranial nerve nuclei on the opposite side of the brain stem. •

Focal Diffuse

Motoneurons and Motor Units Acute Trauma or Vascular Toxins or Infections

Chronic Neoplasms Degenerative

Motoneurons (lower motor neurons) are found in the motor nuclei in the spinal cord (anterior horn cells) and in the brainstem (CN III-VII, IX-XII). They consist of two types: 1. Alpha motoneurons – extrafusal muscle fibres, responsible for force generation a. Fast firing (elements of FF motor units) b. Slow firing (elements of S motor units) 2. Gamma motoneurons – intrafusal muscle fibres, control excitability of stretch receptors in muscle spindles. Adjacent to alpha motoneurons – note co-activation. Components of a motor unit: 1. Cell body of one (alpha) motoneuron 2. Axon (divides into many branches) 3. All neuromuscular junctions (synapses) formed by a single motoneuron 4. All muscle fibres (extrafusal muscle fibres) innervated by one motoneuron (5-2000) S type motor units – slow twitch, little/no fatigue, small tetanic tension, early recruitment FF type motor units – fast twitch, fatigable, large tetanic tension, late recruitment Some S type motor units fire almost always (except during REM sleep). They are the best suited for carrying sustained but small loads. Note that weak contractions can be graded with greater precision – however, exercise is necessary to prevent FF unit atrophy. Inputs to alpha motoneurons (note the contribution of excitatory and inhibitory inputs): 1. Descending pathways a. Corticospinal (pyramidal) tract b. Rubrospinal tract c. Vestibulospinal tract

530.302 – Medical Neurosciences Lecture Notes d. Tectospinal tract (from superior colliculus) e. Reticulospinal tract (excitatory lateral, inhibitory medial) 2. Spinal interneurons – Ia inhibitory interneurons, Renshaw cells 3. Muscle receptors a. Ia afferents from muscle spindles – monosynaptic excitation b. Golgi tendon organs – disynaptic inhibition c. Nociceptive receptors in the skin d. Joint receptors The monosynaptic stretch reflex (latency 25-30ms knee) is evoked from muscle spindles by stretch or vibration. It is stimulus dependent, symmetrical, and does not fatigue. It is comprised of: a. Receptors – annulospiral muscle spindle endings b. Afferents – Ia afferents (fast) c. Synaptic delay – glutaminergic excitatory synapses on alpha motoneurons d. Efferents – axons of alpha motoneurons e. Effectors – homonymous or synergistic muscle Note that it may be facilitated by voluntary contraction of other muscles (Jendrassik manoeuvre), can be evoked by electrical stimulation of Ia afferents (H-reflex), and reflex relaxation of antagonistic muscles occurs via Ia inhibitory interneurons (reciprocal inhibition). •

Diseases of Motoneurons and Motor Units

Diseases of motor units: 1. Myopathies a. Myotonic muscular dystrophy – stiffness, slowness of relaxation, wasting i. Inherited (dominant) – males and females equally affected (up to 2000 triple CTG repeats in c19 coding for myotonin) b. Myasthenia gravis (autoimmune) – fewer ACh binding sites Æ smaller EPP c. Botulism – toxin impairs ACh release at all peripheral cholinergic synapses Æ weakness of striated and smooth muscle (somatic/autonomic) 2. Neuropathies a. Axotomy – injury of axons i. Changes in the distal segment (Wallerian degeneration) ii. Changes in the proximal segment (chromatolysis) b. Peripheral neuropathies – motor and/or sensory. Most common are the demyelinating conditions (diabetic neuropathy, Guillain-Barre syndrome, adrenoleucodystrophy). 3. Sequence of events in motoneuron degeneration: a. Terminal degeneration b. Wallerian degeneration c. Myelin debris d. Microglia macrophage infiltration e. Chromatolysis (breakdown of rough ER) f. Axonal regeneration (1-4mm/day) by arrays of Schwann cells Lower motoneuron disease – affects motoneurons in the spinal cord and brainstem 1. Symptoms: a. Atrophy and muscle wasting/weakness or paralysis b. Flaccidity - decreased/abolished muscle tone c. Depressed/abolished stretch reflexes d. Fasciculations (activation of single motor units) and fibrillations (activation of single muscle fibres) e. Flexor or absent plantar reflex 2. Diseases affecting cell bodies: a. Poliomyelitis – viral infection causing selective neural/muscular degeneration b. Syringomyelia – cystic dilation in the spinal cord (usually cervical), anterior horn degeneration, atrophy of the hand

530.302 – Medical Neurosciences Lecture Notes i.

c.

•

Expansion into the medulla – wasting of the tongue, soft palate, pharynx and vocal cords (IX + XIII) ii. Loss of pain and temperature in affected segments on the same side as the lesion Amyotrophic lateral sclerosis – muscle wasting and spasticity (increased stretch reflexes) due to degeneration of anterior horn cells, motor nuclei of the brain stem (but not II, IV and VI) and upper motor neurons (corticospinal) i. Pathogenesis 1. Autoimmune hypothesis – Ca+2 channel antibodies 2. Oxidative stress hypothesis – superoxide dismutase mutation 3. Excitotoxic hypothesis – lower abundance of GluR2 subunits of AMPA receptors, predisposing to higher Ca+2 flux

Injuries of the Spinal Cord and Brainstem Lesions

Injuries of the spinal cord 1. Hemisection of the spinal cord (Brown-Sequard syndrome) a. Motor defects (ipsilateral) i. Monoplegia – disruption of the corticospinal and rubrospinal tracts ii. Hyperactive reflexes (Babinski, clonus) – disruption of reticulospinal and vestibulospinal tracts b. Sensory defects i. Contralateral loss of pain/temperature sensation (disruption of the spinothalamic tract which decussates spinally) – segmental ipsilateral loss is possible in more extensive lesions ii. Ipsilateral loss of fine tactile perception and proprioception (disruption of the dorsal column which decussates in the brainstem) 2. Acute complete transection Æ spinal shock (areflexia due to loss of facilitatory inputs from reticulospinal and vestibulospinal tracts) a. Complete transection at T8 level – symptoms below the level of the lesion i. All conscious sensation lost ii. Flaccid paralysis and areflexia in both legs iii. Blood vessels dilated, blood pressure depressed (related to preganglionic sympathetics in the lateral grey horn) iv. Thermal sweating absent v. Atonic bladder and bowels vi. Sexual organ dysfunction b. Incomplete recovery – symptoms below the level of the lesion i. Paresthesia (abnormal sensation due to synaptic reorganisation) ii. Recovery of muscle tone iii. Spasticity/clonus – hyperactive stretch reflexes iv. Tendon reflexes 1. Flexor/withdrawal reflex 2. Extensor plantar reflex (Babinski) v. Autonomic dysreflexia – increased (or unstable) blood pressure vi. Reflex emptying of bladder and rectum 3. Aspects of patient management – artificial ventilation, ‘Parastep’ 4. CNS recovery - synaptic plasticity, denervation supersensitivity 5. CNS regeneration – note lack of Schwann cells a. Neutralising antibodies to inhibitory myelin-associated glycoprotein (associated with oligodendrocytes) b. Neurotrophin 3 (NT-3 growth factor – promotes central axon regeneration) c. Tissue bridges with peripheral nerve d. Tissue bridges with foetal spinal cord e. Injections of neural stem cells Brainstem lesions 1. Decerebrate rigidity refers to a large increase in the tone of the extensor muscles following transection between the superior and inferior colliculi in the midbrain (above

530.302 – Medical Neurosciences Lecture Notes vestibular nuclei, below the red nucleus). This persists indefinitely, and involves the reticular formation (lost excitatory input to the medial inhibitor area). 2. Other brainstem lesions are more likely to be fatal due to involvement of cardiovascular and respiratory centres, and the reticular activating system. They produce widespread sensory and motor deficits – note cranial nerve nuclei. •

Forebrain Mechanisms of Motor Control

There are two re-entrant pathways involved in the process of movement initiation, and in control of the force and range of muscle contractions: 1. A circuit involving the cerebral cortex, basal ganglia and thalamus 2. A circuit involving the cerebral cortex, brainstem and cerebellum A cerebrovascular accident is a sudden and focal impairment of function resulting from disorders of blood vessels. Two milder forms exist – transient ischaemic attack (24hrs, resolve within 2 days). 1. Causes of stroke a. 80% due to vascular occlusion Æ cerebral/retinal infarct b. 20% due to haemorrhage (cerebral/subarachnoid) 2. Symptoms depend on location of lesion – loss of neurological function in: a. Arm – middle cerebral artery b. Leg – anterior cerebral artery c. Vision (hemianopia) – posterior cerebral artery d. Speech/writing – left perisylvian (opercular) cortex Æ Broca/Wernicke areas 3. Mechanisms of neuronal death a. Hypoxia Æ ATP depletion Æ Na+/K+ pump inhibition Æ neuronal depolarisation Æ influx of Na+, Cl-, intracellular oedema (Æ increased ICP) b. Intracellular Ca+2 accumulation Æ necrotic/apoptotic cascade c. Enhanced release of excitatory neurotransmitters also causes Ca+2 influx via NDMA glutamate receptors d. Cytoplasmic release of free radicals triggered by Ca+2 4. Treatment – aimed at recovering neurons in the penumbra a. Anticoagulants and thrombolytic agents b. Ca+2/Na+ channel blockers – side effects widespread c. Antagonists of excitatory amino acid (NMDA) receptors – counteract excitotoxicity, side-effects include memory loss d. Experimental oral vaccine in animal models – produces antibodies against the NR1 subunit of the NMDA receptor. Note that these are normally isolated due to the blood-brain barrier. Upper motoneuron disease is the term for motor disorders of the corticospinal and corticoreticular tracts, and other extrapyramidal (descending) systems. Muscle paralysis or weakness (without wasting) involving groups of muscles is typical – note that clumsiness and slowness is out of proportion to loss of strength. Important signs: 1. Spastic increase in muscle tone a. Increased resistance to passive movements b. Unidirectional – affects extensors more c. Velocity dependent – spastic catch d. Clasp-knife phenomenon 2. Hyperactive tendon reflexes (clonus) 3. Extensor plantar reflex – an enhanced withdrawal reflex after a pyramidal or extrapyramidal lesion (release of inhibition) Muscle rigidity is a major sign of Parkinson’s disease – it is seen as bi-directional increased resistance to passive movements. It is velocity independent, and without hyperactive tendon jerks (contrast with spasticity in upper motoneuron disease).

530.302 – Medical Neurosciences Lecture Notes THE VISUAL SYSTEM (A DAMN SIGHT EASIER THAN 2000) •

Retina: Anatomy and Physiology

All vertebrate retinas are composed of three layers of cell bodies and two layers of synapses: 1. Outer nuclear layer – cell bodies of rods and cones 2. Inner nuclear layer – cell bodies of bipolar cells 3. Ganglion cell layer – cell bodies of ganglion cells 4. Outer plexiform layer – photoreceptor-bipolar cell synapse 5. Inner plexiform layer – bipolar-ganglion cell synapse The retina has two distinct regions – the outer sensory retina consisting of photoreceptors and connecting fibres, and the inner neural retina in which modification and encoding of the visual signal occurs before it is sent to the cerebral cortex via the optic nerve. 1. It is supported by the retinal pigment epithelium, which is essential for: a. Formation of photopigments b. Renewal of photoreceptors c. Reduction of damage from scattered light d. Transportation of water and nutrients to the retina. 2. There are two blood supplies supplying the retina: a. Central retinal artery – low volume, relatively sparse, less circulatory reserve, autoregulation. O2 extraction percentage is high but volume is small as the inner retina has low metabolic requirements. b. Choroidal circulation – high volume with a wide-bore, fenestrated capillary bed (choriocapillaris). O2 extraction percentage is low, volume is high (so there is considerable circulatory reserve). i. High metabolic demand of the outer retina is due to 1. The photoreceptor ‘dark’ current and phototransduction 2. Renewal/breakdown of the outer segments of photoreceptors 3. Intracellular renewal/repair of RPE cells ii. The choroidal circulation also helps to remove excess heat from metabolic activity and the degradation of excess light (absorbed by melanin and haemoglobin) c. Note that systemic blood is isolated from the retinal tissue by the inner and outer blood-retinal barriers (endothelium of the retinal vasculature and the RPE respectively) 3. Cellular components of the retina: a. Photoreceptors – rods 2 microns in diameter (1.5 in the fovea), cones taper down from 6 microns b. Horizontal cells c. Bipolar cells d. Amacrine cells e. Ganglion cells f. Mueller cells 4. Retinal diseases tend to affect the retinal vasculature or the chorioretinal interface – in both cases, this leads to breakdown of the blood-retinal barrier. In the outer retina, dysfunction of photoreceptors and RPE occurs. Macula = foveal pit + foveal slope + parafovea + perifovea Rods and cones process the visual signal and can be described in terms of performance functions (including rod/cone spectral sensitivity curves, light/dark adaptation curves). Rods are more concentrated in the central visual field and are related to the detection of colour and fine details. Cones are related to detection of peripheral movement. 1. Perception of various parameters may provide indication of dysfunction: a. Form/Spatial vision – measured by visual acuity (varies with contract, brightness, eccentricity and the testing procedure) b. Colour vision – hue, saturation, brightness and colour interactions are indicators of cone function and processing of the visual signal

530.302 – Medical Neurosciences Lecture Notes c.

Movement – movement detection in the peripheral vs central visual field reflects rod/cone distribution 2. Clinical testing procedures: a. Pupil reactions – reflex pathways to light, near and accommodation b. Visual fields – defects may indicate site of lesion c. Visual acuity – relates to contrast, eccentricity, light level, form, movement d. Colour vision – hue, saturation, brightness discrimination e. Refractive error – reflects ocular structures and retinal image formation Pathology 1. Age related macular degeneration – pigment epithelium degeneration Æ Drusen, fluid leakage behind fovea, foveal cone death 2. Glaucoma – raised intraocular pressure Æ compromises blood vessels of the optic nerve Æ ganglion cell death 3. Retinitis pigmentosa (hereditary) – peripheral rod degeneration Æ night blindness, tunnel vision, black pigment in periphery, thinned blood vessels 4. Diabetic retinopathy – hard exudates of lipid/protein, microaneurysms, new vessels (tortuous) Nerve impulses from eye to cortex – CN II Eye movements – CN III, IV, VI Sensory information of ocular structures – CN V, VII There are six extraocular muscles – lateral, medial, superior and inferior rectus muscles and the superior and inferior oblique muscles (innervation LR6SO43). These work in yoked pairs – e.g. right LR and left MR work synergistically to produce equal movement of both eyes. 1. Types of eye movement a. Ductions – monocular movements b. Versions – symmetrical, synchronous binocular movements c. Vergences – binocular movements where the eyes move symmetrically and synchronously in opposite directions 2. Eye movement systems a. Saccadic (target acquisition) – enables rapid eye movements that relocate fixation of target to the fovea b. Slow/smooth pursuit (tracking) – keeps a moving target on the fovea c. Vestibular system (stabilising) – maintains target despite head/body motion d. Vergence/fusion system (tracking in depth, image fusion) – controls convergence/divergence to allow an image on the fovea at all distances 3. Control pathways a. Supranuclear i. Saccades – contralateral frontal lobe ii. Pursuit movements – ipsilateral occipito-parietal lobe iii. Vestibular fibres run from the semicircular canals to the pons via the vestibular nuclei b. Internuclear – connections between pons, ocular motor and vestibular nuclei c. Infranuclear – ocular motor nuclei lie close to the midline in the midline (CN III and IV) and pons (CN V) Pupillary reflexes each have a distinct associated subcortical pathway: 1. Light reflex consists of four neurons (parasympathetic) a. Retina Æ pre-tectal nucleus – note that nasal retinal impulses decussate, but temporal impulses do not (so contralateral and ipsilateral involvement) b. Pre-tectal nucleus Æ both Edinger-Westphal nuclei (hence bilateral response to unilateral stimuli) c. Edinger-Westphal nuclei Æ ciliary ganglion via CN III d. Ciliary body Æ sphincter pupillae muscles of the iris 2. Near reflex consists of three components. Note that the it shares the efferent input of the light reflex – so afferent reflex pathway problems may have a light/near dissociation, but efferent reflex pathway problems affect both reflexes. a. Convergence

530.302 – Medical Neurosciences Lecture Notes b. Accommodation c. Pupil constriction – 3 neurons, respond to proximity to the eye Sympathetic pathway Æ pupil dilatation 1. Posterior hypothalamus Æ ciliospinal centre of Budge (C8-T2) 2. Ciliospinal centre of Budge Æ superior cervical ganglion 3. Cervical ganglion Æ sympathetic fibres in the ophthalmic division of CN V Æ ciliary body Æ dilator pupillae muscles •

The Eye as an Optical System

Visible light (400-750nm) Æ retina Æ optic nerve Æ optic chiasm Æ optic radiation Æ lateral geniculate nucleus, pre-tectum and superior colliculus Optical degradation at the foveola may be caused by a number of factors: 1. Lens aberrations a. Spherical – peripheral rays are brought to a focus nearer to the lens than rays through the centre or optical axis i. Normal compensation – cornea is flat peripherally, iris acts as a stop, retinal cones are more sensitive to axial rays (Stalls-Crawford effect) b. Chromatic – short-wavelength (blue) focussed nearer to the lens i. Normally, chromatic aberration is limited as photoreceptors are much more sensitive to the central yellow-green wavelengths 2. Light scatter – light is diffracted by components of the optical media. Yellow macular pigment limits chromatic aberration and reduces entry of scattered light. a. Pathology – dystrophica myotonica 3. Light absorption – cornea and lens absorb UV light, lens absorbs blue light with age a. Pathology – cataracts, corneal dystrophy (keratoconus) 4. Diffraction – diffraction at the pupil edge blurs the image Æ a series of bright and dark rings that get progressively fainter. Airy disc in the middle (84% of total energy). 5. Pupil size – dilatation causes spherical aberration; constriction blocks peripheral light aberrations but diffraction may become significant The eye (~25 mm long) has two refracting/focussing structures: 1. The cornea (40-45 dioptres) a. Measuring the cornea – computerised keratometry 2. The crystalline lens (20 dioptres) a. Transparent, biconvex structure b. Lies behind the iris supported by zonules c. 10 mm diameter, 4 mm thick d. Contributes 1/3 of the focussing power of the eye e. Dioptric power and transparency reduces with age (8 dioptres by 40 years, 2 dioptres by 60 years) Refractive errors (ametropia) are present if the image of a distant target cannot be brought to focus, resulting in a blur circle at the foveola. Note that a pinhole disc selects only axial rays and reduces the size of the blur circle. 1. Emmetropia – normal 2. Ametropia – abnormal. Note the Inuit proposition – ametropia has genetic predisposition as well as physical reinforcement a. Hypermetropia – short eye, focus behind retina, convex spherical lens i. Many people with ‘normal’ vision are slightly hypermetropic as the lens can accommodate – evolutionary advantages b. Myopia – long eye, focus in front of retina, concave spherical lens c. Astigmatism – cornea (or lens) is not spherical. Focal points may be in front, behind, or both – correction requires a combined spherical/cylindrical lens Clinical/pathological stuff: 1. Keratoconus – cornea becomes conical Æ corneal reshaping or transplantation

530.302 – Medical Neurosciences Lecture Notes 2. Diffracted limited point-spread function – the image of a point like a star is only distorted by the diffraction of the light due to the pupil. An eye with aberrations will not produce an optimised image of a point. 3. Radial keratotomy – four cut and/or ‘mini RK’. Results up to –3.0 to –4.0 dioptres 4. Excimer laser PRK and LASIK – laser ablation of corneal tissue (~10% regeneration) a. Optimised laser treatment modifies the PSF of the treated eye towards the diffracted limited PSF b. 5% Æ minor complications, 1-2% Æ visually significant complications 5. Senile cataract – can be removed by: a. Intracapsular cataract surgery, intraocular lenses can then be inserted to replace the crystalline lens b. No-stitch phaco-emulsification with lens replacement •

Visual Pathways – Chapter 27 in Kandel

The optic system is comprised of a number of components. Note that the sensory system can be likened to a sensory motor system – deficits are related not only to deficits in detecting stimuli, but also related to loss of appropriate reactions to these stimuli. 1. Object discrimination - form, shape, size, texture 2. Brightness and contrast 3. Spatial frequency 4. Colour 5. Depth perception via retinal disparities (note binocular and monocular cues) 6. Movement – note difference in peripheral and central/foveal movement stimuli The surface of the retina is divided into the nasal hemiretina and the temporal hemiretina – the left visual hemifield projects onto the nasal hemiretina of the left eye and the temporal hemiretina of the right eye (and vice versa). This gives corresponding points on each retina. Light in the central region of the visual field (binocular zone) is encoded by both eyes; light from the temporal portion (crescent) of the visual field (monocular zone) is encoded only by the ipsilateral nasal hemiretina. The highest resolution is at the area of the macula/fovea. Axons from the ganglion cells in the retina extend through the optic disc, and at the optic chiasm fibres from the nasal hemiretina cross to the opposite side of the brain. Hence, the axons from the left half of each retina project in the left optic tract, carrying a complete representation of the right hemifield of vision (and vice versa). The optic tracts pass to three major subcortical targets – the pretectum, superior colliculus and lateral geniculate nucleus. Note that parallel processing allows encoding of very complicated stimuli. 1. Superior colliculus – structure of alternating grey and white matter layers on the roof of the midbrain. Retinal ganglion cells project directly on the superficial layers to form a map of the contralateral visual field a. Extensive cortical inputs – deep layers have the same visual field map, but also respond to auditory and somatosensory information b. Deep layer cells also discharge vigorously before the onset of saccadic eye movements. These cells form a movement map in the intermediate layers (corresponding to the superficial visual map) – for example, cells responding to stimuli in the left visual field with discharge before a leftward saccade. 2. Pretectum – retinal ganglion cells project to this structure (adjacent to the superior colliculus where the midbrain fuses with the thalamus), which then projects bilaterally to preganglionic parasympathetic neurons in the accessory oculomotor nucleus. a. Mediates pupillary light reflexes 3. Lateral geniculate nucleus (dorsal part) Æ primary visual cortex Æ higher visual areas in cortex (extrastriate). This is done in an orderly manner, such that in each nucleus there is a retinotopic representation of the contralateral half of the visual field. a. About half of the neural mass in the nucleus represents the fovea and surrounding area

530.302 – Medical Neurosciences Lecture Notes b. Different layers encode different information with regards to colour and luminance contrast, and spatial and temporal frequency. i. I, IV, VI – ipsilateral input, II, II, V – contralateral input from retina 1. 2 ventral layers – magnicellular, input from M ganglion cells 2. Interlaminar layer (III) 3. 4 dorsal layers – parvicellular, input from P ganglion cells 4. Other important targets – pulvinar nucleus of the thalamus, lateral geniculate nucleus (ventral part), optic tract nuclei The large geniculocalcarine tract has a very wide distribution – for example, fibres may loop through the temporal lobe before terminating in the primary visual cortex. Total blindness of ipsilateral eye – lesion in the prechiasmic optic nerve Bitemporal heteronymous hemianopsia – lesion across the optic chiasm Ipsilateral nasal hemianopsia – prechiasmic lesion in temporal hemiretina fibres Contralateral homonymous hemianopsia – postchiasmic lesion in the visual radiation Contralateral lower quadrantic anopsia – postchiasmic lesion in parietal lobe (visual radiation) Contralateral upper quadrantic anopsia – postchiasmic lesion in Myers’ loops (temporal)

NEURODEGENERATION Brain damage can occur after acute or chronic insults: 1. Acute – stroke, epileptic seizure, traumatic head injury, perinatal asphyxia 2. Chronic – Alzheimer’s disease, Parkinson’s disease, AIDS dementia, Huntington’s disease Glutamate functions normally in learning and memory, movement and sensation. It is the main excitatory neurotransmitter in the brain. Receptors can be ionotropic or metabotropic: 1. Ionotropic receptors a. NMDA receptors have binding sites for glutamate, glycine and PCP. i. The channel normally conducts Ca+2 and Na+, though Mg+2 occupies and blocks the channel (Mg+2 efflux occurs on depolarisation) ii. Depolarisation + glutamate + glycine Æ opens channel Æ Ca+2 influx Æ depolarisation of the neuron (related to memory) iii. Phencyclidine binds inside the channel, blocking ion flow (noncompetitive antagonist) b. AMPA/Kainate receptors work in a similar fashion – when glutamate binds, there is an influx of Na+ and depolarisation of the neuron 2. Metabotropic receptors are G-protein linked – glutamate binding increases IP3 and DAG Æ release of Ca+2 from intracellular stores and activation of protein kinase C. The excitotoxicity theory suggests that excessive activation of glutamate in the brain leads to nerve cell death. Injury leads to excitatory amino acids and increased glutamate levels. This induces pathological activation of AMPA and NMDA, which have two effects: 1. Increased Ca+2 + I (NMDA) Æ delayed nerve cell death (apoptosis) a. Mechanism – possible activation of calcium-sensitive enzymes (biochemical pathways intrinsic to the neuron) 2. Increased Na+ + I, Cl-, H2O (AMPA) Æ rapid nerve cell death (cell lysis) Pharmacotherapy involves reducing glutamate release (A1 adenosine receptor agonists – negative feedback system) or by blocking receptors: 1. NMDA – MK 801 or memantine are useful for focal strokes and prolonged seizures, although there may be psychotomimetic side effects. 2. AMPA – NBQX is very effective against global ischaemia, unknown side effects The intracellular cascade triggered by glutamate receptor activated Ca+2 release can also be blocked by 1. Free radical scavengers – neuroprotective effects

530.302 – Medical Neurosciences Lecture Notes 2. Protein kinases – gangliosides 3. Suicide genes – block expression

SYNAPTIC TRANSMISSION •

Mechanisms of Synaptic Transmission

Transmitter release is mediated by a number of events: 1. Presynaptic action potential 2. Activation of voltage-dependent Ca+2 channels 3. Increased presynaptic [Ca+2] a. Mobilisation of vesicles – synapsin bound to vesicles in the reserve pool is phosphorylated by calmodulin allowing release to the release pool b. Attachment to docking sites at the active zones c. Fusion with the membrane – synaptophysin (Ca+2 binding protein) involved 4. Release of transmitter by exocytosis from presynaptic terminal 5. Reaction of transmitter with postsynaptic receptor 6. Activation of ligand-gated channels (postsynaptic current Æ postsynaptic potential) 7. Action potential – dependent on temporal and spatial summation Voltage-gated ion channels: 1. Hodgkin-Huxley Na+/K+ channels are necessary for action potential generation and transmission to the synaptic terminal 2. LVA and HVA Ca+2 channels are responsible for an increase in presynaptic [Ca+2] Ligand-gated ion channels: 1. Ionotropic receptors are directly gated, with a single molecule acting as both the receptor and effector a. Ligand gated ion channels mediating EPSPs are permeable to Na+ and K+ (sometimes Ca+2), while channels mediating IPSPs are permeable to Clb. Include GABA, glycine, glutamate, nicotinic ACh, serotonin 5HT3 receptors i. They are composed of 5 subunits, each with 4 transmembrane domains that contribute to the selectivity of the channel ii. Pore permeability has important consequences for effects on membrane potential and cellular function 2. Metabotropic receptors are indirectly gated – recognition of the transmitter and activation of the effector are carried out by different molecules a. Time course is much slower and longer lasting than directly gated receptors b. Examples: i. CAMP system – norepinephrine Æ beta-adrenergic receptor Æ cAMP Æ cAMP-dependent protein kinase ii. IP3-DAG system – acetylcholine Æ muscarinic ACh receptor Æ IP3/DAG Æ Ca+2 release iii. Arachidonic acid system – histamine Æ histamine receptor Æ arachidonic acid Æ lipoxygenase, cyclo-oxygenase c. They are formed from a single protein/subunit with 7 membrane-spanning regions – action on cellular function is produced through i. Direct action of G-proteins on the channel ii. Ion channel phosphorylation by second messenger iii. Regulation of gene expression by phosphorylating transcriptional regulatory proteins Rapid removal of neurotransmitter is essential after release if the cell is to respond to high frequency inputs. This is achieved through diffusion, enzymatic degradation or re-uptake. Neurotransmitters are substances that are released at a synapse by one neuron, and affect other cells in a specific manner. Defining a neurotransmitter depends on the following criteria: 1. Presynaptic terminals must contain and have the ability to synthesise the compound

530.302 – Medical Neurosciences Lecture Notes 2. Compound must be released from the presynaptic neuron on appropriate stimulation 3. Microapplication to the postsynaptic neuron must mimic presynaptic stimulation 4. A specific mechanism must exist for removing the compound from the site of action The postsynaptic response is determined by the transmitter released (note high transmitter diversity) and the receptor subtype present on the postsynaptic membrane: 1. Co-release (multiple NTs) – increase the potential complexity of postsynaptic effects 2. Multiple receptor subtypes – increase the information handling capacity of neurons 3. Note that modality-specific information processing is dependent on neurotransmitter diversity Neuromodulators modulate synaptic transmission by altering the amount of transmitter released form the presynaptic cell, or the response of the postsynaptic receptor to the transmitter. Note that some transmitters can function as both transmitters and modulators. 1. Presynaptic inhibition/facilitation a. Hyperpolarizing or depolarising presynaptic terminal b. Activation of second messenger systems 2. Postsynaptic a. Alteration of Ileak (changes neuronal input resistance) b. Activation of second messenger systems Diseases are associated with specific transmitter systems: 1. Excitatory amino acids – domoic acid poisoning, Guam disease, neurolathyrism 2. Dopamine – Parkinson’s disease 3. GABA and cholinergic neurons – Huntington’s chorea •

Voltage-Gated Ion Channels

The resting membrane potential is determined by the relative permeability of the membrane via ‘leak channels’ to ions (especially Na+ and K+) and the relative concentrations of these. Nernst potential is the equilibrium potential for a given membrane – where electrical and chemical forces are balanced such that there is no net ionic movement. 1. Note that the RMP represents the interactions of the Nernst potential for all ions. 2. At rest, PK >> PNa so the RMP is closer to the Nernst potential for K+ 3. Small changes in membrane potential open voltage-dependent ion channels and drastically alter the relative permeability of the membrane (Æ change in potential) 4. The Goldman equation approximates the membrane potential (-65mV) by combining figures for K+ (-90mV) and Na+ (+55mV) dependent on concentration & permeability Ion selectivity is important – for example, a channel moving K+ and Na+ Æ AP of zero: 1. Proteins in the lipid are hydrophobic; ions are hydrophilic (attract dipolar H2O) 2. Æ Ions become surrounded by the ‘waters of hydration’ (help stabilise the ions) 3. H2O cannot be shed so ions must move through an aqueous pore 4. Ion channels have a hydrophilic domain – within the lumen, interaction with charged amino acids (binding to the Na+ ion and the H2O molecule) provides ion selection Ion channel structure: 1. Voltage-gated ion channels a. Na+ and Ca+2 – 6-membrane spanning regions (4 repeats) i. N and C terminals are intracellular b. K+ – 6-membrane spanning regions (4 subunits) i. Inward rectifiers – 2 membrane spanning regions (4 subunits) 1. S4 – voltage sensor 2. S6 – lines the pore 3. S5-6 – selectivity filter (protein extends back into pore) 2. Ligand-gated ion channels a. NAChR and relatives (GABA, glycine, 5HT3) – 4 membrane spanning regions (5 subunits)

530.302 – Medical Neurosciences Lecture Notes b. Glutamate – 3 membrane spanning regions (4 or 5 repeats) i. N terminal extracellular (binds ligand), C terminal intracellular ii. M2 lines the pore and does not completely cross the membrane Channel diversity 1. K+ channels – most diverse 2. Ca+2 channels – 5 types (L, N, P/Q, R, T) a. Present drugs operate on L-type channels (dihydropyridines, benzothiazepines, phenylalkylamines) and prevent channel opening b. Used in cardiovascular diseases 3. Na+ channels – 9 different isoforms for skeletal muscle, heart, neurons, glial cells a. One channel type (SNS) is only on small nociceptive neurons Channel gating 1. Activation a. Voltage sensor in the S4 region detects transmembrane voltage change b. Æ Conformational change in channels, pore opens 2. Inactivation (some channels, e.g. Na+ in action potentials) a. N terminal forms a plug blocking the channel shortly after it opens b. Repolarisation removes the plug c. ‘Ball and chain’ model – deletions from the N-terminal region Æ increased speed of inactivation (and vice versa) d. Alternatively – three states: closed, open, inactivated (e.g. Shaker B protein) Channelopathies 1. Cl- channels a. Cystic fibrosis i. Most common autosomal recessive disease in Europeans (5% are carriers) ii. CFTR (CF transmembrane regulator) gene is defective iii. Cl- channel functions, but does not transfer to the membrane properly + 2. Ca channels – different mutations of brain-specific gene for P/Q type channels: a. Familial hemiplegic migraine b. Episodic ataxia (type 2) c. Chronic spinocerebellar ataxia (type 6) 3. K+ channels a. Episodic ataxia (type 1) b. Long QT syndromes (delayed repolarisation of cardiac action potential) c. Familial inherited neonatal epilepsy 4. Na+ channels – long QT syndrome •

Ligand-Gated Ion Channels: Glutamate Receptors

Note desensitisation – current tuns off, but the ligand is still present. Mechanism unknown. Glutamate is responsible for most fast excitatory transmission in the brain – it is the endogenous transmitter for many receptor subtypes. It may act directly (ionotropic) or indirectly (metabotropic) – in general, only the NMDA receptor passes Ca+2. 1. Structure a. Ionotropic receptors – AMPA, Kainate, NMDA i. Pentamers of different receptor subunits ii. Three identified classes (but probably more) based on 1. Various combinations of receptor subunits a. Homomeric and heteromeric receptors are functional b. Note that NMDAR1 is essential for NMDA function 2. Splice variants a. DNA Æ pre-mRNA Æ removal of exons Æ different mRNAs due to alternate splicing 3. RNA editing (substitution of different bases)

530.302 – Medical Neurosciences Lecture Notes a. Q/R editing Æ Arg replaces Gln on the M2 region b. Metabotropic receptors i. Single proteins, 7 transmembrane regions ii. 8 receptor subtypes iii. 3 main functional groups 2. Physiology a. Endogenous agonist for AMPA/Kainate and NMDA receptors b. Effects vary (NMDA Vs non-NMDA) i. Time course (NMDA slow, longer lasting) ii. Ion selectivity (NMDA are Ca+2 selective) iii. Voltage-dependent Mg+2 block of NMDA Functional significance of multiple receptor subtypes: 1. Plasticity – long-term potentiation a. Long-term potentiation – experience-dependent modification of synaptic function (‘cellular memory’) i. Non-NMDA receptor function depolarises cells ii. Æ Removal of voltage-dependent Mg+2 block of NMDA iii. Æ Ca+2 influx (important for induction of LTP) iv. Æ Modification of postsynaptic ligand-gated channels v. Æ Diffusion of retrograde messenger to presynaptic terminal vi. Æ Enhancement of transmitter release b. Synchronous activity in synaptic terminals in necessary (may be detected by the NMDA receptor). c. Post-synaptic Ca+2 influx indicates pre- and post-synaptic activity as: i. Presynaptic activity Æ glutamate release ii. Postsynaptic neurone must be depolarised to near-threshold to remove the Mg+2 block 2. Amyotrophic Lateral Sclerosis a. 4 main theories: i. Autoimmune ii. Excitotoxicity iii. Viral iv. Free Radicals – familial ALS, superoxide dismutase disorder b. NMDA receptors i. Excitotoxicity theory is focused on these due to their permeability to Ca+2 and relationship with apoptosis ii. NMDA receptor antagonists are inconsistent in blocking excitotoxic events – indicates alternative Ca+2 pathways c. AMPA receptors i. Made of 5 subunits (GluR1-R4), in-vivo combination unknown ii. GluR2 subunit is responsible for impermeability to Ca+2 1. Post-transcriptional RNA editing at the Q/R site (Gln Æ Arg) Æ Ca+2 impermeability iii. Low abundance of GluR2 subunits (or problems with RNA editing) Æ excitotoxicity d. Motor neuron disease – GluR2 hypothesis i. Motoneurons may have a lower GluR2 abundance (predisposition to increased Ca+2 fluxes Æ excitotoxic damage) ii. Studies only show slightly lower expression of GluR2 in MNs iii. More likely to be related to RNA editing 1. Studies are investigating differences between motoneurons affected (XII, nucleus ambiguus, V) Vs those not typically involved (III, IV, VI)

NEURORADIOLOGY 1895 – Roentgen pioneers the X-Ray

530.302 – Medical Neurosciences Lecture Notes 1896 – William Randolph Hearst commissions Roentgen to take a cathograph of the brain. This was eventually attempted by Edison, taking 21 days before concluding the skull provided an insurmountable obstacle. Around the time of WWI, it was discovered that air entering the cavities of the brain/cranium was visible on X-Ray, allowing the brain to be visualised for the first time. This was essentially the only technique until the 1970s – the pneumocephalogram (air injected into the CSF as a contrast agent). However, this was not very pleasant. At this time, the displacement of the lateral ventricles was being used to predict the location of mass lesions. Alternatively, contrast could be injected into the arteries of the brain and the midline shift interpreted accordingly. Note that the nature of the mass could not be elucidated from the radiograph. The CT was then developed, allowing a number of X-ray ‘slices’ taken and the density of each pixel interpreted mathematically. Following this (~1980s) the MRI was developed (using different physical principals) and allowed sagittal and coronal sections (in addition to 3D reconstructions) for the first time. CT contrast (black Æ white) 1. Air 2. Fat 3. CSF 4. White matter 5. Grey matter 6. Acute haemorrhage (or IV contrast) 7. Bone or calcification (e.g. pineal gland) Common clinical presentations requiring radiological investigation (note that bleeding is generally the acute presentation requiring immediate intervention): 1. Ultrasound can pick up a number of neonatal problems: a. Germinal bleed haemorrhage – bleeding into choroid Æ ventricles b. Hydrocephalus 2. Subarachnoid haemorrhage – aneurysm (MRI is not useful for fresh [50yrs 2. 2.7/1000 children born with severe deafness (mean age of detection 22 months) 3. By age 15, 3.5/1000 children will have a serious hearing problem 4. ~50% of hearing problems in adults is due to noise exposure 5. 1% have significant tinnitus Hearing loss: 1. Reduced sensitivity to sound 2. Reduced ability to discriminate frequency (sounds are distorted) 3. Reduced hearing in noise (Café effect) 4. Poor speech recognition 5. Poor localisation of sound 6. Tinnitus (persistent) 7. Poor speech 8. Poor reading and language skills Causes: 1. Middle ear – infections, trauma, congenital 2. Inner ear – noise, ageing, drugs, infections, congenital 3. Brain pathways – tumours, congenital, ischaemia Frequency range – 10 octaves from 20Hz to 20,000Hz Frequency discrimination – separate two frequencies 0.2% apart Timing discrimination – can distinguish two sounds separated by 6-10 microseconds apart Note that hearing is not the same sensitivity at all frequencies – 150-4000Hz is the optimum range, and this is around where normal speech is represented. •

Functional Anatomy

Functions of the auditory system: 1. Brain auditory centres – integration, speech recognition, sound localisation 2. Auditory nerve 3. Ear – detection of sound, mechanoelectrical transduction – intensity, frequency, temporal features The auditory system comprises the brain, ear and auditory nerve – the peripheral system can be subdivided into an outer, middle and inner ear. The process of sound detection involves the transmission of sound through the middle ear to the inner ear where mechanical vibrations are transduced into neural activity. 1. Outer ear – funnels sound, protects eardrum, assists sound localisation a. Pinna – important for the collection of sound and directing it to the middle ear – the folds and hollows modify the incoming sound. b. Ear canal 2. Middle ear – air-filled cavity separated from the outer ear by the ear drum. Important for amplification of sound, and filtration of extreme frequencies of sound. a. Communicates with the nasopharynx via the Eustachian tube (important for aeration and maintaining equal air pressure across the tympanic membrane) b. Ossicular chain – acts as an impedance transformer to overcome the mismatch between the fluids of the inner ear, and air 3. Inner ear – comprises the three semicircular canals and vestibule of the vestibular system and the spiral cochlea. Involved with sound transduction, analysis of frequency/intensity and noise reduction. a. Cochlear duct – surrounded by perilymph, filled with endolymph. Divides the perilymphatic space into the scala vestibuli and scala tympani b. Organ of Corti – attached to the basilar membrane and comprised of the sensory cells (inner and outer hair cells) surrounded by support cells.

530.302 – Medical Neurosciences Lecture Notes Afferents: Efferents:

Type I (glutamate) – myelinated (90%), only IHC, Æ cochlear nucleus Type II – unmyelinated nerves (10%), only OHC, projects to cochlear nucleus Arise in the ipsilateral and contralateral superior olivary complex, mostly OHC

Central auditory function: 1. Cochlear nucleus – relays nucleus to higher centres and some low-level feature extraction and noise reduction (heart and breathing sounds) 2. Superior olivary nucleus – binaural interactions for sound localisation, auditory reflex centre to activate middle ear muscles 3. Inferior colliculus – binaural hearing, centre for integration with vision and motor systems, sound localisation 4. Auditory cortex – auditory processing, cognitive integration, sound localisation, speech analysis •

Auditory Mechanics and Encoding

Outer/middle ear anatomy: 1. Eardrum – three layers (epithelial, fibrous, mucosal) 2. Ear canal – skin lining the canal is self-cleansing 3. Middle ear mucosa 4. Ossicular chain (malleus, incus, stapes) Sound conduction to the inner ear: 1. Air conduction – displacement of the eardrum and ossicular chain 2. Bone conduction by inertial and compression waves through the skull. Less sensitive (40-50dB) than air conduction but very important for monitoring voice. a. Conductive hearing loss – very quite voice due to lack of monitoring Because of higher density of inner ear fluids, the inner ear provides high resistance to vibration for the same force – there is only 0.1% transmitted. This would be equivalent to ~40dB hearing loss. Hence the middle ear acts as a transformer/amplifier to increase the pressure at the stapes to ensure sound transfers to the inner ear: 1. Area ratio – ear drum is a much larger surface area than the stapes 2. Lever ratio – manubrium of the malleus Vs the long arm of the incus 3. Tympanic membrane ratio – conical shape of the tympanic membrane acts as a lever Displacement of the stapes in the oval window, and the corresponding displacement of the round window, initiates a travelling wave along the basilar membrane and organ of Corti. The cochlea is tonotopically organised – the basal part corresponds to high frequencies; the apical regions correspond to progressively lower frequencies. 1. Lateral movement of the ossicular chain 2. Æ Vertical movement of the organ of Corti 3. Æ Radial movement of the stereocilia Transduction channels are located on the stereocilia and are operated by fine elastin filaments (passing from the ion channel on the shaft of a stereocilium to he tip of the adjacent stereocilium). Opening or closing the channels increases or decreases a standing current through the apical surface of the hair cell, causing a change in membrane potential (via liberation of calcium / activation of voltage-gated calcium channels). Inner hair cells provide the predominant sensory input to the CNS, while outer hair cells appear to serve as motor cells enhancing the small motion of the cochlear partition. 1. Active cochlear amplifier - frequency tuning is due to an energy-dependent process that injects energy into the travelling wave to overcome viscous damping by the fluid. 2. This is facilitated by sound-induced contraction of the outer hair cells a. Prestin – motor protein which oscillates at a very high rate (electromotile) 3. Æ Otoacoustic emissions (investigated in neonatal deafness)

530.302 – Medical Neurosciences Lecture Notes Each auditory nerve fibre only responds to a restricted range of frequencies and intensities – fibres give a characteristic frequency-tuning curve. Note that the best frequency of the nerve fibre is determined by the location of the inner hair cell it innervates. 1. Place principle – cochlea is a filter and is tonotopically organised so that frequency is detected by spatial representation from base to apex (high frequency sounds) a. Travelling wave reaches a peak at different points along the cochlear depending on frequency b. Variations in stiffness of the basilar membrane determine its responsiveness 2. Volley principle – low frequencies are detected by temporal firing of nerve fibres in time to the frequency of the stimulus (limited by refractory period to thiopental > midazolam > ketamine >propofol > etomidate Thiopentone is a barbiturate (introduced 1934) that acts at GABAA receptors, increases the affinity at benzodiazepine receptors and binds in the channel of NMDA receptors. 1. Actions:

530.302 – Medical Neurosciences Lecture Notes a. Brain – potent depressant and anticonvulsant (unconscious in one arm to brain circulation time) b. CVS – potent depressant (direct myocardial, indirect sympathetic depression) i. EEG – slow waves Æ delta waves Æ suppression Æ isoelectric EEG c. Respiratory – potent depressant (apnoea, suppression of laryngea reflexes) d. Other – toxic subcutaneously or intra-arterially, anaphylaxis, crosses placenta, some age-related variations 2. Kinetics: a. Brief duration of action due to redistribution b. Slow liver metabolism (excretion half-life 12-24 hours) 3. Rapid recovery, but a ‘hangover’ Propofol is an alkyl-phenol (emulsified with soya bean oil and egg phosphatide 1. Actions: a. CNS – potent depressant, not anticonvulsant b. CVS – potent depressant, vasodilation, resets baroreceptors c. Respiratory – potent depressant d. Other – painful but non-toxic if not in vein 2. Kinetics: a. Offset by rapid redistribution and rapid metabolism (excretion half-life 1-1.5hr) b. Recovery rapid, minimal hang-over, antiemetic c. Suitable for infusion 3. Rapid, clear-headed recovery Benzodiazepines work at GABAA receptors (indirectly augment affinity of GABA). 1. Actions: a. Hypnotic, muscle relaxant, anticonvulsant, anxiolytic b. Minimal CVS and respiratory depressant when used as a sole agent c. Potent synergy with other drugs (opioids, IV induction agents) 2. Drugs that work at the benzodiazepine receptor: a. Agonists – e.g. midazolam b. Antagonists – flumazenil (reverses effects of agonists and inverse agonists) c. Inverse agonists – DMCM 3. Dose-related effects – anxiolysis Æ sedation Æ amnesia Æ anticonvulsant (persists) Ædrowsiness Æmuscle relaxation Æ sleep 4. Examples: a. Diazepam i. Very long acting (24+ hours) ii. Activate metabolites – oxazepam, temazepam, desmethy-diazepam iii. Poor water solubility, irritating IV preparations b. Midazolam i. Medium duration of action (0.5-1.5 hours after small IV bolus) via liver metabolism ii. Better IV drug (water-soluble), can also be given orally iii. Potent amnesiac c. Flumazenil – competitive antagonist to benzodiazepines i. Brief duration of action after IV bolus (15-20 minutes) ii. Reliable reversal of bolus doses of midazolam 1. Re-sedation may occur with longer-acting benzodiazepines or infusions 2. May cause withdrawal syndrome in addicts 3. Sympathetic overactivity – anti-benzodiazepine effect releases inhibition of side effects of overdose of other drugs iii. Reverses paradoxical reactions to benzodiazepines iv. May be used to diagnose and treat drug overdoses acutely Ketamine is an arylcyclohexylamine that acts as an antagonist at NMDA receptors. Widely used in emergency situations for surgical procedures (due to minimal respiratory depression) 1. Actions:

530.302 – Medical Neurosciences Lecture Notes a. CNS – dissociative state, may appear awake with eyes open, hallucinations, analgesia, CNS stimulation. Use of benzodiazepines – amnesia b. CVS – stimulates sympathetic nervous system c. Respiratory – retains laryngeal reflexes, bronchodilator, minimal depression 2. Kinetics: a. Terminal half life of 3 hours b. Metabolism to nor-ketamine (active) c. Duration of action is very dependant on dose Opioids include the pheynlpiperidines (fentanyl, alfentanil, remifentanil) 1. Opioids are not anaesthetics, but are sedating at high doses 2. Do not guarantee unconsciousness or no recall at any dose 3. Potently synergistic with benzodiazepines Æ unconsciousness, no movement to pain a. Greater likelihood of CVS and respiratory depression b. However, commonly used for sedation by proceduralists 4. Kinetics: a. Great variation in standard response between individuals, and within individuals at different instances – requires monitoring b. Variation in response depending on stimuli involved Intravenous drugs are extremely potent due to their mode of administration. Doses when given need to be carefully titrated.