Neuro Flashcards
- Describe the laminae and their contents
- Laminae I – VI: SENSORY
- Lamina VII: AUTONOMIC
- Laminae VIII & IX: MOTOR
- Lamina X: Gray commissure, contains small neurons and glia.
Neuronal Architecture – Laminae (Sensory)
- Lamina I
- pain neurons tend to be small and non-myelinated
- thus they are exhausted when they reach the spinal cord
- lamina I contains the posteromarginal nucleus, which receives pain and temperature inputs
- first order neurons begin to synapse and partially form the spinothalamic tract
- Lamina II – Substantia Gelatinosa:
- Extends the entire length of the spinal cord, contains small neurons that send excitatory and inhibitory synapses onto the STT ^[spinothalamic] primary cells (gating effect on sensory transmission).
- Rostrally, it continues into the spinal nucleus of V.
- Afferents: small-diameter sensory fibres carrying pain & temperature, larger mechanoreceptor nerves
- Small inhibitory interneurons in the lamina filter and modulate incoming sensory information
- Efferents: contralateral STT (together with cells from Laminae I, IV & V)
- Contains small neurons that send excitatory and inhibitory synapses onto the STT primary cells (gating effect on sensory transmission).
- Contains high concentration of Substance P (neuropeptide, plays a role in pathways modulating pain sensibility) and enkephalinergic internuncials (opioid inhibiting pain transmission)
- Laminae III & IV (V) – Nucleus Proprius ^[aka trigeminal nucleus which is responsible for pain and temperature]:
- Extends the entire length of the spinal cord
- afferent: large sensory fibres carrying PRIMARILY position & light touch, - project to dorsal column nuclei. ^[no efferents?]
- which project to dorsal column nuclei
- afferent: small diameter sensory fibres carrying noxious stimuli (pain and temperature) and interneurons from lamina II
- project to contralateral spinothalamic tract
Neuronal architecture - Laminae (Sensory)
- Lamina VI
- small interneurons
- afferent from muscle spindles (proprioception)
- efferents to motor neurons in laminae VIII and IX
- play a role in spinal reflex arc
- send information to brain via spinocerebellar pathways
Neuronal Architecture – Laminae (Visceral)
- Lamina VII:
- large heterogenous zone: autonomic nervous system and unconscious activity
- size varies through the length of the spinal cord
- afferents from viscera
- efferents: motor information to viscera
- gives rice to cells involved in autonomic system
- Includes
- Dorsal Nucleus (Clarke’s nucl; Posterior Thoracic Nucl) for unconscious proprioception
- extends from C8- L2/3
- major relay station for unconscious proprioception
- afferents: sensory nerves from muscle spindles and tendon organs
- efferent/projection: posterior spinocerebellar tract
- Intermediomedial nucleus
- at all spinal cord levels
- afferents: sensory information from viscera
- efferents to lateral horn
- Intermediolateral Nucleus
- extends T1-L2
- preganglionic sympathetic neurons.
- Sacral autonomic nuclei
- extend S2-4
- preganglionic parasympathetic neurons
##### Neuronal Architecture – Laminae (Motor)
- Motor Neuron Columns:
- α motor neurons: Large multipolar cells innervate extrafusal muscle fibres of skeletal muscles
- γ motor neurons: Small multipolar cells innervate intrafusal muscle fibres of neuromuscular spindles
- Medial (VIII): LMNs to axial and proximal appendicular musculature
- Lateral (IX): LMNs to distal appendicular musculature. Present in cervical and lumbosacral segments
- Shorter distinct columns:
- C1-6: spinal accessory nucleus
- C3-5: phrenic motor nucleus
- S1-3: Onuf’s nucleus (striated mm control of defecation and micturition, pudendal n.)
Neuronal architecture - Lamina X(visceral)
- grey commissure
- surrounds the central canal
- site of decussation of commissural fibres
![[Pasted image 20240221105714.png]]
- Describe the course of the conscious ascending tracts
The tracts associated with conscious sensation are:
- DCML
- spinothalamic tract/spinal lemniscus
Unconscious sensation:
- dorsal spinocerebellar
- cuneocerebellar
- ventral and rostral spinocerebellar
-
Spinothalamic Tract: Originates from C / A∂-type fibres in the lateral part of the dorsal root. Carries information about pain and temperature(lateral), and crude touch and pressure, to the thalamus (anterior). There is a high degree of somatic organisation, allowing for discrimination of location and intensity of pain
- (1) Nerve fibres entering the dorsal horn
- (2) either enter Lissauer’s Tract (LT) and ascend or descend one or two levels.
- (3) then enter the dorsal horn, terminate in laminae I, II, III, IV, where they synapse. Most in Substantia gelatinosa
- (4) After synapsing, 2°fibres cross the midline, ventral to the intermediate grey, then traverse the anterior horn to reach the antero-lateral funiculus.
- (5) They turn and ascend to thalamus (VPL) and the somatosensory cortex
Characterised by a sharp stabbing pain.
Note:
- Fibres that enter caudally are displaced laterally by more rostral fibres.
- Collaterals of these fibres enter the reticular formation in the lower brainstem.
-
Dorsal Column / Medial Lemniscus Pathway: Originates from large diameter, heavily myelinated A-type fibres (Aβ) in the medial part of the dorsal root. Carries conscious information about discriminative touch, 2-point discrimination, vibration, and conscious proprioception to the thalamus.
- (1) Large myelinated fibres enter medial to LT, turn rostrally and ascend in the posterior funiculus. Fibres from the lower limb form the gracile fasciculus, while fibres from the upper limb form the cuneate fasciculus.
- (2) Fibres from the lower limb synapse in the gracile nucleus; fibres from the upper limb synapse in cuneate nucleus in the closed medulla.
- (3) Secondary fibres take an arcuate course, cross the midline at the sensory decussation to form the medial lemniscus then again turn rostrally.
- (4) They turn and ascend to thalamus (VPL) and the sensory cortex
The next tracts carry unconscious sensory information to the cerebellum:
-
Dorsal Spino-cerebellar Tract: Carries unconscious proprioceptive information, concerning muscle force and stretch, from lower limb muscles and tendons to the cerebellum.
- (1) Information coded by Golgi tendon organs (strain) and muscle spindles (stretch) in lower limb muscles is carried in large diameter fibres (Aα) that pass through the dorsal horn and synapse on cells in Rexed’s lamina VII, Nucleus dorsalis / Clarke’s nucleus (C8-L2/3).
- (2) Secondary fibres enter the lateral funiculus, near the dorsal root, and turn rostrally, forming the Dorsal Spino-cerebellar Tract.
- (3) In the upper medulla, this tract enters the inferior cerebellar peduncle. and fibres terminate in the ipsilateral cerebellar cortex.
-
Cuneo-cerebellar Tract: Carries information from upper limb muscles and tendons about muscle force and stretch to the cerebellum. Upper limb equivalent of dorsal spino-cerebellar tract.
- (1) Information coded by Golgi tendon organs (strain) and muscle spindles (stretch) is carried in fibres that enter the dorsal horn then turn rostrally.
- (2) 1° fibres synapse in the Accessory cuneate nucleus, in the medulla (the Clarke’s column equivalent for the upper limb).
- (3) 2° fibres enter the inferior cerebellar peduncle, along with the Dorsal Spino-cerebellar fibres to terminate in the ipsilateral cerebellar cortex.
-
Ventral Spino-cerebellar Tract: Carries predominantly force information from lower limb muscles, to the ipsilateral cerebellum.
- (1) Information from Golgi tendon organs (strain) in the lower limb muscles is carried in fibres that enter the dorsal horn and synapse in the base of the dorsal horn (Rexed lamina VI).
- (2) 2°fibres cross the midline, enter the ventral part of the lateral funiculus, then turn rostrally in the Ventral spino- cerebellar tract.
- (3) In the pons/midbrain, these fibres enter the Superior Cerebellar Peduncle, then re-cross the midline to terminate in the ipsilateral cerebellar cortex
-
Rostral spino-cerebellar tract
Carries predominantly force information from upper limb muscles, to the ipsilateral cerebellum.
- (1): Information from Golgi tendon organs (strain) in the upper limb muscles is carried in fibres that enter the dorsal horn and synapse in the base of the dorsal horn (Rexed lamina VI).
- (2): 2°fibres ascend ipsilaterally
- (3):In the brainstem, fibres enter the cerebellum through the Inferior Cerebellar Peduncle
Other ascending pathways with role in pain sensation
Medial pain system: crude, not well-localised pain.
Medial tracts are usually more primitive.
Note also that tracts that go to the cerebellum do not decussate.
- spinoreticular
- old, multi-synaptic tract
- originates from dorsal horn neurons
- ipsilateral ascending fibres terminating in the reticular formation
- projects to intralaminar nuclei of thalamus
- important role in sensation of deep, burning chronic pain
- spinotectal
- originates from dorsal horn
- ascends contralaterally to superior colliculus & periaqueductal gray
- role in regulating pain
- Lissauer’s tract: a ‘bridge’
- Describe the course of the unconscious ascending tracts
The next tracts carry unconscious sensory information to the cerebellum:
-
Dorsal Spino-cerebellar Tract: Carries unconscious proprioceptive information, concerning muscle force and stretch, from lower limb muscles and tendons to the cerebellum.
- (1) Information coded by Golgi tendon organs (strain) and muscle spindles (stretch) in lower limb muscles is carried in large diameter fibres (Aα) that pass through the dorsal horn and synapse on cells in Rexed’s lamina VII, Nucleus dorsalis / Clarke’s nucleus (C8-L2/3).
- (2) Secondary fibres enter the lateral funiculus, near the dorsal root, and turn rostrally, forming the Dorsal Spino-cerebellar Tract.
- (3) In the upper medulla, this tract enters the inferior cerebellar peduncle. and fibres terminate in the ipsilateral cerebellar cortex.
-
Cuneo-cerebellar Tract: Carries information from upper limb muscles and tendons about muscle force and stretch to the cerebellum. Upper limb equivalent of dorsal spino-cerebellar tract.
- (1) Information coded by Golgi tendon organs (strain) and muscle spindles (stretch) is carried in fibres that enter the dorsal horn then turn rostrally.
- (2) 1° fibres synapse in the Accessory cuneate nucleus, in the medulla (the Clarke’s column equivalent for the upper limb).
- (3) 2° fibres enter the inferior cerebellar peduncle, along with the Dorsal Spino-cerebellar fibres to terminate in the ipsilateral cerebellar cortex.
-
Ventral Spino-cerebellar Tract: Carries predominantly force information from lower limb muscles, to the ipsilateral cerebellum.
- (1) Information from Golgi tendon organs (strain) in the lower limb muscles is carried in fibres that enter the dorsal horn and synapse in the base of the dorsal horn (Rexed lamina VI).
- (2) 2°fibres cross the midline, enter the ventral part of the lateral funiculus, then turn rostrally in the Ventral spino- cerebellar tract.
- (3) In the pons/midbrain, these fibres enter the Superior Cerebellar Peduncle, then re-cross the midline to terminate in the ipsilateral cerebellar cortex
-
Rostral spino-cerebellar tract
Carries predominantly force information from upper limb muscles, to the ipsilateral cerebellum.
- (1): Information from Golgi tendon organs (strain) in the upper limb muscles is carried in fibres that enter the dorsal horn and synapse in the base of the dorsal horn (Rexed lamina VI).
- (2): 2°fibres ascend ipsilaterally
- (3):In the brainstem, fibres enter the cerebellum through the Inferior Cerebellar Peduncle
- Describe the course of the conscious descending tracts
The corticospinal tracts
- Corticospinal fibres originate from both frontal and parietal cortices
- Cells of origin are large triangular or pyramidal cells in layer V of neocortex
- ![[Pasted image 20240313124535.png]]
- where things can go wrong: hemiparesis and failure to abduct eye; ptosis/dilation/down and out; tongue deviation
- ![[Pasted image 20240313124545.png]]
- Originate from cells in M1, SMA, PMA, S1 and descend through the corona radiata, then the internal capsule (posterior limb, posterior portion – CBT occupies anterior portion)
- Enter cerebral peduncles ~ middle 3/5; leg is most lateral
- Pass through the pons, crossed by the pontocerebellar fibres
- Enter the pyramids on the ventral aspect of the medulla
- 80% axons cross in the pyramidal decussation to formthe lateral corticospinal tract. ~10% do not cross andremain in the lateral CST (not shown); another ~10% also remain on the ipsilateral side and form the ventral/anterior corticospinal tract, the majority of these cross before entering the ventral horn
- Glutamatergic fibres terminate at all levels of the spinal cord
- Provide input to lower motor neurons of ventral horn that innervate skeletal muscles, especially flexors. Some send collaterals to thalamus, reticular formation dorsal column nucl,(sensory modulation) and interneurons in spinal cord (motor modulation)
The corticobulbar fibres
The corticobulbar fibres originate from cells in the head and face regions of the motor areas (lateral regions).
It controls both sides bilaterally.
Exceptions include lower part of CN VII and CN XII.
They descend through the corona radiata, then the middle (around the genu) part of the internal capsule.
They enter the cerebral pedncles medial to the CST fibres.
They synapse bilaterally on the motor nuclei of cranial nerves, directly and via interneurons (exc parts of VII and XII) and reticular formation.
They are glutamatergic/excitatory fibres.
![[Pasted image 20240314110956.png]]
Extrapyramidal tracts
There are four main extrapyramidal tracts.
- rubrospinal: important for quality of life, responsible for skilled movements, mainly terminate at cervical levels
- reticulospinal both medial and lateral, essential for life (posture, balance and gaze): modifies reflex control of extensors
- tectospinal: head orientation to external stimuli, mainly terminates at cervical levels
- vestibulospinal, both medial and lateral: responsible for posture and balance, medial tract terminates at cervical levels
### Rubrospinal
- controls flexion in upper limb e.g. involuntary arm movement to keep balance
- irginates from cells in red nucleus in the upper midbrain (level of superior colliculus)
- fibres cross midline in midbrain
- red nucleus receives input from motor areas that are somatotopically organised – output from nucleus is also somatotopic = “corticorubrospinal” pathway
- while it receives input from cortex it is not ITSELF involved in conscious control
- discrete bundle of fibres in the lateral medulla, and in the lateral SC adjacent to the corticospinal tract
- fibres terminate mainly in cervical levels, and mianly innervate flexor groups
- fibres are glutamatergic
### Reticulospinal
- pontine or medial – stimulate limb extensors and inhibit flexors
- does NOT cross
- originate from large cells in PRF
- terminate at all levels of spinal cord (VII, VIII) on ipsilateral alpha and gamma motor neurons
- activates spinal reflexes of antigravity muscles: stimulate limb extensors helping to maintain posture (enhances anti-gravity spinal reflexes that hold the body upright)
- stabilises in anticipation of other movements
- contains enkephalin, substance P as well as glutamate
- medullary/lateral tract
- stimulates limb flexors and inhibits axial and limb extensor muscles
- arises from large cells in the medial medulla
- fibres terminate at all levels of the spinal cord (8,9) on alpha and gamma motor neurons
- inhibits antigravity/axial muscles from relfex control, stimulate limb flexors (inhibits spinal reflexes that hold the body upright e.g. axial and limb extensors)
Tectospinal
- coordinates head and eye movement i.e. involuntary adjustment of head position on visual stimuli
- originate from cells in deep layers of superior colliculus
- SC gets direct input from retina, VC, somatosensory and auditory systems
- inputs are mapped
- fibres cross midline and midbrain
- descend in contralateral central medulla, close to medial lemniscus
- terminate in contralateral intermediate grey (laminae 6,7) in the cervical layers of sc
- primary role in orientation reflexes of the head, especially towards auditory, visual and somatosensory stimuli
### Vestibulospinal
- playa role in maintaining erect position by activation anti-gravity muscles i.e. control extension in extremities
- originate from cells in lateral and medial vestibular nuclei of CN VIII
- these are relay cells that get input from cells in the vestibular ggl (in IAM) and cerebellum
- fibres from the **medial vestibular nucleus descend bilaterallyin te MLF to lower medulla (spinal accessory nucleus) and upper cervical SC to innervate muscles controlling head position and orientation reflexes
- fibres from the **lateral nucleus project to all levels of the ipsilateral SC
- these pathways mainly innervate extensor groups and help maintain posture and balance
- Describe the course of the unconscious descending tracts
Extrapyramidal tracts
There are four main extrapyramidal tracts.
- rubrospinal: important for quality of life, responsible for skilled movements, mainly terminate at cervical levels
- reticulospinal both medial and lateral, essential for life (posture, balance and gaze): modifies reflex control of extensors
- tectospinal: head orientation to external stimuli, mainly terminates at cervical levels
- vestibulospinal, both medial and lateral: responsible for posture and balance, medial tract terminates at cervical levels
### Rubrospinal
- controls flexion in upper limb e.g. involuntary arm movement to keep balance
- irginates from cells in red nucleus in the upper midbrain (level of superior colliculus)
- fibres cross midline in midbrain
- red nucleus receives input from motor areas that are somatotopically organised – output from nucleus is also somatotopic = “corticorubrospinal” pathway
- while it receives input from cortex it is not ITSELF involved in conscious control
- discrete bundle of fibres in the lateral medulla, and in the lateral SC adjacent to the corticospinal tract
- fibres terminate mainly in cervical levels, and mianly innervate flexor groups
- fibres are glutamatergic
### Reticulospinal
- pontine or medial – stimulate limb extensors and inhibit flexors
- does NOT cross
- originate from large cells in PRF
- terminate at all levels of spinal cord (VII, VIII) on ipsilateral alpha and gamma motor neurons
- activates spinal reflexes of antigravity muscles: stimulate limb extensors helping to maintain posture (enhances anti-gravity spinal reflexes that hold the body upright)
- stabilises in anticipation of other movements
- contains enkephalin, substance P as well as glutamate
- medullary/lateral tract
- stimulates limb flexors and inhibits axial and limb extensor muscles
- arises from large cells in the medial medulla
- fibres terminate at all levels of the spinal cord (8,9) on alpha and gamma motor neurons
- inhibits antigravity/axial muscles from relfex control, stimulate limb flexors (inhibits spinal reflexes that hold the body upright e.g. axial and limb extensors)
Tectospinal
- coordinates head and eye movement i.e. involuntary adjustment of head position on visual stimuli
- originate from cells in deep layers of superior colliculus
- SC gets direct input from retina, VC, somatosensory and auditory systems
- inputs are mapped
- fibres cross midline and midbrain
- descend in contralateral central medulla, close to medial lemniscus
- terminate in contralateral intermediate grey (laminae 6,7) in the cervical layers of sc
- primary role in orientation reflexes of the head, especially towards auditory, visual and somatosensory stimuli
### Vestibulospinal
- playa role in maintaining erect position by activation anti-gravity muscles i.e. control extension in extremities
- originate from cells in lateral and medial vestibular nuclei of CN VIII
- these are relay cells that get input from cells in the vestibular ggl (in IAM) and cerebellum
- fibres from the **medial vestibular nucleus descend bilaterallyin te MLF to lower medulla (spinal accessory nucleus) and upper cervical SC to innervate muscles controlling head position and orientation reflexes
- fibres from the **lateral nucleus project to all levels of the ipsilateral SC
- these pathways mainly innervate extensor groups and help maintain posture and balance
- List the somatic motor cranial nerves: entry, exit, function, location in brainstem
Recall that 3, 4, 6 and 12 have pure somatic motor nuclei and sit medially.
Oculomotor
Motor nucleus
Superior colliculus
Edinger Westphal
Superior colliculus
Ciliary (parasympathetic)
Ciliary & pupillary muscles
Trochlea
Motor nucleus
Inferior colliculus
Superior oblique muscle
Trigeminal
Motor nucleus
Superior colliculus - pons
Principal V
Pons
Semilunar (sensory)
Spinal V
Medulla - upper spinal cord
Semilunar (sensory)
Mesencephalic
Superior colliculus - upper pons
VERY SPECIAL! Sensory cell bodies within the CNS
Sensation (proprioception) of face
Abducens
Motor nucleus
Pons
Lateral rectus muscle
Facial
Motor nucleus
Lower pons
Super salivatory
Lower pons
Pterygopalatine & Submandibular (parasympathetic)
Solitary nucleus (taste)
Open & closed medulla
Geniculate (sensory)
(Spinal V)
Medulla - upper spinal cord
Geniculate (sensory)
Somatic sensation around the ear
Glossopharyngeal
Solitary nucleus (rostral)
Open & closed medulla
Inferior ganglionof IX (in jugular foramen)
Solitary nucleus (caudal)
Open & closed medulla
Inferior ganglionof IX (in jugular foramen)
Spinal V
Medulla - upper spinal cord
Superior ganglionof IX (in jugular foramen)
Nucleus ambiguus
Open & closed medulla
Inferior salivatory
Openmedulla
Otic (parasympathetic)
Parotid gland
Vagus
Dorsal motor nucleus of X
Open & closed medulla
Walls of viscera (parasympathetic)
Spinal V
Medulla - upper spinal cord
Superiorganglionof X (in jugular foramen)
Solitary nucleus
Open & closed medulla
Inferior ganglionof X (in jugular foramen)
Taste (epiglottis); pharynx, larynx, trachea, esophagus, thoracic and abdominal viscera (visceral afferent)
Accessory (cranial)
Nucleus ambiguus
Open & closed medulla
Intrinsic muscles of thelarynx; spinal = scm, trapezius
Hypoglossal
XII motor nucleus
Open & closed medulla
Muscles of the tongue except palatoglossus
- List general sensory cranial nerves and their features
see C Brock table
- Describe visceral/branchial motor cranial nerves and their features
- Describe special sensory cranial nerves and their features
CN1 Olfactory Sensory Special Sensory: smell cribiform plate (ethmoid
bone)
Rostral to brain stem –
lies under frontal lobe
CN2 Optic
Retina ganglia optic
nerve optic chiasm Optic
tract thalamus (lateral
geniculate nucleus)
occipital lobe
Sensory Special Sensory: Sight
(joining of retinal ganglion cells)
Optic canal (sphenoid bone) Rostral to brainstem –
connects to occipital
lobe via thalamus
CN8 Vestibulocochlear
Travels through internal
acoustic meatus
(temporal bone) before
splitting into trochlear
and cochlear nerves
Sensory Special Sensory: Hearing (cochlear) and balance (vestibular) Internal acoustic meatus Pons (lateral and
caudal aspect
- Label a diagram of dorsal brainstem
- Label a diagram of ventral brainstem
- Describe the sensory territory of V1/2/3
- Ophthalmic branch or V1 - sensations from the nasal cavity, skin of forehead, upper eyelid, eyebrow and nose
- Maxillary branch or V2 - sensations from lower eyelid, upper lips and gums, teeth of the maxilla, cheek, nose, palate, and pharynx
- Mandibular branch or V3 - sensations from teeth of the mandible, lower gums and lips, palate and tongue
Describe innervation of facial nerve branches
Nerve reaches the muscles of facial expressions, reaches the parotid gland and split into five branches:
- temporal
- zygomatic
- buccal
- mandibular
- cervical
Nerve reaches the muscles of facial expressions, reaches the parotid gland and split into five branches:
- temporal
- zygomatic
- buccal
- mandibular
- cervical
- frontalis
- orbicularis oculi - circular, around the eye responsible for closing the eye
- levator labii superioris - elevating the upper lib
- zygomaticus
- buccinator - innervated by CN VII (drooling, big buccinator)
- risorius - smiling muscle
- procerus
- corrugator supercilli
- nasalis
- orbicularis oris - surrounds the lips and close your mouth
- depressor anguli oris - depressing angle of the mouth
- platysma - covers the neck
- depressor labii inferioris
- What relationship does sympathetic innervation of eye have to trigeminal nerve
Note: the trigeminal nerve does NOT have autonomic fibres BUT does have hitchhiking sympathetic and parasympathetic fibres.
The nasociliary nerve (off ophthalmic) carries sympathetic fibres, picked up in the cavernous sinus and distributes them:
- long ciliary branches (V1) to dilator pupillae muscles
- via branches of the ciliary ganglion (of III - oculomotor nerve), short ciliary nerves ^[post-ganglionic]
- sympathetic fibres to levator palpebrae superioris travel in upper division of oculomotor nerve (III)
- note that sympathetic fibres do NOT synapse, just pass through
- e.g. superior cervical ganglion—> internal carotid artery
- Name and describe the roles of the trigeminal nuclei
Motor nucleus of V
- located at mid pons,at level of entry of the nerve
- as it is a branchiomotor nucleus, we find it laterally, close to the sensory nucl.
- innervates mm connected to the embryonic mandibular arch: mm of mastication, mylohyoid, digastric (ant belly) + tensor veli palatini, tensor tympani
- receive bilateral corticobulbar input from motor cortices (contralateral more strongly)
#### Supratrigeminal nucleus
- part of the reticular formation
- acts as pattern generator for mastication
- in conscious person it is constantly active
- in erect position activates jaw closing
- in horizontal position activates the lateral pterygoid to prevent asphyxia
- general anaesthesia inactivates the nucleus ^[hence intubation is required]
Mesencephalic nucleus
- only sensory nucleus in the brain that acts as a ganglion within the CNS (ie it is equivalent to a dorsal root ganglion of the spinal cord, or the trigeminal ganglion, where cell bodies are found)
- dendrites of the pseudo-unipolar sensory cells originate at muscle spindles of the jaw mm (as well as TMJ itself?) (via V3) and as mechanoreceptors from periodontal ligaments in teeth and gums (via V2 and V3).
- these large,heavily myelinated fibres form the mesencephalic tract,which surrounds the nucleus
- axonal processes of some of these cells project directly to the Motor nucl V, most synapse in the supratrigeminal nucl before they reach Trigeminal Motor nucleus
ntine nucleus
otherwise known as principal nucleus.
It is located in the mid pons, at level of entry of the nerve, lateral to the motor n.
It is a homologue of the dorsal column nuclei - ie., relays
information about discriminative touch sensations from the face
and oronasal cavity.
Information is carried by fast-conducting, heavily myelinated fibres.
Where is the information projected to in the cortex?
Spinal trigeminal nucleus
The spinal trigeminal nucleus is a large nucleus extending from the caudal-pons to about C3 level of spinal cord.
It has smaller diameter fibres from V1,V2 andV3, turn caudally on entering the pons, forming
the spinal trigeminal tract on the lateral aspect of the nucleus.
The fibres only synapse once they reach the target level of the nucleus. Then they follow the spinothalamic tract up to the VPM of the thalamus.
Divided into 3 parts:
- pars/nucl oralis (medullary-pontine junction),
- pars/nucl interpolaris (open medulla),
- pars/nucl caudalis (closed medulla).
Oralis and Interpolaris are small, and receive afferents from the mouth
Caudalis is a homologue of substantia gelatinosa (Rexed II).
The nucleus processes information concerning pain and temperature from the territories of V1,V2
and V3. This nucleus blends into dorsal horn of the spinal cord and the lower tract
blends into Lissauer’s tract
There are three main afferents to the spinal nucleus:
- Trigeminal nociceptive fibres from cornea (V1), teeth (V2 & 3), temporomandibular joint (V3), dura mater of anterior and middle cranial fossae (V2 & 3)
- Facial (CNVII), Glossopharyngeal (CNIX) and Vagal (CNX) afferents from pharynx, larynx, pharyngotympanic tube, outer and middle ear (cell bodies in geniculate ggl, inf ggl of IX, or inf ggl of X)
- Cervical afferents from nociceptive fibres of posterior roots of C1-3 (note: C1 is usually absent) from dura mater of post cranial fossa, spinal dura, intervertebral joints and suboccipital mm
Note: taste fibres or chemoreceptors carried by these nerves (VII, IX, X) which hitchhike with the trigeminal nerve, synapsing in the solitary tract nucleus.
**Describe stroke syndromes
**
MCA- supploes motor cortex and sensory cortex (upper limb and face), temporal lobe (Wernicke), frontal lobe (Broca)
Symptoms of lesion:
- CL paralysis of upper limb and fae
- CL loss of sensation upper and lower limbs and face
- aphasia if in dominent hemisphere
- hemineglect is nondominant side
ACA
- motor and sensory cortices, lower limb
- CL paralysis and loss of sensation in lower limb; R ACA= anosmia; personality/attitude/memory= frotal lobe damage
ASA: supplies lateral CS tract, medial lemniscus and caudal medulla esp hypoglossal nerve nucleus, tectospinal tract.
LEsion: CL hemiparesis of U and L limbs, decreased CL proprioception and ipsilateral hypoglossal dysfunction – ie tongue deviates ipsilateral side. Note that stroke is most commonly bilateral. Pain and temperature intact because isSTT is lateral and supplied by VA
Note also this is @medial medulla syndrome@ caused by infarct of paramedian ASA branches and vertebral arteries.
PICA- lateral medulla, vestibular nuclei, lateral STT, spinal tg N, N ambiguus, sympathetic fibres and inferior cerebellar peduncle.
Lesion: vomiting, vertigo and nystagmus. Reduced pain and temperature sensation from ipsilateral face and contralateral body, dysphagia, hoarseness, reduced gag reflex, ipsilateral Horner, ataxia ipsilateral cerebellar signs. Dysmetria.
AICA: Latearl pons: CN nuclei- VIII, VII, spinal T g nucleus, cochlear nuclei, sympathetic fibres; middle and infeerior cerebellar peduncles. Vomiting, vertigo, nystagmus, paralysis of face– specific to aica aka latearl pontine syndrome- reduced lacrimation, salivation, taste 2/3, corneal reflex. Face reduced pain and temperature, ipsilateral hearing, Ipsilateral horner, ataxia, dysmetria.
PCA- occipital cortex esp visual cortex
CL hemianopia with macular sparing
—
Basilar: @locked in sydnrome’
pons medulla lower midbrain, CST, CBT, ocular CN nuclei, paramedian pontine reticular formation.
Note also:
- Amaurosis Fugax: Transient monocular blindness due to retinal (Ophthalmic) artery occlusion. A red flag for oncoming stroke.
- Carotid “T” Occlusion: Face-Arm-Leg weakness/numbness on contralateral side, global aphasia if dominant side affected, visual sparing.
- —
Pontine stroke syndromes typically a result of occluded perforations
- Foville/dorsal pons: ipsilateral lateral gaze palsy and LMN facial palsy
- Rymond’s/ventral pons: ipsilateral lateral rectus palsy and contralateral hemiplegia
- —
-
- Weber’s Syndrome
- I/L ophthalmoplegia and ptosis, dilation of pupil, no light response, no accommodation, C/L paralysis of arm and leg (CNIII nuclei &/or nerve fibres, corticospinal fibres)
- Benedikt’s Syndrome
- C/L involuntary limb movements, C/L loss of sensation (red nucleus and ascending SCP fibres, spinal and medial lemnisci)
- Compare and contrast Rinne and Weber hearing tests and explain findings if hearing loss is conductive or sensorineural
hearing loss can be described as
- Conductive - outer or middle ear damage
- Sensorineural - inner ear or vestibulcochlear (CNVIII) nerve, or pathway damage.
To distinguish between these hearing losses, two simple auditory examinations may be conducted:
Weber test:
Tuning fork (512 Hz) is placed in the midline of the forehead. In normal hearing, the vibration should be heard equally, on both sides. In conductive hearing loss, stronger vibration is localised on the damaged side. This is explained by the loss of the masking effect of ‘background noise’, normally coming through the tympanic membrane, on the bone conduction. In sensorineural hearing loss, the stronger vibration is felt on the healthy side.
Rinne test:
Compares air and bone conduction. Tuning fork is placed in front of the external auditory canal, and then on the mastoid process. Patient is asked which sound appears louder. In normal hearing, and sensorineural hearing loss, the air conduction will be heard louder. In conductive hearing loss, the sound from the skull (mastoid process) will be heard louder.
For more precise detection of hearing loss, audiometry is performed.
- Interpret audiometry graph
Audiometry measures hearing acuity using a variety in sound intensity and pitch by identifying the hearing thresholds at different frequencies of sounds.
- Label sagittal/axial/coronal diagrams of brain
- Label the following sections of the brainstem – rostral and caudal midbrain, rostral and caudal pons, open and closed medulla. Predict the effect of lesions
See doc- labelled brainstem
- Label the basal ganglia, describe the circuitry and relate to hypokinetic disorders
Basal ganglia:
- Striatum: caudate, putamen, (n accumbens)
- Pallidum: globus pallidus – medial (internal) and lateral (external) segments (includes substantia nigra ‘pars reticulata’ which may be considered functionally continuous with GPi. It is only separated by internal capsule fibres)
- putamen plus globus pallidus makes lentiform mucleus
- Sub-Thalamic Nucleus
- Substantia Nigra pars compacta
- Sub-thalamic nucleus and substantia nigra are regulators of the basal ganglia
-
Caudate
- Connected mainly to frontal and pre-frontal areas, and Posterior Parietal Cx.
- Influence on social/moral behaviours.
- More active during the acquisition of new motor skills and planning ahead during more complex motor intentions.
-
Putamen
- Mainly connected to somatic cortical areas.
- Has a mapped representation of the body.
- More involved in cognitive loops
Striatum = caudate + putamen
- Complex structure, but one functional unit with connections to the cortex (1000s:1) .
—
-
Cognitive Loop (Caudate):
- Planning ahead for motor intentions.
- Once learned → motor loop.
-
Limbic Loop (N. Accumbens):
- Involves reward/motivational behaviours, memory, and motor expression relevant to emotions (smiling/gesturing).
- In Parkinson’s Disease (PD), there are problems with expressions.
-
Oculomotor Loop (Caudate):
- In PD, there are problems with saccades.
-**
Motor loop (putamen)
- Scaling strength of muscle contractions
- in collaboration with SMA
- Putamen provides a reservoir of learned
programs
- Execution of motor programs involves decision/plan of what to do, integrating all cortical inputs to determine appropriate motor programs, with motor instructions sent to Motor Cx.
- decision or planning what to do occurs in frontal/parietal; temporal, insular and cingulate cortices —->
- basal ganglia integrates all cortical inputs to determine approporiate motor programs —>
- thalamic nuclei sends motor instuctions to motor cortex
- SMA and M1 execute motor programs
- enact action from M1
Cognitive Loop:
- e.g. for any learnt motor program
- Strong projection to caudate which becomes active during learning new motor skills – reinforcement learning.
- Thought to incorporate planning ahead during new motor tasks & action selection.
- Returns to prefrontal and premotor cortices via VA & MD nuclei of thalamus.
- When the new task is well practiced, the task comes under control of the motor loop.
Example loop:
- prefrontal and PPC
- Putamen, caudate and GP
- VA/MD thalamus
- SMA
Limbic Loop
- e.g., Memory, motivational behaviours, gesturing, facial expressions…
-
Nucleus Accumbens
- Anterior end of putamen/caudate
- Connected to inferior prefrontal Cx (limbic system)
- Returns signals to Cx via MD nuclei of thalamus
- Limbic Cx determines appropriate emotional status for the environmental conditions
- Important in gesturing and expression of affect
- Rich in dopaminergic input may explain loss of affect / ‘mask-like’ appearance of PD patients.
Example loop:
- Limbic Cx
- N. Accumbens
- MD Thalamus
- Inf. Prefrontal Cx
Oculomotor Loop
- e.g., Fixation
- Substantia Nigra pars reticularis (SNr)
- Connected to the ‘frontal eye fields’ and parietal association cortex
- Returns to Cx via VA & MD nuclei of thalamus
- During fixation, SNr tonically inhibits cells in the superior colliculus (SC)
- When a deliberate saccade is about to be made, SNr activity stops, to disinhibit SC.
Example loop
- frontal eye fields and PC to caudate and SNr (inhibits SC)
- VA/MD thalamus
- frontal eye fields
- frontal eye fields and PC directly to SC
-
Direct: Go!
- Direct pathway feeds information to the thalamus via striatum and GPi
- Results in an increase in muscle activity
-
Indirect: Stop!
- Indirect pathway includes a ‘side loop’ from GPe > STN > GPi
- Net effect is suppression of muscle activity
- This pathway dominates during inactivity
Parkinson’s Disease: Effect of DA Loss
- Dopaminergic cells in the SNc are lost; striatum neurons eventually die, leading to disengagement of the direct pathway and default prevalence of the indirect pathway.
- Increased excitation and decreased inhibition of GPi result in enhanced inhibition of the thalamus, leading to hypokinesia i.e. difficulty starting motor program.
- Symptoms include tremor, rigidity, poor facial expression, and saccades.
- tremor and rigidity of both flexors and extensors not explained by hypokinesia
![[Pasted image 20240314140120.png]]
Huntington’s Chorea
- Uncontrolled, abrupt, and jerky movements of distal muscles due to a chromosome 4 defect causing GABAergic cell death in the striatum.
- Early D2 MSNs and later D1 MSNs are affected, applying harder brakes to STN and reducing basal inhibition on the thalamus, leading to execution of otherwise suppressed motor behaviors.
- Results in dementia due to retrograde loss of cortical neurons as striatal targets die.
![[Pasted image 20240314140134.png]]
Movement Disorders
- Athetosis: Slow, involuntary convoluted writhing movements; symmetry maintenance is difficult.
- Chorea: Quick, involuntary “dance-like” movements, not repetitive or rhythmic.
- Hyperkinesia: Chorea and Huntington’s disease are examples.
- Ballism: A form of hyperkinesis.
- Describe the contents and location of the cavernous sinus, and describe the expected clinical signs and symptoms of cavernous sinus thrombosis
Contents of the cavernous sinus:
- trigeminal ganglion
- V1, V2; III, IV, VI
- internal carotid artery
- sympathetic nerves
Cavernous sinus syndrome is characterized by ophthalmoplegia and sensory deficits over the head due to combined deficits of the three cranial nerves (third, fourth, and sixth) responsible for eye movements and pupil function, and at least one branch of the trigeminal nerve.
may cause isolated or combined ophthalmoplegia, painful ophthalmoplegia, anesthesia in CNIII, unitemporal or bitemporal visual field defects, acromegaly, and galactorrhea
- A lesion in spinocerebellum would cause what signs? A lesion in cerebro? A lesion in…?
- spinocerebellum:
Ataxic Gait; Uncoordinated, Clumsy Movements of the Limbs; Stagger to Side of Lesion.
- cerebrocerebellum:
- Hypotonia & Intention Tremor- ipsilateral to cerebellar lesion
- Dysmetria - Overshooting Targets: a failure to provide cerebral cortex with information necessary to plan and execute the movement accurately
- Dysdiadochokinesia - Loss of Rhythmic Control, especially with alternate limb patterns
- Loss of Timing and Control of Speech
- vestibulocerebel:
- Ataxic Stance (Swaying – Like a Toddler)
- Nystagmus (Lateral, Fast-Slow Eye Movements)
- Which two CNs are responsible for the light reflex arc. Describe the arc. Describe how to test it
The pupillary response or pupil reflex constricts the pupil in response to light ^[https://www.ncbi.nlm.nih.gov/books/NBK537180/].
The afferent segment of the pupillary response are the ganglion cells that form the optic nerve. They project from the retina to the midbrain. travels to the pretectal olivary nuclei. It decussates in the nasal retina but not in the temporal retina.
The interneuron segment of the pupillary response are the cells of the pretectal nucleus. They project bilaterally to the parasympathetic nuclei of CNIII, known as Edinger-Westphal nuclei (preganglionic parasympathetic nuclei in the midbrain.)
The efferent segment runs from the Edinger- Westphal nuclei to the pupillary constrictor muscle to constrict the pupil, via the ciliary ganglion, which sends postganglionic axons to directly innervate the iris sphincter muscles ^[https://www.ncbi.nlm.nih.gov/books/NBK537180/].
First order pre ganglionic parasympathetic fibres exit the mifbrain in the oculomotor nerve, without crossing, synapsing in ciliary ganglion.
Second order post ganglionic neurons send axons from the ciliary ganglion to the sphincter pupillae via short ciliary branches.
The direct response is constriction of pupil in the ipsilateral eye; the consensual response is constriction of pupil in the contralateral eye.
It is tested by shining a light into one pupil and looking for a response in the other pupil (which constricts as well).
The swinging lamp sign: move light to the contralateral pupil; the ipsilateral pupil will then dilate after light has moved away from it (this is called an afferent pupillary defect) ^[https://www.derangedphysiology.com/files/cranial%20nerve%20exam.pdf]
The pupillary reflex exam is considered part of a neurological exam.
- Describe the MLF and its function. Describe lesions of MLF
- Axon bundles close to the midline from Interstitial nucl of Cajal (just above the aqueduct in midbrain) to the upper cervical spinal cord.
- Important in coordinating head-eye movement.
- Connects nucl III, IV, VI (internuclear fibres - must communicate to move together e.g. to look to right, left with both eyes).
- Has input from gaze centres (tectum), cerebellum, vestibular organs (CN VIII).
- Carries fibres of the tectospinal, med. vestibulospinal, and reticulospinal tracts.
- Innervates some neck & upper limb mm.
Lesion e.g. in MS results in RINO
presents as an inability to perform conjugate lateral gaze and ophthalmoplegia due to damage to the interneuron between two nuclei of cranial nerves (CN) VI and CN III (internuclear).[1] This interneuron is called the medial longitudinal fasciculus (MLF). The MLF can be damaged by any lesion (e.g., demyelinating, ischemic, neoplastic, inflammatory) in the pons or midbrain. The MLF is supplied by branches of the basilar artery and ischemia in the vertebrobasilar system can produce an ischemic INO.
- What is the origin of the sympathetic nervous system
T1-L2 : Paravertebral chain
- Label a sagittal diagram of the eye
- Label the inner/middle/outer ear
- Describe the circle of Willis
- There are 2 major arteries supplying blood to the brain - the Vertebral A. and the Internal Carotid A.
- The ‘communicating arteries’ (ant & post) form an anastomosis between these two systems - the Circle of Willlis.
Circle of Willis
- There are 2 major arteries supplying blood to the brain - the Vertebral A. and the Internal Carotid A.
- The Internal Carotid A:
- ascends within the carotid sheath
- enters the cranium through the carotid
note: no branches outside skull
- The Vertebral A:
- ascends the cervical vertebrae within the f. transversaria
- enters vertebral canal by penetrating the posterior atlanto‐occipital membrane
- enters the cranium via the f. magnum
- Describe the blood supply to the brainstem
The vertebral and basilar arteries supply the brainstem and cerebellum.
#### Vertebrobasilar System
- Vertebral artery
- Posterior inferior cerebellar artery
- Posterior spinal artery
- Anterior spinal artery
- Basilar artery
- Anterior inferior cerebral artery
- Superior cerebellar artery
- Posterior Cerebral artery
Vertebral Artery
- Branch of the 1st segment of the subclavian artery
- Runs within foramen transversarium of C1-6
- turns at C2 to enter C1 foramen
- Enters dura between C1 and foramen magnum
- Joins the contralateral partner to form the basilar artery in front of the pons
- Within the cranium, they are ventrolateral to the medulla.
- End adjacent to the upper medulla at the junction of the L and R Vertebral Aa –> Basilar A.
- Branches supply the medulla and most of the inferior surface of the cerebellum
Branches
- Posterior spinal arteries are paired branches and occupy the posterolateral sulcus
- Anterior spinal arteries form a single vessel that occupies the anterior median sulcus
- Run down the full extent of the cord, reinforced by segmental branches at each level
- Posterior Inferior Cerebellar Artery (PICA)
Anterior and Posterior Spinal Arteries
- Branches of V4 (intercranial) segments of the vertebral artery
- Anterior spinal artery supplies the anterior part of the medulla before meeting its partner at the foramen magnum to supply the anterior cord
- occlusion can have neural consequences because it supplies medulla
- Posterior spinal arteries do not meet
- Supply posterior 1/3 of the spinal cord (Posterior spinal arteries)
- Supply anterior 2/3 of the spinal cord (Anterior spinal artery)
Basilar Artery
- Formed by the union of vertebral arteries at the pontomedullary junction
- Unpaired
- Major branches: anterior inferior cerebellar artery, superior cerebellar artery, brainstem perforators (short, long, circumflex), posterior cerebral artery
- note that there are other unnamed branches e.g. perforators and circumflex to pons
3 Cerebellar Arteries
Three in total to supply hemispheres and deep nuclei:
- Superior
- Anterior inferior
- Posterior inferior
![[Pasted image 20240311195049.png]]
### Posterior Inferior Cerebellar Artery (PICA)
- Branch of V4 (intracranial) segment of the vertebral artery
- Courses between the medulla and cerebellum then passes to the inferior cerebellar surface
- Supplies lateral medulla and inferior cerebellum
- also supplies some of pons
### Anterior Inferior Cerebellar Artery
- also supplies some of pons
- The 1st branch of the basilar artery arises anterior to the pons
- Branches supply the anterior inferior cerebellum, lateral pons, cranial nerves VII and VIII
Superior Cerebellar Artery
- Branches of the distal basilar artery, immediately proximal to PCA
- May be duplicated
- Supplies superior cerebellum, cerebellar nuclei, cranial nerves III and IV
Brainstem Territories Supplied by Branches of Vertebral and Basilar Aa
![[Pasted image 20240311195124.png]]
- Vascular lesions of these branches result in specific symptoms.
- Lower Medulla:
- Branches of the anterior spinal arteries and direct branches of the vertebral artery supply territories that include lower, spinal V nucleus and tract, arcuate fibers, and medial lemniscus, pyramids, spinothalamic tracts.
- Posterior spinal artery territory includes both the gracile and cuneate nuclei of the dorsal column system.
Posterior Cerebral Artery
- Curves laterally and posteriorly around the midbrain (above the tentorium cerebelli).
- Superior Cerebellar Artery does a similar thing (below the tentorium cerebelli).
- Supplies tectum, most of the cerebral peduncle (except the most medial part) via perforators, oculomotor (III) nucleus, and Edinger Westphal nucleus.
- The proximal part is joined by the Posterior Communicating Artery.
- Runs posteriorly along the medial/inferior margin of the temporal lobe, then dorsally along the parieto-occipital sulcus.
- Central branches supply the thalamus, pineal, midbrain, posterior parts of the putamen, and globus pallidus.
- Cortical branches supply the entire inferior surface of the temporal lobe, lateral and medial surfaces of the occipital lobe (including V1, V2, and V3).
- Describe the blood supply to Broca and Wernicke
The middle cerebral artery supplies blood to Wernicke’s and Broca’s regions in the brain. Damage to the superior division, which supplies the lateroinferior frontal lobe, damages Broca’s area and affects language expression.
- An intention tremor is related to which part of the cerebellum?
The most common site for cerebellar lesions that lead to intention tremors has been
reported to be the superior cerebellar peduncle,in cereberocerebellum.
dEFICITS of spinocerebellum - dysmetria, dysdiadochokinesia, scanning speech, hypotonia
vestibulo - nystagmus, ataxicstance
spino - gait ataxia
- Label the layers of the meninges
Meninges
The brain and spinal cord are surrounded by three membranes, which are collectively called the meninges. The three membranes are called the dura mater, arachnoid mater, and pia mater.
Dura mater
The dura mater is the external membrane;that is, the outermost membrane of the three meningeal layers. The dura mater itself consists of two layers:
- The periosteal layer covers the skull’s inner surface.
- The meningeal layer is technically the true dura mater, as this covers the brain [+].
The meningeal layer of the dura mater extends inward in four places formingdural folds or septa. These foldsdivide the cranial cavity, which createsthe subdivisions of the brain. The dural folds act to restrict movement of the brain.
The falx cerebri divides the 2 cerebral hemispheres as it descends from midline of the roof of the skull (appr parallel to sagittal suture) to the corpus callosum.
The tentorium cerebelli separates the brain and the cerebellum.
Note the blue lines between the layers of the dura. These are the dural venous sinuses that drain the blood from the brain to the internal jugular vein.
Although the dura attached to the bone of the skull, head injury that may damage dural vessels may lead to the pooling of blood between the dura and the skull, described as epidural bleed—> epidural haematoma.
Arachnoid mater
The arachnoid mater is the middle membrane of the meninges. This membrane is elastic and can be described as loose fitting. This is because the membrane doesn’t follow the bumpy surface (formed from the grooves)of the brain. The space between the arachnoid mater and the dura mater is called the subdural space. This is a thin, space which is spanned by veins draining blood from the brain to the dural sinuses, which deliver the deoxygenated blood to the heart via the internal jugular vein.
The space between the arachnoid mater and the pia mater is called the subarachnoid space. This space is filled by cerebrospinal fluid (CSF), and is significantly wider than the subdural space. The subarachnoid space also contains the largest blood vessels that supply the brain. The arachnoid mater and subarachnoid space are named due to the spiderweb-like extensions that extend from the arachnoid mater to the pia mater. These extensions holdthe two layers together.
Pia mater
The pia mater is the internal membrane(that is, the innermost membrane of the meninges). This membrane is attached firmly to the brain by astrocytes, and so follows every curve formed by the grooves (unlike the arachnoid mater). The pia mater is the most delicate of the three membranes. Due to its close relationship with the brain tissue, there is no subpial space.
- What cells surround the cranial nerves?
Schwann cells
Can develop neoplasm : considered extra-axial
- What are the functional roles of the brainstem
- mapping internal environment
- mapping external environment
- vital processes regulation
- modulate brain activity in response to multiple inputs
- mapping body surface’
- pattern generator e.g. for vital functions
Describe inputs and outputs of the cerebellum
- cerebropontocerebellar:C/L - MCP –> cerebrocerebellum–>
- cerebroreticulocerebellar–> MCP ICP –> I/L -> cerebrocerebellum –>
- CEREBROOLIVO (input also from red)CEREBELLAR –> ICP (CLIMBING) C/L –> cerebrocerebullum –>
- spinocerebellar all to I/L, all but ventral via ICP (SCP) -> spinocerebellum
- vestibuloceebellar -> ICP -> I/L -> vestibulocerebellum
Projections from cortices to deep nuclei:
- dentate
- modifies I/L motor activity via SCP
- progects to CST via VL thalamus to modulate conscious descending activity
- glose emboliform rubral
- I/L
- via SCP to red nucleus -> rubrospinal
- influence proximal flexor UL muscles
- fastigial vestibula
- ICP
- LMNS of spinal cord - extensor muscle tone - posture
- also contributes to MLF – coordinating eye movement
- fastigial reticular – ICP medial and lateral RSTs
fastigial uses ICP, rest use SCP. cerebro uses MCP except cerebroolivo
lateral zone –> fastigial nucleus
paramedial –> GE
median -> F
Note also re vestibulocerebellar pathway – direct afferent input via SCP from SC and primary VC
- What is the function of the reticular activating system? What are the three basic areas?
Reticular Activating System:
- Arouses the cortex
- Maintains wakefulness
- Interacts with the limbic system, autonomic nervous system, and reticular activating system in the physiological processing of emotion.
Brainstem reticular nuclei:
- Modulates intentional and reflexive motor activity e.g. reticulospinal tract projections to spinal cord, and cerebellum
- Modulates pain transmission (PAG to raphe nuclei, medullary reticular formation to posterior horn of spinal cord)
- Controls ANS functions (viscera to autonomic nuclei)
- Controls arousal and consciousness (ARAS)
three basic areas:
In the medial column – the raphe nuclei.- mood and PAG
In the paramedian column – gigantocellular nuclei (because of larger size of the cells)- RST
In the lateral column – parvocellular nuclei (because of smaller size of the cells)- arousal
- Describe somatotopy of sensory and motor cortices
‘The brain cannot see’ - therefore, it uses maps to identify . process incoming information.
Primary centres are the first port of call for information coming into the cortex. They represent a single modality i.e. vision, somatosensory, auditory etc.
Associative areas cross-reference all information coming into the brain so that it can be interpreted. These are multi-modal-
Note
- spinocerebellum
- medial lemniscus
- What structures comprise the limbic system? What is the function of the components?
The limbic system categorises human emotional experiences as pleasant or unpleasant mental states
- amygdala in the archistriatum of the archicortex or hippocampus
- located within the inferior horn of the lateral ventricle. Below it, seen on the inferior surface of the brain, is the parahippocampal gyrus.
- The ‘_uncus’_is the most medial part of the temporal lobe
- GP of paleostriatum of paleocortex or entorhinal cortex
- receives input from all areas of cortex, especially the high order association areas of neocortex, amygdala
- holds representations of emotion and pain
- where the interoceptive meets the exteroceptive self
- outputs to hippocampus
- together these two comprise the limbic cortex
Limbic
The limbic lobe is an evolutionarily old cortical area. Hippocampus and the parahippocampal gyri form the floor of the inferior limb of the lateral ventricle. The limbic cortices receive information from the amygdala and olfactory cortical areas. Memory formation is linked to the hippocampus. Information from the hippocampus travels through the fornix to terminate in the mammillary bodies, nuclei of the hypothalamus. From here, the information is sent to the the anterior nuclei of thalamus, and to the frontal lobe, through the cingulate cortex.
Due to its central position and inputs from a cortical centres, the limbic system links the conscious, intellectual cortical functions with the unconscious, autonomic functions of the brain stem and diencephalon. It also facilitates memory storage and retrieval, establish emotional states, and expressing emotional states through gesturing.
The amygdala
- is the brain’s alarm system
- responds maximally to threatening stimulithat are relayed there from areas of neocortex (especially face recognition, auditory, olfactory and somatosensory areas, as well asprefrontal areas)
- also gets input from solitary nucleus, cardiorespiratory areas, hypothalamus and brainstem reticular formation.
Hippocampus
The major INPUT to the hippocampus is from higher order, multi-sensory areas of neocortex via the entorhinal cortex.
In addition, the hippocampus receives some direct inputs from pre-frontal cortex, the anterior cingulate gyrus and from the brainstem reticular formation.
The major OUTPUT from the hippocampus is the fornix. The fornix is a distinct bundle of fibres that arises from the surface of the hippocampal gyrus, passing posteriorly, then upwards and anteriorly; the two fornices join as they pass forwards attached to the lower margin of the septum pellucidum, then separate and dive through the hypothalamus to terminate in the mammillary bodies (part of the hypothalamus).
Some fibres from the fornix cross in the midline; others terminate in the septal area.
*note also the cingulate gyrus which registers pain and the emotional experiences, and septal area which has a key role in bonding experiences: trust, empathy and pro-social feelings. Also regulates theta rhyhtms in hipppocampal neurons. Afferents from hippocampus, reticular formation, hypothalamus and amygdala; output to PFC, anterior cingulate gyrus, medial hypothalamus, mamillary bodies, medial thalamus
Postero-medial cortex and self
- Postero-medial Cx (PMC) occupies a very high place in the functional hierarchy
- It mediates awareness of the environment and therefore consciousness
- Its main constituents are the
- posterrio cingulate cortex
- precuneus
- medial prefrontal cortex
- angular gyrus
- It hasnoconnections with primary areas
- Its afferent inputs include:
- parietal and temporal association areas: to make sense of self and surroundings
- premotor regions and frontal eye fields: motor planning areas; controls eye movement and visual attention
- anterior cingulate gyrus: part of limbic, regulates emotions and regulate behaviour
- claustrum, basal forebrain and amygdala: forebrain has roles in sleep, thermoregulation, learning and memory
- dorsal thalamus
- Efferents:
- are largely reciprocalbut also include neostriatum and periaqueductal grey
- Is the most highly metabolically active cortical region, consuming 35% more glucose than other areas of Cx
- note it has dense connections with entorhinal cortex (hippocampus and neocortex) - has memory retrieval role
- Describe the systems implicated in in anxiety and depression?
Changes in Function of Brain Regions
- Increased connectivity in depression of parts of the Default Mode Network including the medial prefrontal cortex, posterior cingulate and hippocampus thought to be related to rumination or preoccupation
- Reduced connectivity in depression of parts of the Cognitive Control i.e. to suppress rumination
-
Hypothalamic-Pituitary-Adrenal Axis Changes
- Elevated HPA axis activity is associated with the stress response
- 40-60% of depressed inpatients show hypercortisolism (evidence of increased HPA activity), especially older patients with melancholic or psychotic depression. However, this test has poor specificity and is therefore not used in clinical practice.
- Dexamethasone suppression test
- In normal subjects: administration of dexamethasone suppresses cortisol secretion for 24 hours
- In those with hypercortisolism: cortisol secretion is not suppressed
Changes in Sleep
- Mania is associated with decreased need for sleep:
- i.e. waking from little or no sleep with an excess of energy
- Depression is associated with:
- Decreased deep (slow wave) sleep
- Increased nocturnal arousal
- Increased nocturnal awakenings
- Reduction in total sleep time
- Increased time in REM sleep
- Increased core body temperature
- Most antidepressants suppress REM sleep
- Agomelatine (a melatonin receptor agonist) normalizes sleep without suppressing REM sleep
Kindling Theory in Bipolar Disorder
- Anticonvulsants may work by reducing the ‘kindling’ of neurons in bipolar disorder
- Brain cells that are involved in an episode are thought to be more likely to be involved in subsequent episodes
- With each episode more and more cells are thus sensitized
- If untreated, the inter-episode period becomes shorter and each subsequent episode’s severity worsens (which is a common observation)
- Describe the production and flow of CSF
- formed in choroid plexus in lateral, 3rd and 4th ventricles
- formed in lateral ventricles
- passes through to 3rd via foramen of munro
- from 3rd ventricle, to 4th ventricle via cerebral aqueduct
- some from 4th to central canal (spinal cord)
- majority of CSF passes through foramina of Magendie and Luschka into cistrna magna, cerebellopontine cisterns
- CSF then enters the subarachnoid space and is absorbed into the venous circulation, by the arachnoid granules
- Name the three deep nuclei of the cerebellum and their function
fastigial, globose, emboliform, and dentate
Fastigial nuclei
- receive spinocerebellar and labyrinthine afferents
- project to the spinal cord and ventral thalamic nucleus
Globose & Emboliform nuclei (interposed nucleus)
- sends i nterpositiorubrothalamic tract to the lateral thalamic nucleus and red nuclus
Dentate nucleus
- receives corticopontocerebellar fibers
- sends dentatorubrothalamic and dentatoolivary tracts
Mnemonic: Don’t Eat Greasy Food (Dentate, Embolform, Globose, Fastigial)
- Name the two types of fibres which input to cerebellum and their origin
Climbing Fibres
- Cell bodies in ION.
- Receive input from cerebral motor cortex and cerebellum via Red nucleus.
- Excite single Purkinje (Pj) cells (1:1 ratio).
- Send collaterals to the deep nuclei.
- Slow rate of activity.
- Provide motor error feedback for appropriate motor timing.
- Most active during learning/training.
- thought to encode sensory input independently of attention/awareness.
Mossy Fibres
- From all areas that provide excitatory input to the cerebellum, except ION.
- A single mossy fibre activates many granule cells, which in turn activate ~200,000s Purkinje cells.
- Have collateral branches to deep nuclei.
- cuneo, spino, ponto, vestibule
- Outline signs of cerebellar dysfunction
Lesions and cerebellar signs:
- D: dysdiadochokinesia () and dysmetria (failure to provide Cer Cx with adequate information needed to plan and execute the movement accurately)
- Ataxia
- Nystagmus
- Intention tremor
- Slurred speech/scanning (loss of timing and control)
- Hypotonia
- Describe the process of transducing a light to electrical signal
- In the outer segment of the photoreceptor light is ‘transduced’ into an electrical signal, through a G-protein-mediated interaction with light sensitive ‘opsins’. Photoreceptors are the most highly metabolically active cells in the body (ie., they are very oxygen hungry).
- bipolar cell: Bipolar cells are located in the middle layer of the retina (INL). Theyget synaptic input from photoreceptor dendrites (in the OPL) and pass information onto ganglion cells.In primates there are around 11 different types of bipolar cell, which process the inputs from photoreceptors in different ways.They play a critical role in ‘managing’ theinformation that is passed on from photoreceptors to ganglion cells.As far as we knowthere are no diseases that stem from problems with bipolar cells.
- ganglion cells: Ganglion cells pass visual information to the brain. This information is a distillation of data from various ganglion cell types that encodecolour, position/acuity or contrast.
- Theyhave long axons that form the innermost layer of the retina, the Nerve Fibre Layer, as they course across the retina, in a stereotypical pattern, towards the optic disc. There they make a 90° turn and leave the eye as the optic nerve (CNII). Their functional characteristics are determined largely by the way they wire up to bipolar cells, although ‘amacrine cells’ also interconnect the GC-bipolar synapses to modulate signal transmission.
The ‘vertical meridian’ is a virtual line that passes through the macula, and divides the retina (almost) in half.
GC axons from retina temporal to the vertical meridian project to the same side of the brain
GC axons from retina nasal to the vertical meridian cross the midline in the optic chiasm.
Step 2: This pattern of GC projections means that the left visual hemifield projects to the right side of the brain (and vice versa)
When you attend to an object each eye sees the object (represented by the white circle in the middle) in the centre of its visual field - so in the diagram, each retina sees both the green and red parts of the visual field (indicated by colouring on the ‘retinas’).
![[Pasted image 20240307093139.png]]
When both eyes are open, the 2 visual fields merge into one (Note the blending of green and red towards the centre of the visual field strip). This field is made up of two ‘hemifields’, on either side of the spot, shown here as green (right visual hemifield) and red (left hemifield).
Because of the pattern of retinal projections at the optic chiasma, the visual hemmifields are represented in the opposite cerebral hemisphere(ie.the right/green hemifield projects through the leftoptic tract, and on to the left cerebral hemisphere).
Step 3 : input from GC to brain
There are four key destinations for projections from the retina.
Suprachiasmatic nucleus
Part of the hypothalamus that regulates circadian rhythms or sleep/wake cycle. Further projections include the pineal gland, to regulate melatonin. The ganglion cells that project to the SCN are distinct from the 3 most commontypes of cells (midget, parasol, bistratified). Rather they expresstheir own photosensitive opsin, melanopsin, and do not rely solely on photoreceptors for excitation.
Pretectal area
This projection provides the input for the circuits that control the pupillary reflex and islargely derived from melanopsin-containing ganglion cells.Cells in the pretectal area project bilaterally to the Edinger-Westphal nucleus (CN III), which sends parasympathetic output to the ciliary ganglion, and thence the constrictor pupillae muscle.
Superior colliculus
These inputs are mapped onto the superficial SC, which receives corresponding, mapped inputs from the visual cortex. SC also receives mapped inputs from the auditory system, and somatosensory system. SC co-ordinates ‘saccadic’ eye movements towards novel stimuli (auditory / somatosensory) for rapid (self-preserving) responses.
dorsal LGN
All information destined for conscious perception must pass through the thalamus, before going to neocortex. the dLGN is the ‘visual nucleus’ of the thalamus, and projects directly to primary visual cortex / V1, also known as ‘striate cortex’.
Projections to the SC and dLGN are mapped
This means that adjacent points in the visual field are represented in adjacent parts of the brain target, preserving the relationship between points. Inthe dLGN there is a map of the visual field in each layer, in an approximately alternating (left eye/right eye) pattern.
Step 5: ### The dLGN sends a mapped projection to primary visual cortex - V1 / Striate cortex / Area 17
- Describe the transduction of sound
Waves travelling to the ear are interpreted as sound. To initiate the sensation of hearing, two physical processes are involved:
Pressure - air particles press against the ear drum and cause it to vibrate and initiate the mechanical part of hearing. The amplitude of the pressure determines the intensity of sound.
Auditory receptors (hair cells) in the cochlea initiate the auditory transduction. The denomination of ‘inner’ and ‘outer’ is in relation to the cochlear axis. Inner hair cells are the primary auditory sensory cells.
- sound waves arrive to the tympanic membrane
- tympanic membrane vibrates
- auditory ossicles vibrate
- displacement of fluid molecules in the membranous labyrinth and basilar membrane
- vibration of basilar membrane
- vibration of organ of Corti
- bending of cilia on hair cells
- change in K+ conductance of hair cell membrane
- oscillating receptor potential (Cochlear microphonic)
- intermittent glutamate release
- intermittent action potentials in afferent cochlear nerves
**Bending of stereocilia depolarises the cell and sends a signal to the auditory nerve
*Opening of mechano-electrical transduction channels (METs) by sound vibration causes entry of K+ and depolarization of the inner hair cell.
*Depolarization opens voltage-dependent calcium channels in the inner hair cell membrane.
*Calcium entry causes transmitter release (glutamate) at the inner hair cell–spiral ganglion cell synapse.
*Released glutamate activates receptors in the spiral ganglion cell, which depolarises and fires an action potential
*Action potentials propagate along the auditory nerve to the brain.
Action potentials in the spiral ganglion cells are collected in the cochlear nerve (CNVIII) that leaves the inner ear (petrous part of temporal bone) through the internal acoustic meatus to reach the pontomedullary junction, where it enters the brainstem.
It synapses in the cochlear nuclei (ventral & dorsal) to form central auditory pathways. Observing the image on the right, you may notice that there are multiple relays on both sides of the brainstem for each ear. We will follow the main central auditory pathway (red):
After synapsing in the ventral cochlear nucl, the axons ascend to the pons to synapse in the superior olivary nucleus bilaterally. Once synapsing in the olivary nucleus, axons form the lateral lemniscus, which ascend to the inferior colliculus of the midbrain. After synapsing in the inferior colliculus, it ascends further to the medial geniculate nucleus of the thalamus, which relays the auditory information to the primary auditory cortex, in the Heschl’s gyrus of the temporal lobe. ^[at lip of lateral fissure, oriented perpendicular to surface of brain in a lateral-medial direction].
- What is prefrontal? Wernicke? PMC?
Areas in the prefrontal cortex are involved in “executive functioning”. This includes abstract thought, planning, consequences of actions, and learned social behaviors. It is thought the prefrontal cortexplays a significant role in working memory.
Broca’s area is involved in language expression. Lesions of Broca’s area are associated with difficulty in speaking in complete sentences, however, language comprehensive is unimpaired. This this type of aphasia is called expressive.
Wernicke’s area is involved in understanding language.
A lesion in Wernicke’s area is associated with an inability to understand both spoken and written language. Patients speak with normal fluency (i.e. rhythm and syntax) but sentences may be meaningless. This is known as receptive or fluent aphasia.
Postero-medial cortex and self
- Postero-medial Cx (PMC) occupies a very high place in the functional hierarchy
- It mediates awareness of the environment and therefore consciousness
- Its main constituents are the
- posterrio cingulate cortex
- precuneus
- medial prefrontal cortex
- angular gyrus
- It hasnoconnections with primary areas
- Its afferent inputs include:
- parietal and temporal association areas: to make sense of self and surroundings
- premotor regions and frontal eye fields: motor planning areas; controls eye movement and visual attention
- anterior cingulate gyrus: part of limbic, regulates emotions and regulate behaviour
- claustrum, basal forebrain and amygdala: forebrain has roles in sleep, thermoregulation, learning and memory
- dorsal thalamus
- Efferents:
- are largely reciprocalbut also include neostriatum and periaqueductal grey
- Is the most highly metabolically active cortical region, consuming 35% more glucose than other areas of Cx
- note it has dense connections with entorhinal cortex (hippocampus and neocortex) - has memory retrieval role
- What are primary and secondary cortical areas?
-
‘Primary’ / 1° areas have a single function, and do not interconnect with each other.
- ‘Secondary’ / 2° areas deal with specific aspects of a modality (eg colour). They may also ‘share’ some information.
- ‘Association’ areas_associate_information across modalities.
-
‘Higher order’ areas are sometimes referred to as ‘hubs’ and extract information across a wide range of modalities, as required for example, when understanding the rhythm, cadences, and meaning of speech. This is a fundamental feature of cognition.
Recall that projection, commissural and association fibres connect regions of the brain.
key- What are higher associational fibres?
Key association fibres include:
- arcuate fasciculus: connects Broca with Wernicke’s (see also [[Neurology - Lecture 4]])
- superior occipitofrontal fasciculus connects the posterior parietal cortex and premotor cortex
- uncinate fasciculus connects orbital cortex with anterior temporal lobe
- Provide differential diagnoses for double vision
- diplopia as muscular= NMJ, myasthenia gravis
- MS
- CN palsy 346
- Honer- symp n injury
- List the structures of eye, their innervation, type of innervation and broad function
- cornea
- innervated by long ciliary branches of V1
- sensory innervation (for light touch as well as pain)
- function: helps to protectthe corneal surface from damage from accumulation of particulate matter
- conjunctiva
- long ciliary branches of V1
- sensory i.e. light touch
- protection - helps detect particulate matter
- upper eyelid
- long ciliary branches of V1
- sensory (light touch )
- sweeps the tear film across the corneal surface
- lower eyelid
- V2 Maxillary (Infraorbital N)
- sensory (light touch )
- retina
- Optic nerve
- special sensory
- Transmits sensory information to cortex
- lacrimal gland
- V1 and facial nerve
- touch and pain fibres/secretomotor (parasympathetic)
- tears secreted and swept over surface for lubrication and cleaning
- levator palpebrae superioris
- Upper division of Oculomotor nerve, T1-4 fibres carried by V1 branches to Upper division of III
- somatic motor and sympathetic
- dilator of the orbit; elevates the upper eyelid / tarsal plate; mediates ‘eyes wide open’ in a stress response; provides tone to the resting, open position
- orbicularis oculi
- facial (orbital branches)
- somatic motor
- sphincter of orbit
- lateral rectus
- abducens
- somatic motor
- abducts eye
- superior oblique
- trochlear
- somatic motor
- works with inferior rectus when looking downwards
- superior inferior and medial rectus
- oculomotor inferior division
- somatic motor
- various movements:
- ciliary
- oculomotor via ciliary ganglion
- parasympathetic
- Draws the lens and lens capsule forward, allowing the lens to bulge and bend light more, during near vision = Accommodation
- sphincter pupillae
- oculomotor via ciliary ganglion
- parasympathetic
- reduce light by constricting pupil and during accommodation
- dilator pupillae
- T1-4. Could be via Long Ciliary brs of V1, OR from symp branches that pass through ciliary ganglion (with III)
- sympathetic
- increase light in sympathetic response allows maximum light to reach posterior chamber
- Describe photoreceptors, and distinguish between rods and cones
Humans have 4 types ofphotoreceptors.
RODS:named as such as based on their narrow, rod-like appearance.
Note the inner and outer segments of the photoreceptors. The inner segments are responsible for providing energy and the replenishment of proteins important for cell function. Indeed, photoreceptor inner segments have the highest concentration of mitochondria in the human body, indicating the high energy demand of these cells. The outer segment of the photoreceptors contain light sensing photopigments. The light sensitive pigment expressed by rods is rhodopsin. Rods respond in low levels of light in the 425-575 nm range.
CONES:respond in bright light across the entire ‘visible spectrum’ (indeed the cone responses determine what the visible spectrum is).
Each human cone expresses one of threephotopigments / cone opsins that is sensitive to light:
- Short wavelengths (~400-500 nm), which we see as (or call)blue - hence ‘blue / S-cones’
- Medium wavelengths (430-650 nm),which we see as (or call)green - hence ‘green / M-cones’
- Longwavelengths (450-675nm),which we see as (or call)red - hence ‘red / L-cones’
Note that the peaks of the curves (below) indicate the frequency where each of the cone types _responds at maximum strength_ (peak sensitivity).
In daylight, perceived colour is determined by the relative activation of the 3 cone types
Genes that encode the M- and L-opsins are both on the X-chromosome, leading to a higher incidence of red-green colour vision defects in males, compared with females.
The nucleotide sequences coding the M- and L- ospins are almost identical: L-opsin has arisen as a mutation of the M-opsin gene. The S-opsin gene is on a different chromosome.
- Describe macula
- macula lutea
- The high density of yellow xanthophyll pigment, filters damaging blue wavelengths of light, and has anti-oxidative qualities. Macula (=spot) lutea (=yellow).
- It is the part of the retina used in most of your minute-to-minute activities. It is approximately in the centre of the retina, and has a very high density of cells in all layers, and a relative absence of large retinal vessels coursing across it. Rather, retinal vessels tend to arch around the macula (as do the axons of ganglion cells).
- fovea centralis
- The ‘fovea’ (dip/depression) is in the centre of the macula (centralis) and is the part of the retina that has the highest capacity for resolving fine details (‘acuity’). The presence of a shallow depression is its most distinctive feature, but the depression itself does not contribute to acuity.
- At the location of the fovea there is the highest density of cone photoreceptors (no rods), and the least amount of neural convergence of signals from photoreceptors through to GC. That means that a single GC can get a signal from a single cone, at the fovea (but nowhere else in the retina).
- There are no retinal vessels at the fovea, and the depression itself it likely secondary to that important adaptation.
- Macula is responsible for almost all our ‘useful’ vision – reading, recognising faces, discriminating details
- it has high levels of vitamin A derivatives that filter damaging short wavelength light = hence macula lutea
- Reduced vascularity of macula and absence of retinal vessels from the fovea is of key importance to optical quality because it prevents shadowing of the photoreceptors by vessels and blood cells
- Describe retina and its components
Cross section through the retina.
The retinais made up of 2 layers of connections/synapses (inner and outer plexiform layers), and 3 layers of cells (ganglion cell layer, inner and outer nuclear layers) including the photoreceptors and theoutmost layer of light transducing elements, the photoreceptor outer and inner segments (PRS).
The transducing elements (PRS) are extensions of the ONL cells (photoreceptors)and are intimately related to the retinal pigmented epithelium (RPE).
![[Pasted image 20240307091119.png]]
![[s182_9_002i.jpg]]
![[EE020b.jpg]]
Note also the presence of blood vessels (small red dots).
Key cells of the retina:
- photoreceptor
- Both rods and cones have cell bodies in the outer nuclear layer, and axonal processes in the outer plexiform layer. The outer segments of photoreceptors are intimately associated with the retinal pigmented epithelial (RPE) cells. Light entering the retina passes though 5 layers of cells and connections before entering the outer segment of a photoreceptor.
- In the outer segment of the photoreceptor light is ‘transduced’ into an electrical signal, through a G-protein-mediated interaction with light sensitive ‘opsins’. Photoreceptors are the most highly metabolically active cells in the body (ie., they are very oxygen hungry).
- Disorders and diseases affecting photoreceptors:
- Retinal detachment.The molecular processes involved in visual transduction include reactions that take place in the RPE. In addition, the outer retina receives its nutrients (O2 and glucose) by diffusion, from the underlying choroid. During detachment, the distance between the outer retina and choroid increase, therefore nutrient delivery reduces (Fick’s law). Thus, detachment of the retina from the RPE (retinal detachment) results in vision loss. Photoreceptors can survive only for about 24 hours if detached from the RPE; therefore the condition of ‘retinal detachment’ requires urgent attention.
- Photoreceptor dystrophies are inheritable/genetic disorders that lead to progressivephotoreceptor death, and are a significant cause of vision loss in teenagers and young adults, who were normally sighted at birth (“retinitis pigmentosa”).
- bipolar cell: Bipolar cells are located in the middle layer of the retina (INL). Theyget synaptic input from photoreceptor dendrites (in the OPL) and pass information onto ganglion cells.In primates there are around 11 different types of bipolar cell, which process the inputs from photoreceptors in different ways.They play a critical role in ‘managing’ theinformation that is passed on from photoreceptors to ganglion cells.As far as we knowthere are no diseases that stem from problems with bipolar cells.
- ganglion cells: Ganglion cells pass visual information to the brain. This information is a distillation of data from various ganglion cell types that encodecolour, position/acuity or contrast.
- Theyhave long axons that form the innermost layer of the retina, the Nerve Fibre Layer, as they course across the retina, in a stereotypical pattern, towards the optic disc. There they make a 90° turn and leave the eye as the optic nerve (CNII). Their functional characteristics are determined largely by the way they wire up to bipolar cells, although ‘amacrine cells’ also interconnect the GC-bipolar synapses to modulate signal transmission.
- Diseases of GC: In glaucoma ganglion cell axons become compressed at the optic disc, which results in ganglion cell death, usually in the periphery, and in distinct patches of the retina.
- Peak GC density is about 30,000 cells / mm sq, at 1 mm eccentricity. This is 30x greater than the average GC density across the retina.
- Each GC represents a line of direct communication to the brain. There are about 100,000 direct lines of information coming out of the foveal region and going to the brain; in peripheral retina there would be <5,000. Thus, the brain gets more information, of better ‘quality’, from the fovea / macula, than it does from other parts of the retina.
Note:
##### The retina is not uniformly effective at the 3 key elements of vision (colour, acuity and contrast / motion)
Different regions of the retina are specialised for different functions. These functions are determined by
- Differences in photoreceptor distribution e.g. photoreceptor topography: there is a 1mm region where cones outnumber rods ^[note rods and cones generated in utero and do not regenerate]
- Differences in the components of the neuralcircuits that process the information coming from photoreceptors, and the way they are ‘wired’. - gnaglion cell topography (there is a 400 um region of the fovea where ganglion cells and rods are absent)
Macula layers
![[Pasted image 20240307091745.png]]
- macula lutea
- The high density of yellow xanthophyll pigment, filters damaging blue wavelengths of light, and has anti-oxidative qualities. Macula (=spot) lutea (=yellow).
- It is the part of the retina used in most of your minute-to-minute activities. It is approximately in the centre of the retina, and has a very high density of cells in all layers, and a relative absence of large retinal vessels coursing across it. Rather, retinal vessels tend to arch around the macula (as do the axons of ganglion cells).
- fovea centralis
- The ‘fovea’ (dip/depression) is in the centre of the macula (centralis) and is the part of the retina that has the highest capacity for resolving fine details (‘acuity’). The presence of a shallow depression is its most distinctive feature, but the depression itself does not contribute to acuity.
- At the location of the fovea there is the highest density of cone photoreceptors (no rods), and the least amount of neural convergence of signals from photoreceptors through to GC. That means that a single GC can get a signal from a single cone, at the fovea (but nowhere else in the retina).
- There are no retinal vessels at the fovea, and the depression itself it likely secondary to that important adaptation.
- Describe/label fundoscope
The optic nerve is 4 mm away from the fovea.
The retina is transparent, allowing you to view the vessels of the choroid (orange streaks) which form a layer on the outerside of the retina.
The region in the centre of the image which has no retinal vessels running across it is the macula. We use the maculafor all of our ‘most useful’ vision - that is, reading and writing, recognizing faces, seeing colours, seeing details.
![[Pasted image 20240307092031.png]]
- Macula is responsible for almost all our ‘useful’ vision – reading, recognising faces, discriminating details
- it has high levels of vitamin A derivatives that filter damaging short wavelength light = hence macula lutea
- Reduced vascularity of macula and absence of retinal vessels from the fovea is of key importance to optical quality because it prevents shadowing of the photoreceptors by vessels and blood cells
- the optic disc or blindspot is the site for sensory fibres e.g. ganglion cell axons to exit the eye to go to the brain. These fibres constitute the optic nerve - CN II
- There are about 1.3 million ganglion cell axons that enter the opti nerve
- 25% of the fibres come from the central 2 mm of the retina, including the fovea
- Describe meningism and how to investigate for it
Is there meningism?
- ‘Meningism’ refers to a cluster of signs and symptoms indicating meningeal irritation or inflammation
- Neck rigidity is the hallmark
- Photophobia is common
- Pain may be increased with stretch of meninges
- Kernig’s sign (pain on straightening legs with hips flexed)
- Brudzinksi’s sign (active flexion of hips/knees on passive flexion of neck)
- Always a serious symptom, demands further investigation
- Important causes are:
- Subarachnoid blood
- Meningitis (bacterial, viral)
- Mild cases may be confused with migraine or cervicogenic headache
Blood cultures. A blood sample is placed in a special dish to see if it grows microorganisms such as bacteria. ... Imaging. Computerized tomography (CT) or magnetic resonance imaging (MRI) scans of the head may show swelling or inflammation. ... Spinal tap.
Dinstinguish between bacterial and viral causes of meningitis
- Meningitis
- Headache
- Fever
- Neck Stiffness
- Photophobia
- Confusion, seizures and/or neurological deficits
- suggests either encephalitis/myelitis or focal lesion/abscess
- Manifestations of infection elsewhere
- Eg rash, pneumonia, sinusitis, otitis media
Meningitis - aetiology
- Infectious
- Bacterial (fatal without antibiotics, more common in children)
- Viral (most common, usually self-limiting)
- Fungal (uncommon, fatal without antifungals)
- Parasitic (uncommon, high mortality)
- Non-infectious
- Autoimmune diseases
- Drugs
- Malignancy
Bacterial meningitis
Organism
- Streptococcus pneumoniae (Gram-positive diplococcus)
Risks
- Hyposplenism, <2 years, elderly, HIV infection, hypogammaglobulinaemia (multiple myeloma)
Associations
- Mastoiditis, sinusitis, otitis media, pneumonia, bacteraemia
Neisseria meningitidis (Gram-negative diplococcus)
Bacteraemia with rash
- Listeria monocytogenes (Gram-positive bacillus)
- Immunosuppressed (T cell deficiency), pregnancy, neonates
- Subacute
- Zoonosis – unpasteurised dairy products, deli meat, raw salads
Group B Streptococcus (Gram-positive coccus in chains)
- Neonates – early onset within the first week of life, late onset 1-4 weeks of life
- Maternal colonisation & chorioamnionitis
Mycobacterium tuberculosis (acid-fast bacillus)
- TB exposure in the past, reactivation, immunosuppressed
- Subacute-chronic presentation, tuberculomas
Viral meningitis
- Mostly self-limiting without treatment
- Not all cases of suspected viral meningitis will be confirmed by identification of a viral agent - only a small subset is directly identifiable
- Enterovirus (picornavirus) & parechovirus
- Herpes simplex 2»1 (human herpes virus)
- Varicella-Zoster Virus (human herpes virus)
Diagnosis of CNS Infections
- Clinical history including exposures/risk factors
- +/- Imaging – CT/MRI (encephalitis, brain abscess, epidural abscess)
- +/- EEG (encephalitis esp due to HSV1)
- Microbiological (diagnostic and definitive organism identification)
- LP - CSF analysis
- Abscess aspirate - culture
- Tissue biopsy – histology & culture
- Blood cultures
- Immunoassay – antibody/antigen detection
note also PCR can be used to identify pathogens
Diagnosis – lumbar puncture
Lumbar Puncture – routine tests
- Opening pressure
- MCS – microscopy (cell count +/- Gram stain), culture, sensitivity
- Protein
- Glucose
|Normal|Bacterial|Viral|
|—|—|—|
|CSF WCC <5 x10^6/L|WCC differential: All mononuclear|100s-1000s Polymorphic predominance|
|CSF protein 150-450 mg/L|Raised, frequently >1000|Normal or slightly/moderately increased|
|CSF glucose >2/3 serum|<2/3 serum|Normal or slightly low|
|Xanthochromia (presence indicative of bleeding in subarachnoid space)|CSF RCC (if not a bloody tap)|Opening pressure: Raised, Variable|
Lumbar Puncture – additional tests
- Special stains
- Special culture
- Mycobacterial
- ZN/AFBs for TB
- Giemsa for eosinophils and amoeba
- Antigen tests
- Cryptococcus neoformans
- Molecular tests
- Herpes simplex 1&2
- Enterovirus
- Meningococcus & pneumococcus
- Interpret CSF analysis
eg bacterial vs viral, bleeding
- bacterial: usually 80-90% OMNs, >50% lymphocytes, glucose <40 mg/dL serum glucose ratio <0.4 sn and sp, almost always elevated serum protein, 1000-5000 /uL
- ## viral: lymphocyte predominence, usually normal glucose and protein, 100-1000/uL WCC
- Describe the components of BBB/BCB and explain how this is relevant to antibiotics
This is a physiological barrier that involves structural and mechanistic adaptations, as well as cell-cell molecular signalling.
As its name suggests, the BBB prevents harmful substances from entering the brain from the blood. This not only protects the brain from blood-borne infections, it also protects the brain from the normal fluctuations of solutes in the EC environment. The brain is protected from some amino acids and ions.
While the BBB is protective against soluble substances, it doeslet solutes that are essential for brain function pass through via facilitated diffusion. These include important nutrients (for example, glucose), essential amino acids, and some electrolytes. The BBB also facilitates the removal of blood-borne waste metabolites, and passesthem from the brain out into the bloodstream.
While the BBB is highly protective against solutes, itis not as protective against lipid-soluble molecules (these are hydrophobic) inc. fats, fatty acids, O2, and CO2.
The endothelial cell walls of the capillaries are joined together by tight junctions. These prevent solutes from entering the brain. This structure differs from the majority of capillaries,where there are permeable intercellular clefts (small openings) between the endothelial cells.
The endothelial cells of the brain capillaries are surrounded by a relatively thick basement membrane. Embedded intermittently within the basement membrane are pericytes, which communicate directly with the endothelial cells to help maintain the BBB. They are also involved in the regulation of blood flow through the capillaries.
Astrocyte”feet” (also called processes)completely surround the capillaries in the brain. Astrocytes are not part of the BBB as such, but they function to help the endothelial cells form tight junctions, and provide biochemical support.
NOTE
There are a few small areas of the brain that lack a BBB, these areas are called circumventricular organs.These areas include the posterior pituitary gland, the pineal gland, and the area postrema.
The pituitary and pineal glands are endocrine glands, while the area postrema controls the vomiting response.
It’s important that the brain have access to these regulatory areas in order to monitor hormone levels. Also the area postrema must have access to the bloodstream to control the vomiting response (monitoring for poisonous substances, to elicit vomiting, in order to rid the body of these harmful substances).
- Describe the differences between UMN and LMN lesions
Upper Motor Neuron - spastic weakness
- Increased tone
- Pyramidal pattern of weakness (relative preservation of upper limb flexors and lower limb extensors)
- Hyper-reflexia
- Exacerbated deep tendon reflexes / Clonus
- Babinski sign +ve
- Hoffman’s Sign +ve
- Superficial abdominal reflexes are absent
- Cremasteric reflex (L1) is absent
- Minimal muscle atrophy secondary to disuse
- Difficulty placing foot on edge
Lower motor neuron – flaccid weakness
- Decreased tone
- Non pyramidal weakness
- Diminished or loss of deep tendon reflexes
- Babinski sign -ve
- Hoffman’s sign -ve
- Marked muscle atrophy
- Muscular fasciculations present (When there is slow destruction of LMN cell)
- Muscular contracture (shortening of the paralysed muscles)
- Describe the three types of dysphase
In Australia and the UK, aphasia means complete loss of a particular language skill, while dysphasia means a partial loss.
Language Components – Input to Output Connection
- The major input and output areas for language are separated by the Sylvian fissure.
- The shortest available route between the two centers is thus a curved (arcuate) path running around the posterior end of the Sylvian fissure.
- The major direct connection between Wernicke’s and Broca’s Areas uses this obvious route, and is known as the Arcuate Fasciculus.
Possible Sites of Injury to the Language Apparatus
1. Wernicke’s aphasia
- Loss of comprehension plus word-meanings
2. Broca’s aphasia
- Loss of expression plus grammar
3. Conductive aphasia (Arcuate fasciculus)
- Loss of repetition
4. Transcortical sensory aphasia
- Loss of comprehension but preserved repetition
5. Transcortical motor aphasia
- Loss of expression but preserved repetition
Broca’s Aphasia
- A common dysphasia, predominantly affecting expression.
- The hallmark is a delay or complete failure at the expression phase of language processing, which affects both expression of the patient’s own ideas as well as repetition.
- Impairment of the syntactical engine leads to preferential loss of syntactical words (“if”, “then”, “but”) and relative preservation of content words (“stroke”, “ambulance”, “cigarettes”). This is evident in spontaneous speech and in repetition tasks (“No ifs ands or buts”).
- Speech is slow, hesitant (non-fluent) and syntactically simple (“telegraphic”, as if written in an old-fashioned telegram where each word cost money). For instance: “Blood pressure… doctor give tablet”.
- The patient is usually frustrated.
- For these reasons, it is often called “Expressive Dysphasia”.
Broca’s Aphasia
- In a classic case of Broca’s Aphasia, comprehension is largely intact, but it is never completely intact.
- There are two main reasons why comprehension may be mildly impaired in what otherwise looks like a predominantly expressive Broca’s Aphasia:
- There may be some mild damage to Wernicke’s Area.
- The “syntactical engine” is likely to be damaged, so sentences requiring complex or non-standard parsing maybe misinterpreted. (“The lion was killed by the tiger. Which animal died?” Patients with Broca’s aphasia may simply perceive “Lion…killed…tiger”).
Wernicke’s Aphasia
- A reasonably common aphasia, but rarely a pure syndrome. (More often a mixed aphasia with dominant involvement of Wernicke’s Area.)
- The hallmark is impaired comprehension. Questions are not answered appropriately and complex commands are not carried out. In milder versions, with only partial damage to Wernicke’s, this may be the only obvious feature.
- Repetition is impossible in a complete case.
- For both of these reasons, Wernicke’s Aphasia is often called “Receptive Aphasia”.
- Because of the complex interdependence of Wernicke’s and Broca’s Areas, there are actually major impairments in expression, as well.
Wernicke’s Aphasia
- In true Wernicke’s Aphasia, there is lexical impairment, and a poor mapping of sounds to meanings, causing word-substitutions (paraphasias).
- There can be near-misses at the sound end of the mapping (literal or phonemic paraphasia - “pish” instead of “fish”) or at the meaning end of the mapping (verbal or semantic paraphasia - “clock” instead of “watch”).
- Broca’s area is working well, but its output is based on poor lexical information (garbage in, garbage out) and the patient cannot self-monitor speech, or comprehend the first half of a sentence while trying to express the second half.
- Patients often have anosognosia (unawareness of the deficit).
- Speech is thus fluent and grammatically normal, but is often empty, meaningless or littered with phonemic and semantic paraphasias. (“The dird went in the doctor, my tablet was in the page with the words, and he gop a headache”).
Global Aphasia, Mixed Dysphasia
- In complete global aphasia, comprehension and speech are both absent.
- In cases that are almost complete, the patient is reduced to single words (“yes” and “no”, or common nouns) and may only understand simple questions or single-word prompts (“drink?” “yes”).
- More commonly, there is a dysphasia with incomplete impairment in comprehension and expression. Speech is non-fluent and littered with errors. The problems with comprehension are only noted when specifically tested with complex commands.
Transcortical Aphasias
- Lesion is not intrinsic to language areas
- Does affect their connections with the rest of the cortex
- Hallmark is intact repetition either with a comprehension issue, expression issue or both
- Both or mixed: one’s own language is foreign. Can repeat words verbatim but with impaired understanding
Conduction Dysphasia
- This is a rare but interesting dysphasia. It provides good evidence that the “language of thought” is not our native language (English, etc), even though our thoughts are often presented to us in a linguistic form and some forms of higher thinking may be impossible without language.
- The hallmark is impaired repetition, in the presence of normal comprehension. Ideas can be understood, and then re-expressed, but the original words are lost, as though repeating a story a day later.
- For instance, when asked to repeat: “The fuel truck crashed and spilled petrol on the road,” a patient might say “A truck carrying petrol crashed, and there was petrol all over the road.”
- Because Broca’s Area is separated from the lexicon, however, paraphasic errors are common in spontaneous speech, so it may resemble mild Wernicke’s Dysphasia.
Anomia
- Anomia = the inability to name objects
- Common in all dysphasias (Wernicke’s/lexicon needed to retrieve the word, Broca’s to prepare the word for motor output).
- Has poor localizing value.
- Many dysphasias recover to leave a mild dysnomia as the only residual sign.
- Ease of recall depends on frequency of use, so mild dysnomias will only affect low-frequency words (“telescope”), leaving high-frequency words intact (“pen”).
- Compare and contrast Broca’s and Wernicke’s aphasias, especially presentation
- What distinguishes headaches from migraines and raised ICP?
- Is there evidence of raised intracranial pressure (postural headache- raised ICP relieved when patient supine, visual change)?
Is there evidence of raised intracranial pressure?
- The hallmark of raised ICP, on history, is a headache worse on lying flat, (though this can also come from scalp tenderness or neck discomfort)
- Raised pressure may also compress the optic nerves, producing papilloedema, but this is a relatively late sign
- Papilloedema is often subtle, and requires careful examination by the most experienced doctor available. Absence of papilloedema is not proof of normal ICP.
Consequences of Raised Intracranial Pressure
- Optic nerve compression, with serious threat to vision
- Raised ICP reduces cerebral perfusion pressure (arterial pressure – intracranial pressure), which may cause drowsiness (a fall in the Glascow Coma Score, or GCS), coma and death.
- Patient may respond to raised ICP with hypertension and bradycardia (the Cushing response), but this is a late and inconsistent sign. Coupled with respiratory depression, usually from brainstem compression, this is known as Cushing’s triad.
- Severely raised pressure may cause compression or herniation of the brainstem or cerebellum, which is a major, life-threatening emergency – signs can include unconsciousness, the Cushing response, cranial nerve abnormalities (particularly dilated or ‘blown’ pupils), hemiparesis, or quadriparesis
- A raised ICP may be confirmed by doing a lumbar puncture, but this is unsafe in the presence of raised ICP due to a mass lesion – a pressure gradient can develop and increase the risk of herniation
- Explain causes of raised ICP
- The skull is a closed, rigid container
- Small changes in volume of intracranial contents can cause large changes in pressure, especially if rapid, with stretch of meninges and blood vessels, causing headache
- The extra volume can come from:
- a ‘mass’ lesion (tumour, abscess, haematoma)
- bleeding
- oedema (around a mass lesion, with inflammation, or following a stroke)
- increased cereberospinal fluid (CSF), from increased CSF production, blockage to flow, or impaired absorption
- Slowly progressive mass lesions may produce few signs or symptoms, often with no headache at all, especially in older patients who have relatively atrophic brains and increased CSF spaces
- Describe how to distinguish between benign and serious headaches/warning signs
- explain the clinical significance of headaches
**
- Headaches can be a warning symptom:
- Cerebral tumours
- Raised intracranial pressure
- Intracranial haemorrhage
- Aneurysms
- Meningitis, encephalitis
- Giant cell arteritis (temporal arteritis)
- Headaches themselves can cause significant morbidity:
- Tension headaches
- Migraine
- Other headache sub-types
- ~40% of individuals report ≥1 severe disabling headache per year
- Headaches are also common as a nonspecific epiphenomenon:
- Many febrile illnesses, malaise
- Ischaemic stroke
- Describe Brown-Sequard. Where is the lesion?
- Hemi-section of the cord
- Trauma
- Ipsilateral LMN paralysis in the segment of the lesion and muscle atrophy
- Ipsilateral spastic paralysis below the level of the lesion
- Ipsilateral band of loss of sensation in the segment of the lesion
- Ipsilateral loss of tactile discrimination and vibration & proprioceptive sensation below the level of the lesion
- Contralateral loss of pain and temperature sensation below the level of the lesion (since the lateral spinothalamic tract crosses obliquely, the sensory loss occurs two or three segments below the lesion distally)
- Contralateral BUT not complete loss of tactile sensation below the level of the lesion (because tactile information travels through both tracts, and is thus preserved)
- What are some physical signs in Huntington’s disease? What are some histopathological signs?
- Genetics: Autosomal dominant condition linked to chromosome 4, involving the protein huntingtin and triplet nucleotide repeat expansion; exhibits anticipation.
- Characteristics: Progressive movement disorders and dementia due to degeneration of striatal neurons.
![[Pasted image 20240315134757.png]]
Clinical Features
- Insidious onset typically between 35 to 45 years of age.
- Symptoms include chorea, dementia, emotional/psychiatric symptoms, sometimes parkinsonian syndrome, and depression.
Huntington’s Disease Pathology
- Marked by atrophy of the caudate and putamen, alongside widespread (secondary) cerebral atrophy affecting the striatum and cerebral cortex.
![[Pasted image 20240315134817.png]]
### Diagnosis of Huntington’s Disease - Differentiation from other causes of chorea, dementia, and psychosis.
- Utilizes genetic testing for HD, MRI, and PET scans to confirm diagnosis.
- Describe the main types of stroke, provide 3 modifiable and non-modifiable risk factors
- An acute onset of cranial neurological deficit or symptom with an underlying cerebrovascular origin.
- 80-85% Ischaemic in Origin (Vessel Occlusion): Involves occlusion of arterial supply of the brain, including transient ischaemic attack (TIA), completed stroke, stroke-in-evolution, reversible ischaemic neurologic deficit.
- 15-20% Haemorrhagic in Origin (Vessel Rupture):
Annual Incidence: Approximately 150 per 100,000 in Australia.
Symptoms and Signs will vary based on lesion location
- Headache (usually with haemorrhagic), acute onset neurological symptoms (dizziness, balance disturbance, visual/hearing abnormalities, speech/language abnormalities, muscle weakness/incoordination, swallow disturbance), altered consciousness.
Note that symptoms can also occur in combination.
Differential Diagnosis
- Includes intracranial tumor, infection, seizure, demyelination, non-occlusive/non-haemorrhagic cerebrovascular disorder (a result of too much or too little blood supply, interfering with oxygen supply or drainage), hypoglycemia, psychiatric disorder.
Extent of Stroke
- Determined by the location and size of the occluded vessel, duration of occlusion, and potential for collateral blood supply.
Cerebral Blood Flow (mL/100g/min)
- Indicates stages from increased oxygen extraction to failure of electrical function (symptomatic) to failure of cellular homeostasis (cell death).
- we can salvage the penumbra but not the occlusive zone
Causes of Arterial Occlusion
- Atherosclerosis (intracranial, carotid), cardiac thromboembolism, pro-coagulant state esp. in young, arterial injury, iatrogenic.
- Describe the features of psychosis
Psychosis = severe impairment of reality testing
If any one (or both) of the following is present the term “psychosis” can be used:
1. Delusion, and cannot be convinced to the contrary. Common is persecutory. Also reference? receiving special messages. Grandiose. Mood congruent. Thought alienation. Capra? - doppelganger replacement.
2. Hallucination (excluding non-pathological hallucinations e.g. hypnagogic, hypnopompic). False perception but compelling enough. Any sensory modality. Most common auditory.
Broad categories of “psychosis”
1. Primary psychiatric disorder eg schizophrenia
2. Medical disorder
3. Substance/alcohol/medication related
- What are some general features of neurodegenerative disease?
-
Common Themes:
- Progressive neuronal loss
- the progression follows a pattern
- it is selective i.e. occurs in specific location and will present differently based on site
- Neurons often functionally related, leading to stereotypic signs.
- Accumulation of intraneuronal protein aggregates due to mutations, altered processing, or balance issues (clearance < synthesis).
- Progressive neuronal loss
Intraneuronal Protein Aggregates
- Recognized histologically (diagnostic “inclusions.”)
- Resistant to degradation and damaging to neurons (toxic gain of function i.e. ROS production + Loss Of Function, stress response).
- Act similar to prions in causing conformational changes in normal proteins (propagation) but not transmissible ^[see [[Singh, 2024]]]
- What is Alzheimer’s? Symptoms? Tretemnt
- Nature: Cortical degenerative disease leading to dementia and progressive loss of cognitive function.
- Symptoms: Insidious onset, thought content disorders, perception disorders, affect disorders, behavioral disturbances, personality changes, amnesia, aphasia, immobility.
- Etiology: Unknown; 5-10% familial, increased in Down’s Syndrome.
- Incidence: Increases with age (1% of 60-64, >40% above 85). Both environmental and genetic factors may contribute.
- Genetics: Genes on chromosomes 21, 14, 1.
- Diagnosis: Combination of clinical assessment and radiology allows for an 80-90% correct diagnosis rate. Definitive diagnosis through autopsy.
Pathophysiology of Alzheimer’s Disease
-
Genetics: Relate to metabolism of APP, with familial mutations in APP or enzymatic processors, or increased copy number in trisomy 21/Down’s.
- APP soluble fragment cleaved, monomers aggregate, creating plaques and tangles
- Apolipoprotein E (ApoE) alleles, with Ɛ4 dose equating to high risk.
- Key Features: Increased intraneuronal accumulation of Tau and Amyloid beta (Aβ) due to excess production or inadequate removal, leading to plaques in neuropil for Ab and tangles for tau, which can move from IC to EC environment.
- Role of Inflammation? Under investigation.
Alzheimer Disease Pathology
![[Pasted image 20240315133631.png]]
![[Pasted image 20240315133657.png]]
- Visual Comparisons: Normal brain vs. Alzheimer’s disease, showcasing cortical atrophy, widened sulci due to neuronal loss, narrowed gyri, ventricular dilatation, and thinned cortical ribbon.
Alzheimer Disease Histopathology
- Key Findings: Neuritic plaques, neurofibrillary tangles, and amyloid angiopathy.
-
Tau Immunohistochemistry: Highlights neurofibrillary tangles.
- ![[Pasted image 20240315133751.png]]
-
Neuritic Plaques:
- Focal spherical structures
- Occur along neurofibrils
- In hippocampus, amygdala, neocortex
- Central amyloid core with surrounding dilated, tortuous, dystrophic neurites, reactive astrocytes, and microglia at the periphery.
-
Neurofibrillary Tangles:
- Elongated flame-shaped or basket weave pattern
- in hippocampus and amygdala
- intracellular bundles of filament in cytoplasm *encircle or displace nucleus
- may persist as ghosts after neurons death
- composed of paired helical filaments and hyperphosphorylated tau.
- ![[Pasted image 20240315133949.png]]
Note many histopathological techniques to pick up findings
Other Aspects in Alzheimer’s Disease
- Cerebral Amyloid Angiopathy: Intramural deposits of amyloid in small arterial vessels, sporadic or associated with Alzheimer’s disease
- results in hardening of vessel walls
- potentially leading to intracerebral bleeding, dementia, or epilepsy.
- cannot constrict to stop bleeding due to deposits in wall
- ![[Pasted image 20240315134019.png]]
-
Hirano Bodies and Granulovacuolar Degeneration:
- HB: elongated glassy eosinophilic, crystalline beaded bodies
- GVD of neurons
![[Pasted image 20240315134107.png]]
Changes in the Aging Brain
- Atrophy: Marked by decreased brain weight, shrinkage of gyri, expansion of sulci, and enlargement of ventricles.
- Including vascular changes, pigment accumulations (lipofuscin), loss of pigment (substantia nigra), and the presence of senile plaques, both neuritic and non-neuritic
Diagnosis
- Currently, an autopsy or brain biopsy is the only way to make a definitive diagnosis of AD.
- In clinical practice, the diagnosis is usually made on the basis of the history and findings on Mental Status Examination.
- Computerised tomography (CT) scans, magnetic resonance imaging (MRI), single photon emission computerised tomography (SPECT) and positron emission tomography (PET) to visualise the living brain.
- CT/MRI Brain are particularly important for ruling out potentially treatable causes of progressive cognitive decline, such as chronic subdural hematoma or normal-pressure hydrocephalus.
- Hippocampal atrophy can easily be seen on an MRI scan and is currently used to aid diagnosis of AD.
- Lumbar puncture: CSF levels of tau and phosphorylated tau are often elevated in AD, whereas amyloid levels are usually low. At present, however, routine measurement of CSF tau and amyloid is not recommended except in research settings.
PET/SPECT Scan
- PET-FDG (Positron emission tomography- 18F Fluorodeoxyglucose) scans are now available through the MBS for more accurate earlier diagnosis
- helps to differentiate between other diseases, and other dementias
- PET scans works by measuring the concentration of glucose in the brain to reveal how different parts of the brain are using energy.
- Single photon emission computed tomography (SPECT) image brain perfusion
PET scanning
- Glucose metabolism in the brain is altered in dementia and these changes can be visualised using FDG-PET scan.
- Recent research also suggests that FDG-PET can detect early brain changes before the emergence of dementia symptoms and predict progression to dementia.
Treatment
- The majority of patients with newly diagnosed Alzheimer’s disease should be offered a trial of cholinesterase inhibitor for symptomatic treatment of cognition and global functioning by improving communication between neurons.
- A number of drugs are currently available in Australia for use by people with AD. These drugs fall into two categories, cholinesterase inhibitors and a partial N - methyl-D-aspartate (NMDA) antagonist (Memantine).
- Psychotropic medications are often used to treat secondary symptoms of AD, such as depression, anxiety, agitation, and sleep disorders.
- They are considered symptomatic therapies and are not believed to be neuroprotective or to alter underlying disease course.
Cholinesterase inhibitors
- Acetylcholinesterase inhibitors (AChEIs) work by blocking the actions of an enzyme called acetylcholinesterase (AChE) which destroys an important neurotransmitter for memory called acetylcholine.
- It improves the availability of acetylcholine at the synapse.
- All currently approved AChEIs: 1. Donepezil, 2. Rivastigmine, 3. Galantamine
- And sometimes temporarily improve cognitive function.
NMDA antagonist
- Memantine is neuroprotective.
- Memantine targets a neurotransmitter, glutamate that is present in high levels in AD.
- Memantine blocks glutamate and prevents too much calcium moving into the neurons causing damage.
- This agent may be used alone or in combination with AChE inhibitors.
- Currently approved for treatment in Australia.
Duration of treatment
- There is no consensus on how long to continue cholinesterase inhibitors in patients who are tolerating therapy.
- Some clinicians, patients, and families choose to stop treatment after a six-month trial if there has been no subjective or objective improvement.
- Others feel that it is not possible to determine which patients are responders based on initial response and therefore suggest continuing medication as long as the patient agrees to it and tolerates it.
- Unless the medication is already at the lowest dose, it should be tapered by 50 percent for two to three weeks before stopping to minimize risk of worsening symptoms.
- What is Parkinsons, symptoms and treatment
Parkinson Disease Overview
- Nature: Progressive movement disorder affecting the extrapyramidal system, crucial for coordinating communication between the brain’s neurons and the body’s muscles.
- Key Areas Affected: *Substantia Nigra and Locus Ceruleus, characterized by the loss of dopaminergic neurons.
- Treatment Response: Positive response to dopamine replacement therapy (e.g., L-DOPA).
Clinical Features
- Lack of blink reflex, arm swing.
- Symptoms include tremor, rigidity, akinesia, and postural instability.
- In 10-15% of patients, cortical neurons are affected, leading to Lewy body dementia.
- Depression is a common symptom.
- Associated with diseases like Progressive Supranuclear Palsy, Corticobasal Degeneration, and Multiple System Atrophy.
- Note dementia is a secondary presentation
Epidemiology
- Prevalence ranges from 0.5 to 1% among individuals 65 to 69 years old, increasing to 1 to 3% among those 80 years and older.
- A minor proportion is familial, with autosomal dominant and autosomal recessive patterns.
- Environmental toxins and repeated head injuries can cause Parkinsonism by damaging neuronal pathways.
Parkinson Disease Pathology
- Midbrain Cross Sections: Left shows a pale substantia nigra compared to the right with normal melanin pigmentation.’
- ![[Pasted image 20240315134534.png]]
- Pons Cross Sections: Loss of pigmentation in the Locus ceruleus.
- ![[Pasted image 20240315134548.png]]
- ![[Pasted image 20240315134608.png]]
- Histopathology: Loss of pigmented catecholaminergic neurons and presence of Lewy bodies in remaining neurons (appear round to elongated cytoplasmic eosinophilic inclusions), composed of α-synuclein, parkin, ubiquitin, tightly packed.
- Lewy bodies are pathognomic for PD
- mitochondrial dysfunction may also play roles.
![[Pasted image 20240315134703.png]]
Mechanism: Basis of Dopamine Replacement Therapy
![[Pasted image 20240315134716.png]]
Restore to normal levels and enable normal movement i.e. to mitigate symptoms of Parkinson’s disease.
- What is ALS, sumptoms and treatment
- Nature: A neurodegenerative disorder involving the destruction and loss of upper and lower motor neurons, leading to denervation and atrophy of corresponding muscle fibers.
- Etiology: Over 90% of cases are sporadic with an unknown cause, with a speculated viral trigger. Incidence rate is 2 per 100,000. A minority of cases are hereditary, linked to mutations in genes such as SOD1, ALS2, NEFH, and VAPB. The SOD1 gene, which codes for superoxide dismutase, suggests that excess free radicals may contribute to neuronal cell death in ALS.
- Prognosis: ALS is universally fatal, typically due to respiratory compromise or infection, within 2-5 years of diagnosis.
Clinical Features
- Progressive loss of voluntary muscle contraction, and wasting/atrophy of affected muscles.
- Spontaneous muscle twitching of motor units (fasciculations).
- Difficulties in chewing, swallowing, and facial movements.
- Progressive physical disability, while mental functions and physical sensation remain intact.
Amyotrophic Lateral Sclerosis Pathology
![[Pasted image 20240315135144.png]]
- CNS Involvement: Motor neurons show shrinkage with lipofuscin pigment accumulation and presence of spheroids (focal neurofilament accumulations). Corticospinal tracts thin due to cortical motor neuron loss, while loss of fibres in the lateral columns leads to fibrillary gliosis imparting some firmness(lateral sclerosis). ^[astrocytes and their processes proliferate instead of fibroblasts. collagen is not laid normally as in normal scar]
- Peripheral Muscle Pathology: Denervation and atrophy of muscle fibers result in clinically noticeable muscle wasting (amyotrophy).
Differential Diagnosis
ALS should be distinguished from conditions like mass lesions, infections, exposure to toxins and drugs (e.g., lead poisoning), motor neuropathy with conduction block, paraneoplastic syndromes, and hyperthyroidism.
- What is Parkinson’s pathophysiology
Parkinson’s Disease: Effect of DA Loss
- Dopaminergic cells in the SNc are lost; striatum neurons eventually die, leading to disengagement of the direct pathway and default prevalence of the indirect pathway.
- Increased excitation and decreased inhibition of GPi result in enhanced inhibition of the thalamus, leading to hypokinesia i.e. difficulty starting motor program.
- Symptoms include tremor, rigidity, poor facial expression, and saccades.
- tremor and rigidity of both flexors and extensors not explained by hypokinesia
![[Pasted image 20240314140120.png]]
, diffesrs- What is MS symptoms and treatment
Presenting Features of MS
- Optic neuritis
- Sensory symptoms
- Motor deficit
- Cerebellar
- Brainstem (esp. diplopia)
- Transverse myelitis (motor, sensory or bladder)
- Fatigue
Diagnosis of MS
- At least 1 clinical episode
- Clinical episodes separated in time and place
- Ancillary tests used to prove asymptomatic episode
- MRI
- CSF
- Evoked Potentials looking for white matter tract issues
- Visual
- Somatosensory
- Brainstem
- Important to exclude other causes
Differential Diagnosis Of MS
- Other demyelinating disorders
- Acute disseminated encephalomyelitis (ADEM), Neuromyelitis optica (NMO)
- Autoimmune diseases
- Sjogren’s, SLE, Behcet’s, sarcoid, antiphospholipid
- Vascular disorders
- AV fistula, cavernomas, CNS vasculitis, CADASIL
- Infections
- HIV, Lyme disease, syphilis
- Metabolic disorders
- B12, leukodystrophies
- Genetic syndromes
- Mitochondrial, Spinocerebellar ataxias, hereditary spastic paraplegia
- Neoplasms
- CNS lymphoma, paraneoplastic syndromes, spinal cord tumours
- Others
- Conversion disorders, Chiari malformations, spondylosis
Treatment Aims
- Reduce relapses – immune modulatory and immune suppressant agents
- Prevent permanent disability
- Above agents
- Shorten symptoms from acute attacks
- Pulse methylprednisone – but no evidence it reduces long term disability
- Symptomatic treatment
- What is MS pathophysiology
Immunology of MS
- Unregulated immune system – genetic, Vit D, smoking, viral trigger (EBV) - resembles myelin
- Triggered attach on CNS myelin, with resultant plaque
- Repair with remyelination but risk of neuronal loss esp. with repeated insults
- Repeated insults to white matter and some cortical damage and atrophy
- Secondary neurodegeneration ? Oxidative stress
- Inflammation most an issue early in disease
- Why some get more atrophy and not always: correlated with white matter lesions
Evolution of demyelinating plaque
- immune engagement
- acute inflammatory damage
- repair
- post-inflammatory gliosis
- further remyelination limited by gliosis
Steps in Immune Activation
- Autoreactive myelin specific T helper cells (Th1 and Th17) normally controlled by regulatory T cells
- Failure of regulation when autoreactive T cells stimulated by antigens
- T cells express adhesion molecules to BB barrier and penetrate. Th1 secrete IFN gamma and Th17 secrete IL-17
- Activated T cells re-encounter myelin and activate microglia
- Microglia express class II molecules which further promotes T cells, microglia and PMN
- What is MG pathophysiology
- antibodies to post synaptoc nAChR
- target nAChRs of normal muscle cells
- competitive inhibiition of Ach
- nAChRs internalised and the complement system is activated leading to muscle cell lysis,
- impaired signal transduction via NMJ
- skeletal muscle weakness and fatigue
- What is Huntingotn pathophysiology
Huntington’s Disease Overview
- Genetics: Autosomal dominant condition linked to chromosome 4, involving the protein huntingtin and triplet nucleotide repeat expansion; exhibits anticipation.
- Characteristics: Progressive movement disorders and dementia due to degeneration of striatal neurons.
![[Pasted image 20240315134757.png]]
Clinical Features
- Insidious onset typically between 35 to 45 years of age.
- Symptoms include chorea, dementia, emotional/psychiatric symptoms, sometimes parkinsonian syndrome, and depression.
Huntington’s Disease Pathology
- Marked by atrophy of the caudate and putamen, alongside widespread (secondary) cerebral atrophy affecting the striatum and cerebral cortex.
![[Pasted image 20240315134817.png]]
### Diagnosis of Huntington’s Disease - Differentiation from other causes of chorea, dementia, and psychosis.
- Utilizes genetic testing for HD, MRI, and PET scans to confirm diagnosis.
Huntington’s Chorea
- Uncontrolled, abrupt, and jerky movements of distal muscles due to a chromosome 4 defect causing GABAergic cell death in the striatum.
- Early D2 MSNs and later D1 MSNs are affected, applying harder brakes to STN and reducing basal inhibition on the thalamus, leading to execution of otherwise suppressed motor behaviors.
- Results in dementia due to retrograde loss of cortical neurons as striatal targets die.
![[Pasted image 20240314140134.png]]
- Describe how to determine if ICP is elevated
Is there evidence of raised intracranial pressure?
- The hallmark of raised ICP, on history, is a headache worse on lying flat, (though this can also come from scalp tenderness or neck discomfort)
- Raised pressure may also compress the optic nerves, producing papilloedema, but this is a relatively late sign
- Papilloedema is often subtle, and requires careful examination by the most experienced doctor available. Absence of papilloedema is not proof of normal ICP.
- Describe how to derermine if meningism is present
Is there meningism?**
- ‘Meningism’ refers to a cluster of signs and symptoms indicating meningeal irritation or inflammation
- Neck rigidity is the hallmark
- Photophobia is common
- Pain may be increased with stretch of meninges
- Kernig’s sign (pain on straightening legs with hips flexed)
- Brudzinksi’s sign (active flexion of hips/knees on passive flexion of neck)
- Always a serious symptom, demands further investigation
- Important causes are:
- Subarachnoid blood
- Meningitis (bacterial, viral)
- Mild cases may be confused with migraine or cervicogenic headache
- What are the top three causes of reading difficulties and blindness?
Causes of reading difficulties
- macular degeneration (10%)
- glaucoma (3%)
- diabetic eye disease (2%)
Causes of blindness in all ages
- cataract (12%),
- glaucoma (14%)
- refractive error (4%)
- all other (11%)
- Define vision impairment and legal blindess
- Vision impairment is any diagnosed condition of the eye or visual system that cannot be corrected to within normal limits.
- Disease, damage or injury causing vision impairment can occur to any part of the visual system - the eye, the visual pathways, to the brain and/or visual cortex.
Severe vision impairment: 6/60 - 3/60 - otherwise known as legal blindness
Blindness fro 3/60 to 1/60
Blindness is 1/60 with light perception
Blindness with no light perception
- Define cataracts and its cubtypes
Cataract
- cataract is the most common eye disease
- increasing prevalence with age
- 70% Australians > 80 yrs have cataracts, or have had cataract surgery
Cataract – 3 of many different types
- ‘capsular’
- ‘cortical’
- ‘nuclear’
What is cataract?
Cataract is loss of lens transparency
Nuclear Cataract
- hardening of the core of the lens (hence ‘nuclear’ as in ‘nucleus’) that expands through the layers
- associated with yellowing/ ‘brunessence’ of the lens (due to accumulation of glutathione-3-hydroxy kynurenine glycoside)
- causes reduced transmittance of light (especially blue), increased scatter, and increased fluorescence. Things appear more reddish, and ‘blurry’.
- Associated with aging.
Cortical Cataract
- changes to lens proteins that start at the margin of the lens, and spread through the more superficial layers towards the optic axis
Capsular Cataract
- modification of the lens capsule, anteriorly or posteriorly
- often occur subsequent to eye surgery, or trauma
- Describe the pathogenesis of glaucoma and signs. Explain why it goes undetected
‘Glaucoma’ is a spectrum of related disorders characterized by progressive death of ganglion cells (GC) and axon loss (optic nerve).
It is an ‘anterior segment’ disorder that has its impact in the posterior segment, causing death of ganglion cells.
Strongly associated with increased intraocular pressure (IOP). However, about 50% of diagnosed glaucoma occurs in the absence of increased IOP
Pressure on the posterior aspect of the iris causes the iris to buckle, compressing the trabecular meshwork and restricting the drainage of aqueous. Alternatively, the trabecular meshwork and drainage network can become ‘clogged’ and restrict the passage of aqueous…this is open angle glaucoma
Increased IOP in the anterior segment is transferred posteriorly through the vitreous. Pressure distorts the sclera at the lamina cribrosa, compressing GC axons leading the GC death.
Mechanism of GC loss involves:
- Decline in the retrograde supply of neurotrophins to GC from their axon terminals
- Release of excitotoxic amino acids by damaged GC, 2-8 fold.
- Apoptotic cell death of GC
Note that it tends to affect peripheral vision so frequently not noticed until quite late
- Describe the pathophysiology of AMD and name its 2 subtypes
Multi-factorial disease characterized by the loss of central (macular) vision
Vision loss due to degeneration of the photoreceptors, specifically those in the macular region
The causes of this photoreceptor loss are not clear, but is associated with degeneration of the RPE and/or neovascularization of the outer retina.
Pathophysiology
Central 2 mm is the source of 25% of visual input to the brain – mostly from midget GC
If you lose macular vision you become legally blind.
Drusen / ‘white spots’ are one of the earliest signs of AMD
Area of cell loss, centered on the macula.
Principal cell types affected are light- sensitive photoreceptors, and their supporting pigmented epithelial cells.
Principal cell types affected are light- sensitive photoreceptors, and their supporting pigmented epithelial cells.
Two types: dry and wet
- Describe the pathophysiology of DR
- Progressive dysfunction of the retinal blood vessels caused by chronic hyperglycemia.
- DR can be a complication of diabetes type 1 or diabetes type 2.
- Initially, DR is asymptomatic, if not treated though it can cause low vision and blindness.
Microvascular occlusion is caused by:
- Thickening of capillary basement membranes
- Abnormal proliferation of capillary endothelium
- Increased platelet adhesion
- Increased blood viscosity
- Defective fibrinolysis
Microvascular leakage is caused by:
- Impairment of endothelial tight junctions
- Loss of pericytes
- Weakening of capillary walls
- Elevated levels of vascular endothelial growth factor (VEGF)
- Describe the pathophysiology and epidemiology of trachoma
- Most common infective cause of blindness
- Is still occurring in some remote areas in Australia, but has declined from 14% (2009) to 4% (2014)
- Approx. 4% of blindness worldwide
- Chlamydia trachomatis (serotype A-C)
- Chronic conjunctivitis
- Transmitted by flies or close contact
- Poor socio-economic communities; hygiene
Four key features
I. Follicular conjunctivitis – active repeated episodes over years
II. Tarsal conjunctival scarring
III. Trichiasis
IV. Corneal opacity
The bad news
Australia is the only developed country in the world to still have cases of trachoma.
(as per previous slide) rates in some Communities can be as high at 5% which is considered endemic levels.
Trachoma was eradicated from mainstream Australia 100 yrs ago.
In 1975 $1.4m was committed to the National Trachoma and Eye Health Program (under Fred Hollow’s Foundation).
The good news
Of 200 “at risk” Communities, 150 no longer have trachoma.
According to the National Indigenous Eye health Survey (NIEHS) and the National Eye Health Survey (NEHS) the level of blindness has decreased from 2.8% (2008) to 0.3% (2016).
2017 – Commonwealth Government committed $20.6m over 4yrs to support trachoma eradication targets.
- Describe the epidemiology and RFs, gnetics andmortality of schizophrenia
Prevalence of schizophrenia
- Point prevalence = 4.6 per 1000 persons
- Life-time prevalence = 4.0 per 1000 persons
- No gender difference in prevalence
- Poorer countries – lower prevalence, female excess
Incidence of schizophrenia
- Incidence = 0.16 – 0.42 per 1000 persons
- Males > females (1:1.4)
- Urban > non-urban or mixed environments
- Migrant > non-migrant
Mortality in schizophrenia
- Mortality rates 2-3 X higher than the general population
- On average people with schizophrenia die 12-15 years earlier than the general population
- Most of the excess deaths are from recognized medical disorders (esp. cardiovascular disease)
- Lifestyle factors
- Psychotropic medication
- Health care access and delivery issues e.g. due to positive and negative symptoms
Genetics – family studies & twin studies - greater risk if relative has: 1st degree 5-15% chance
- pattern of inheritance non-Mendelian: polygenic, interacting with themselves and with environment, other non-genetic factors involved (identical twin risk 50%)
- susceptibility genes: support that it is a neurodevelopmental disorder, a disorder of neuronal connectivity
Genetics – genome-wide association studies
- ZNF, first identified, and other loci
- miRNA - neuronal proliferation, synapse maturation, dendrite formation
Environmental factors in schizophrenia
- obstetric complications, maternal infection or malnutrition, city birth, late winter/spring birth
- What physical changes occur in brains of people with schizophrenia
Neurochemical findings in schizophrenia
- Abnormal dopaminergic neurotransmission (“hyperdopaminergic”)
- nigrostriatal: blocked = parkinsonism
- mesolimbic = blocked = reduction in delusions and hallucinations
- to cortex = cognitive side effects
- = hyperprolactinaemia
- Possible roles for glutamate, GABA, and serotonin
Dopamine hypothesis
- illicit drugs increasing dopamine
Glutamate in schizophrenia
- NMDA receptor antagonists
- Ketamine
- Decreased glutamate in CSF
- susceptibility genes
- Anti-NMDA receptor encephalitis
- What NTs play a role in schizophrenia and why
glutamate and dopamine
- Abnormal dopaminergic neurotransmission (“hyperdopaminergic”)
- nigrostriatal: blocked = parkinsonism
- mesolimbic = blocked = reduction in delusions and hallucinations
- to cortex = cognitive side effects
- = hyperprolactinaemia
- Possible roles for glutamate, GABA, and serotonin
- Compare and contrast dysphasia and dysarthria
dysphasia means a partial loss
Dysarthria
- Dysarthria is a motor impairment of the mouth, tongue, or pharynx, leading to slurred or poorly articulated speech.
- In a pure dysarthria, there is no problem with language processing or word selection. All the correct words are present in the patient’s speech but they are just less clearly pronounced.
- As with any motor impairment, the potential causes are:
- Diffuse CNS impairment (e.g., drunkenness)
- An upper motor neuron lesion (e.g., stroke)
- A cerebellar lesion (e.g., stroke)
- A lower motor neuron lesion (e.g., cranial nerve lesion, particularly VII and XII)
- A lesion of the neuromuscular junction (e.g., myasthenia gravis)
- A muscle lesion (very rare as a cause of dysarthria)
- A non-neuromuscular mechanical lesion (e.g., loose dentures, cleft palate)
Spastic Dysarthria vs Nonspastic Dysarthria
- The hallmark of any upper motor neuron is increased tone, increased effort in overcoming opposing muscles, and a mildly disturbed temporal pattern.
- The same features are found in a UMN lesion of the muscles of speech production.
- Spastic speech is slow, strained, with a longer time spent on some syllables than is usual; it looks effortful.
- The hallmark of a lower motor neuron lesion is wasting and weakness with little or no disturbance of temporal patterning.
- In an LMN dysarthria, speech proceeds with a normal rhythm but consonants are pronounced indistinctly; it resembles severe mumbling.
Cerebellar (Scanning) Dysarthria
- The hallmark of cerebellar motor impairment is that the motor components are put together awkwardly, with impaired temporal patterning, difficulty with rapid sequences (dysdiadochokinesis), and a failure to scale the effort of the movements accurately (dysmetria).
- The same features are found in cerebellar lesions affecting speech.
- Cerebellar speech has an irregular rhythm with some syllables slower and some faster than usual, and some too loud or too soft, and unexpected breaks within words or words joined. It may be difficult to distinguish from spastic dysarthria.
Total Anarthria vs Total Aphasia
- Both of these are associated with complete lack of speech, so how do you tell them apart?
- Distinguishing these can be very important for correct stroke management.
- Anarthria: difficulty moving the tongue or palate, difficulty swallowing, intact comprehension.
- Aphasia: deficits in comprehension.
- Associated deficits may point to the relevant brain region (anterior circulation vs posterior circulation).
- Milder deficits during the onset or recovery from anarthria/aphasia may be easier to distinguish than the deficits during the worst of the event.
- Compare and contrast expressive and receptive dysphasia
Broca’s Aphasia
- A common dysphasia, predominantly affecting expression.
- The hallmark is a delay or complete failure at the expression phase of language processing, which affects both expression of the patient’s own ideas as well as repetition.
- Impairment of the syntactical engine leads to preferential loss of syntactical words (“if”, “then”, “but”) and relative preservation of content words (“stroke”, “ambulance”, “cigarettes”). This is evident in spontaneous speech and in repetition tasks (“No ifs ands or buts”).
- Speech is slow, hesitant (non-fluent) and syntactically simple (“telegraphic”, as if written in an old-fashioned telegram where each word cost money). For instance: “Blood pressure… doctor give tablet”.
- The patient is usually frustrated.
- For these reasons, it is often called “Expressive Dysphasia”.
Broca’s Aphasia
- In a classic case of Broca’s Aphasia, comprehension is largely intact, but it is never completely intact.
- There are two main reasons why comprehension may be mildly impaired in what otherwise looks like a predominantly expressive Broca’s Aphasia:
- There may be some mild damage to Wernicke’s Area.
- The “syntactical engine” is likely to be damaged, so sentences requiring complex or non-standard parsing maybe misinterpreted. (“The lion was killed by the tiger. Which animal died?” Patients with Broca’s aphasia may simply perceive “Lion…killed…tiger”).
Wernicke’s Aphasia
- A reasonably common aphasia, but rarely a pure syndrome. (More often a mixed aphasia with dominant involvement of Wernicke’s Area.)
- The hallmark is impaired comprehension. Questions are not answered appropriately and complex commands are not carried out. In milder versions, with only partial damage to Wernicke’s, this may be the only obvious feature.
- Repetition is impossible in a complete case.
- For both of these reasons, Wernicke’s Aphasia is often called “Receptive Aphasia”.
- Because of the complex interdependence of Wernicke’s and Broca’s Areas, there are actually major impairments in expression, as well.
Wernicke’s Aphasia
- In true Wernicke’s Aphasia, there is lexical impairment, and a poor mapping of sounds to meanings, causing word-substitutions (paraphasias).
- There can be near-misses at the sound end of the mapping (literal or phonemic paraphasia - “pish” instead of “fish”) or at the meaning end of the mapping (verbal or semantic paraphasia - “clock” instead of “watch”).
- Broca’s area is working well, but its output is based on poor lexical information (garbage in, garbage out) and the patient cannot self-monitor speech, or comprehend the first half of a sentence while trying to express the second half.
- Patients often have anosognosia (unawareness of the deficit).
- Speech is thus fluent and grammatically normal, but is often empty, meaningless or littered with phonemic and semantic paraphasias. (“The dird went in the doctor, my tablet was in the page with the words, and he gop a headache”).
- What system is implicated in anxiety and mood disorders
Fight/Flight Response:
- Physical: Involves the autonomic nervous system – adrenaline and noradrenaline, leading to increased heart rate, redistribution of blood to vital areas, increased respiratory rate, sweating, widened pupils, decreased digestion, and muscle tension.
- Cognitive: Shifts attention to surroundings to search for threats. e.g. seen in PTSD
- Behavioral: Fight or flee; if unable to escape - behaviors like foot tapping, pacing, snapping at people may occur. Can sometimes be warning signs to an issue
Neurotransmitters in Anxiety Disorders:
- Noradrenaline: Produced in the locus coeruleus of the pons; cell bodies of noradrenergic system located here, its stimulation produces fear, while ablation prevents fear.
- projects to cortex, limbic system, brainstem and spinal cord
- Serotonin: Produced in the dorsal raphe nuclei of the brainstem (Cell bodies of system here); SSRIs are efficacious for anxiety reduction, but LSD (a serotonin agonist) is associated with anxiety.
- projects to cortex, limbic system, hypothalamus
- note: probably better understood as a neuromodulator
- Gamma-Aminobutyric Acid (GABA): GABA-A receptors are widely distributed through the CNS. Benzodiazepines increase chloride ion flow into cells, (net) reducing neuronal firing and (inverse agonists) significantly reducing anxiety.
Neurobiological Components:
- Fear conditioning involves the amygdala and the ventromedial prefrontal cortex (PFC).
- neural stimulus acquires the capacity to evoke fear
- hard to undo
- Extinction of fear is mediated by sections of the frontal cortex.
- subsequent learning allows the organism to no longer treat the conditioned stimulus as dangerous
- Attention orienting to threat involves the amygdala and ventrolateral PFC.
- threat in environment captures attention e.g. snake
- clinical anxiety is a perturbed attention to threat, and is involved with amygdala and ventrolateral PFC
Neurocircuitry of Anxiety:
- Involves mainly the frontal lobes and limbic system.
- Key circuits include the “Fear circuit” (amygdala, orbitofrontal cortex, and anterior cingulate cortex circuits) and the “Worry circuit” (arising from cortico-striato-thalamo-cortical circuit) ^[implicated in OCD].
Mood:
- Abnormal dopaminergic neurotransmission (“hyperdopaminergic”)
- nigrostriatal: blocked = parkinsonism
- mesolimbic = blocked = reduction in delusions and hallucinations
- to cortex = cognitive side effects
- = hyperprolactinaemia
- Possible roles for glutamate, GABA, and serotonin
- List some symptoms of NMJ disroders
- Muscle pain
- Weakness
- Cramp
- Fatigue
- Wasting
- Family History
- Note: Importance of absence of sensory Sx
- What are some NMJ disorder investigations
- Blood Tests
- CK ^[no strenuous exercise in week], Antibodies e.g. for autoimmune etiologies, TFTs e.g. for thyroid associated myopathies
- Genetic Studies - but limit of e.g. WGS is expecting certain variant to be useful
- Neurophysiology - EMG, NCS
- Muscle Biopsy - ‘forgiving’, but painful and not patient-friendly. Only useful if muscle is diseased and not dead. Can be open or core
- Imaging i.e. MRI of muscle, esp. to guide biopsy
In general limited.
Neurophysiological Ix of Weakness
- Repetitive Stimulation
- Decrement for MG
- Exclude neuropathy
- EMG – differentiate between neuropathic and myopathic features: observe wavelength and amplitude
- Myopathic EMG – small polyphasic potentials, may have spontaneous activity
- What is the basis of and symotoms for MG, L-E syndrome
- Compare and contrast MG and L-E
Myasthenia Gravis
- Autoimmune disease
- Antibodies to Acetylcholine Receptor (AChR)
- 2 age incidences
- Young= female dominated
- Older= less sex difference
- Prevalence 20 per 100,000, incidence 3-4 per million
Myasthenia - Pathogenesis
- Anti-AChR Abs
- Associated autoimmune diseases
- Infants of MG mothers have transient disease
- Response to immune mediated treatments
- B-cell mediated disease
- T-cells important as thymic abnormalities well recognized= probably primary T cell disease that evokes B response
- Abs are polyclonal IgG
- MUSK Abs in 10-20% of generalized disease
Myasthenia and Antibodies
- AChR Abs in 80-85% of generalized and 55% of ocular
- AChR –ve generalized disease, 70% are MUSK +ve
- AChR Abs
- Block Ach binding site
- Cross-linking of AChR on postsynaptic receptor
- C’ activation with destruction of postsynaptic receptor
- Muscle-specific tyrosine kinase (MUSK) reduces AChR clustering
Clinical Features of MG
- Ocular or generalised forms
- Ocular weakness- either ptosis or diplopia (high number of NMJs in the eye– greater eloquence of movement)
- Initial symptom in 2/3
- Limb weakness – generalised weakness
- Most often proximal muscles
- Can include bulbar muscles
- Exacerbating factors – intercurrent illnesses, esp. infection and drugs (A/Bs and anaesthetics)
- Myasthenic crisis – sudden respiratory failure
- Fluctuating weakness exacerbated by exercise and improved with rest – ‘fatigue’
Myasthenia - Investigations
- Antibodies
- +ve in 85% if generalised disease or 50% of ocular
- Neurophysiology
- Repetitive stimulation
- Single fibre study
- Pharmacology Testing
- edrophonium challenge - other agents used these days. Inhibit AChase to reverse presenting symptoms
- Imaging
- chest CT for thymoma or hyperplasia - identify a red flag
Myasthenia Gravis - Treatment
- No good RCT’s available
- Broad symptom management approach
- Cholinesterase Inhibitors – pyridostigmine
- Corticosteroids but long-term side effects
- Azathioprine
- Plasmapheresis – esp. if myasthenic crisis (resp weakness)
- IVIG – useful in acute setting
- Thymectomy – esp. if thymic hyperplasia
- Other immunosuppressants, eg mycophenylate, rituximab (CD20)
Lambert Eaton myasthenic Syndrome
- Antibodies against presynaptic voltage calcium gated channel
- SCLC in 50-60% i.e. paraneoplastic
- Generalised weakness
- Ocular involvement less common
- Reflexes depressed but increase with reinforcement
- Augmentation on repetitive stimulation esp. at high frequency or post-contraction
- Rx 3,4 diaminopyridine
- What happens in transverse cord lesion, hemicord, central cord, anterior cord syndromes
Complete transaction of the spinal cord
- Combination of LMN injury at the level of the cord lesion and UMN injury below the level of cord lesion
- Complete loss of sensation and motor function below the level of the lesion
- Bilateral LMN paralysis and muscular atrophy in the segment of the lesion
- Bilateral spastic paralysis below the level of the lesion
- Bilateral loss of all sensation below the level of the lesion (Because of the lateral and anterior spinothalamic tracts cross obliquely, the loss of thermal and light touch sensation occurs two or three segments below the lesion distally)
- Loss of bowel and bladder function due to loss of descending autonomic fibres
- Lesions below the cord at L2-L3 level - Cauda equina lesion - LMN, autonomic and sensory fibers are involved
Anterior cord syndrome
- Fracture, Anterior spinal artery involvement (e.g. stroke)
- Bilateral LMN paralysis in the segment of the lesion and muscular atrophy
- Bilateral spastic paralysis below the level of the lesion
- Bilateral loss of pain, temperature and light touch sensation below the level of the lesion
- Tactile discrimination, vibratory and proprioceptive sensation are preserved
Central Cord Syndrome
- Hyperextension injury to the spine
- “Sacral Sparing”, with bilateral spastic paralysis below the level of the lesion - lower limb fibres or less affected than the upper limb fibres, because of the lamination of the descending fibres in the lateral corticospinal tracts
- Bilateral loss of pain, temperature, light, touch and pressure sensations below the level of the lesion with characteristic “Sacral Sparing” due to the laminated arrangement of the ascending fibres in the lateral and anterior spinothalamic tract
- The sparing of the lower part of the body is noted by the presence of peri-anal sensation, good anal tone, and ability to move the toes distally
Brown-Sequard syndrome
- Hemi-section of the cord
- Trauma
- Ipsilateral LMN paralysis in the segment of the lesion and muscle atrophy
- Ipsilateral spastic paralysis below the level of the lesion
- Ipsilateral band of loss of sensation in the segment of the lesion
- Ipsilateral loss of tactile discrimination and vibration & proprioceptive sensation below the level of the lesion
- Contralateral loss of pain and temperature sensation below the level of the lesion (since the lateral spinothalamic tract crosses obliquely, the sensory loss occurs two or three segments below the lesion distally)
- Contralateral BUT not complete loss of tactile sensation below the level of the lesion (because tactile information travels through both tracts, and is thus preserved)
- What are mirror neurons?
- Premotor cortex contains mirror motor neurons
- which appear to ‘read’ the intentions of others and are important for learning new motor skills by imitation.
- Lesions impair the ability to perform visually/verbally cued motor tasks despite the capability to perform the movement in another context
- This area is also active during the imagination of motor tasks (possible involvement of mirror neurons).
- Describe the biopsychosocial model
Describes pain as
multidefensional, and involves nociceptive (identificaiton and localisation of pain), nocifensive, emotional/affective and cognitive pathways that interact and influence each other to produce the phenomenon of pain
- Multidimensional response requires multiple brain regions!!
- This include but are not limited to sensory/motor/multisensory regions (somatosensoty, motor cortex, thalamus), pain affect/cognitive control (anterior cingulate cortex and prefrontal cortex, insular cortex), emotion (amygdala and hippocampus), descending modulation (PAG, locus coeruleus)
- What are some syndromes or disorders with psychosis
Broad categories of “psychosis”
1. Primary psychiatric disorder eg schizophrenia
2. Medical disorder
3. Substance/alcohol/medication related
Medical conditions which may be associated with psychosis
Neurological
- Dementia (esp. Lewy Body Dementia)
- Cerebrovascular disease
- Epilepsy (esp. complex partial seizures), peri- and post-ictal psychosis ^[DO NOT treat with anti-psychotics typically]
- Huntington’s Disease
- Wilson’s Disease
Endocrine:
- hyper and hypo para/thyroidism
- Cushing’s disease
Autoimmune:
- cerebral lupus
Toxicological:
- lead and mercury poisoning
Nutritional:
- B6 def
Trauma:
- TBI
Substances of abuse which may be associated with psychotic features
- Amphetamines
- LSD
- Phencyclidine
- MDMA (Ecstasy)
- Cocaine
- Other
Can persist post-intoxication.
Medications
- corticosteroids
- dopamine agonists
- L-DOPA
- SSRI/SNRI
- tricyclic
- anti-epileptics
- statins
Core primary psychiatric conditions associated with psychosis
- Schizophrenia and related disorders
- Delusional disorder
- Brief psychotic disorder
- Mood disorders with psychotic features
- DESCRIBE lesions o MLF
The medial longitudinal fasciculus (MLF) is a myelinated composite fiber tract found in the brainstem. The MLF primarily serves to coordinate the conjugate movement of the eyes and associated head and neck movements.
Containing both ascending and descending fiber tracts, the MLF is found on each side of the brainstem near the midline, ventral to the periaqueductal grey matter, and ascends to the interstitial nucleus (of Cajal) 1.
The MLF links the nuclei of the vestibulocochlear nerve (CN VIII) and the three primary nerves controlling the movements of the eye:
oculomotor nerve (CN III): oculomotor nucleus trochlear nerve (CN IV): trochlear nucleus abducens nerve (CN VI): abducens nucleus
Ascending fibers are contributed to by the four vestibular nuclei. Descending axons from the medial vestibular nuclei partially decussate and continue as the medial vestibulospinal tract at the level of the spinal cord. The dorsal trapezoid, posterior commissural and lateral lemniscal nuclei all contribute fibers, thereby linking both vestibular and cochlear nuclei of CN VIII to the MLF.
The MLF integrates the information received about the movement of the eyes and the movement of the head and plays a central role in the optokinetic and vestibulo-ocular reflexes. Fibers within the fasciculus connect the abducens nucleus with the contralateral oculomotor nucleus allowing horizontal conjugate lateral gaze and saccadic eye movements. Fibers are also carried from the vestibular nuclei to integrate with the oculomotor and trochlear nuclei, which serve to influence eye movements during movement of the head and neck
Internuclear ophthalmoplegia (INO) describes a clinical syndrome of impaired adduction in one eye with dissociated horizontal nystagmus of the other abducting eye, due to a lesion in the medial longitudinal fasciculus (MLF) ipsilateral to the eye unable to adduct. It is a common finding in multiple sclerosis
Clinical presentation
Patients present with impaired adduction in one eye (ipsilateral to MLF lesion) with dissociated horizontal nystagmus of the other abducting eye 1-3. In addition to these classic features:
convergence may be preserved, with lesions below the level of the CN III nucleus (posterior INO of Cogan) having preserved convergence while lesions at the level of the CN III nucleus (anterior INO of Cogan) having impaired convergence 10
may have vertical eye movement anomalies (due to rostral interstitial MLF involvement): ipsilateral hypertropic skew deviation, reduced vertical gaze holding, convergence-retraction nystagmus 11
With more extensive brainstem involvement, ‘INO plus’ syndromes may also be present:
one-and-a-half syndrome: INO combined with a conjugate gaze paralysis in the other direction such that one eye fails to adduct on attempted lateral gaze (the ‘half’) and may have dissociated horizontal nystagmus on abduction, while the other eye neither adducts nor abducts (the ‘one’)
- List all the neuron cell types, their histological features and functions
Cells of the Central Nervous System
- Neurons: Functional component (conduct impulses)
- Glial Cells: Support and protect neurons. Main types:
- Astrocytes: Provide metabolic support to neurons, form the blood-brain barrier, and are important for repair and scarring of nervous tissue.
- Oligodendrocytes: Produce myelin surrounding the neurons in white matter.
- Ependymal Cells: Line ventricles and may have both secretory and absorptive functions. Modified ependymal cells form the choroid plexus and produce CSF.
- Microglia: Macrophages in the CNS.
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All but microglia can cause glioma, because microglia is of macrophage/HSC lineage.
- Describe naming of neural tumours
-oma
- Where is an adult vs child neoplasm expected to be found
- adult: astrocytoma, glioblastima, oligodendroglioma= glioma, less ependymoma, neurocytoma
- child:ependymoma, choroid plexus papilloma, pilocytic astrocytoma
- What are simple characteristics of CNS neoplasms and describe some characteristics of two neoplasms
Characteristics of Neoplasms in CNS
- The distinction between benign and malignant neoplasms is less distinct in the CNS because either are space-occupying lesions, which is the real source of agony with CNS neoplasms, impinging on normal CNS parenchyma
- however it does have significance re: surgical prognosis
- Most malignancies of the CNS do not metastasize outside of the CNS.
- The subarachnoid space and the CSF provide a pathway for seeding of neoplasms that reach the CSF pathway.
Why are brain tumours bad?
- Even a “benign tumour” can have severe consequences if in an unresectable or vital location.
- Tumours don’t have to metastasise to kill – affect vital structures
- may be unresectble
- surgery is a balance of consequence to patient vs benefits of debulking
- often diffuse or multifocal, difficult to resect with good margins
- good margin will involve removing vital tissues, with bad consequences
- BBB: therapeutic consequences
—
Astrocytoma
- 80% of adult primary brain tumors
- Usually found in cerebral hemispheres
- Most often in 4th - 6th decades
- Presenting signs and symptoms:
- Seizures
- Headaches
- Focal neurologic deficits related to the anatomic site of involvement
- - Grade 2 astrocytoma: Increase cellularity but no pleomorphism, mitosis, or necrosis
- Grade 3 astrocytoma: Increase cellularity, pleomorphism, and mitosis
- H+E: x200
- H+E: x400
- Grade 4 (either astrocytoma, IDH-mutant grade 4, or glioblastoma, IDH-wildtype): Marked pleomorphism, microvascular proliferation &/or pseudopalisading necrosis
Oligodendroglioma
- Frequency: 5% to 15% of gliomas
- Age Group: Most common in the 4th to 5th decades
- Symptoms: Several years of neurological complaints, often including seizures
- Location: Mostly in cerebral hemispheres, with a predilection for white matter
- Growth Pattern: Typically slow-growing
- Unique Features:
- Calcification due to slow growth
- Delicate ‘Chicken wire’ vessels
- ‘Fried egg’ appearance to cells
- Round nuclei
- Perinuclear halo
- Images:
- Chicken wire vessel pattern:
- - Fried egg appearance:
- What are some symptoms of brain tumours
- astro: headache, seizures, focal deficits
- oligo: several years of neuro complaints including seizures
- epend: obstruction of CSF flow
- choroid: hydrocephalus
- gnaglio: indolent/protracted partial complex epilepsy
- medullo: truncal ataxia, headache, CSF obstruction
- What histological signs indicate stage 2-4 neoplasm ie for astrocytoma
In general higher grade means poorer differentiation and prognosis.
- Grade I tumors: Circumscribed (encapsulated or not) and exhibit mild increase in cellularity
- Grade II tumors: Moderate increase in cellularity, but their margins are poorly-defined or diffuse
- Grade III tumors: Increased cellularity, moderate cellular pleomorphism, and mitosis
- Grade IV tumors: Marked pleomorphism and show microvascular proliferation and/or pseudopalisading necrosis
Source
WHO Grading ^[applicable to all tumours]
- Gd 1: Low proliferation, possibility of cure following LR; grade stable
- Gd 2: High cellularity, recur as infiltrative; may be grade unstable, i.e., progression
- Gd 3: More aggressive recurrence with shorter time to demise; often require adjuvant chemoradiation
- Gd 4: Aggressive, high proliferation, rapid growth, usually fatal outcome – some tumors may still be curable with aggressive treatment
- Grade 2 astrocytoma: Increase cellularity but no pleomorphism, mitosis, or necrosis
-
Grade 3 astrocytoma: Increase cellularity, pleomorphism, and mitosis
- H+E: x200
- H+E: x400
- Grade 4 (either astrocytoma, IDH-mutant grade 4, or glioblastoma, IDH-wildtype): Marked pleomorphism, microvascular proliferation &/or pseudopalisading necrosis
- Identify most common tumours for different regions of the brain
Primary Neoplasms of CNS
- Neurons: Neurocytoma, gangliocytoma (very rare)
- Astrocytes: Astrocytoma
- Oligodendrocytes: Oligodendroglioma
- Ependymal cells: Ependymoma
- Choroid plexus: Papilloma, carcinoma
- Meningothelial cells: Meningioma
- Epithelial cells: Pituitary adenoma, craniopharyngeoma
- Pineocytes: Pineocytoma, pineoblastoma
- Lymphocytes: Lymphoma
- Schwann cells: Schwannoma
- Pediatric undifferentiated neoplasms: Medulloblastoma
Primary Brain Tumors: Glioma
- Astrocytoma
- Oligodendroglioma
- Ependymoma
Neuronal Tumors
- Types: Gangliocytoma, Ganglioglioma, Neurocytoma
Other Parenchymal Tumors
- Include: Primary CNS Lymphoma, Germ Cell Tumors, Schwannoma, Metastatic Tumors
- Primary CNS lymphoma: 2% of extranodal lymphomas and 1% intracranial tumours – most common in CNS neoplasm in immunosuppressed e.g. AIDS and post transplantation. no need for debulking. Use chemotherapeutic agent
- GC tumours occur along midline mostly pinear and suprasellar regions, tumour of young: 90% in first two decasdes; 0.2-1% in Europeans, 10% in Japanese
- Meningioma: 20% of primary intracranial tumors, age 40-70 years, more common in females, especially in the spine. Usually attached to dura
- arises from meningothelial cells of arachnoid granulations
- extra axial
- slow growing
- WHO grade a strong predictor of clinical course, typically low grade
- prognosis depends on size and completeness of resection
- macro: firm and rubbery (due to connective tissue)
- micro: whorls of meningothelial cells, psammomma bodies (calcified)
- Schwannoma: 8% of intracranial and 29% of intraspinal tumors, common in 4th-6th decade, associated with NF-2; arises from spinal and cranial nerves esp. 8th i.e. acoustic neuroma, slow growing and rarely malignant; NF-2 (Schwannomatosis = bilateral acoustic neuromas and meningiomas)
- Metastatic Tumors: Mostly carcinomas, 25-50% of intracranial tumors, meninges a frequent site of involvement by metastatic disease; 80%/common sites of origin include lung, breast, skin (melanoma), kidney, and GI tract
- metastatic tumours may be first manifestation of cancer
- some metastases can present with intracranial haemorrhage e.g. melanoma and RCC
- Define the following: ; first pass clearance; absorption and bioavailability; first pass clearance; metabolism
What is first pass metabolism?
- Orally administered drugs that are absorbed travel through the portal system and the liver before entering systemic circulation
- If a percentage of the drug is metabolised by the liver only the remainder of that drug will be able to enter systemic circulation to exert its effect (reduced bioavailability)
- requires a larger dose orally than parenterally
Metabolism
- The process of chemical modification of a drug
- Mainly via enzymes
- Liver primary site of metabolism
- other sites include: kidneys, lungs, intestines
- For the majority of drugs metabolism results in the formation of a more water-soluble compound or metabolite that can be more readily excreted
- clears the parent compound from circulation and promotes excretion
Prodrug - drugs that require activation (metabolism) to elicit a therapeutic action
**CYP enzymes
- CYP enzymes responsible for Phase 1 (functionalisation) metabolism
- CYP enzymes found in the smooth endoplasmic reticulum
- Abundant in hepatocytes
- More than 50 varieties. Three main families
- Genetic polymorphisms occur altering clearance of particular medications
- Responsible for many drug interactions
- Liver disease can effect the performance of these enzymes
Hepatic clearance
- Depends on hepatic blood flow (Q) and extraction ratio (EH)
- Hepatic extraction ratio (EH):
- the fraction of drug entering the liver in the blood that is irreversibly removed by metabolism on each pass through the liver. (0.7 = 70% removed)
- Hepatic clearance (Cl)= Q. EH
- Hepatic clearance can be:
- low extraction:
- clearance capacity by limited by liver enzymes to clear drug (clearance is independent of blood flow)
- high extraction
- clearance capacity limited by delivery of drug to the liver (blood flow)
- low extraction:
Absorption
Before a drug can be distributed to its site of action it must be absorbed
Drugs need to be able to cross biological membrane(s) to reach systemic circulation.
Lipid soluble drugs readily pass through lipid membranes Ionised drugs have difficulty crossing cell membranes Aquaporins in cell membranes allow the passage of small uncharged water soluble substances
Passive diffusion and carrier-mediated transport allow movement of drugs through the body
Variables that affect drug absorption:
Blood flow
Rich blood supply enhances absorption
Solubility
A drug must be in solution to be absorbed
Ionisation
Many drugs are weak acids or bases
Ionised form does not diffuse readily through cell membranes; unionised form is usually more lipid soluble and more capable of crossing cell membranes (Extent of ionisation is dependent on the pH of the environment)
Formulation
Drug formulations can be manipulated to achieve desirable absorption characteristics (eg slow release or enteric formulations)
Route of administration can affect both onset and magnitude of drug action.
A drug can enter systemic circulation by being injected there (IV) or absorbed from extravascular sites
Distribution
The process of reversible transfer of a drug between one location and another (one is usually blood) in the body. After a drug enters systemic circulation it can be distributed to various compartments of the body.
Some drugs remain exclusively in the blood
Distribution will depend on
Permeability across tissue barriers
Binding within the compartments
pH partitioning
Fat:water partitioning
- Provide examples of drugs on each ladder of analgesia
These classes of medications are used for pain and inflammation.
They appear on the first step of the WHO ladder and are considered ‘simple analgesia’. When used with paracetamol a lower dose is required of the NSAID is required.
They are a mainstay of analgesic therapy, but because of their mechanism of action do have side effects and precautions that must be considered before prescribing.
The COX enzymes
COX-1
Expressed in most tissue
Also found in blood platelets
Primarily involved in tissue homeostasis
Responsible for production of prostaglandins involved in:
Gastric cytoprotection Platelet aggregation Renal blood flow autoregulation Initiation of parturition
COX-2
Induced in many inflammatory cells
Responsible for prostinoid mediators of inflammation
Activated by:
Inflammatory cytokines Interleukin-1 Tumour necrosis factor-⍺ Antipyretic effects: Temperature balance is regulated by hypothalamus, NSAIDs rest this control returning it to normal point when fever is present Do not alter normal temperature Achieved by inhibition of prostaglandin production in the hypothalamus
Analgesic effects:
Used for mild to moderate pain caused my inflammation or tissue damage
Peripherally ↓ prostaglandin production that sensitise receptors to inflammatory mediators
Paracetamol (acetaminophen):
First line therapy in most pain managment strategies (first rung on the WHO ladder)
Mechanism of action is not fully understood
Inhibition of central prostaglandin synthesis
Paracetamol has negligible anti-inflammatory effects.
Does not have gastric or platelet adverse effects associated with NSAIDs
Although generally less effective than NSAIDs for musculoskeletal pain, its favourable safety profile in therapeutic doses justifies a trial of paracetamol first line for mild to moderate pain in most indications.
Often reduces doses needed of other agents (NSAID and opiod sparing)
Paracetamol may also be used to reduce the use of NSAIDs and thus the risk of NSAID adverse effects.
Indications:
Mild-to-moderate pain Fever Adjunct to moderate-severe pain
Adverse Effects:
Uncommon Occasionally skin reactions Opioids Considered 'strong' analgesics and occupy the top rung of the WHO ladder An opioid is any substance that produces morphine like effects All receptors are G protein coupled receptors There are many opioid receptors but the mu receptor is the one MOST responsible for analgesia and all opioids act on this receptor (but many act on others too - which mostly contribute to the side effect profile)
Opioids promote opening of potassium channels and inhibit opening of voltage-gated calcium channels
↓ neuronal excitability ↓ transmitter release Inhibition at a cellular level
Majority of receptors located in the brain and spinal cord
OPIOIDS HAVE VERY LIMITED ROLE IN MUSCULOSKELETAL CONDITIONS
- Compare and contrast COX-2 vs NSAIDs
Antipyretic effects:
Temperature balance is regulated by hypothalamus, NSAIDs rest this control returning it to normal point when fever is present Do not alter normal temperature Achieved by inhibition of prostaglandin production in the hypothalamus
Analgesic effects:
Used for mild to moderate pain caused my inflammation or tissue damage Peripherally ↓ prostaglandin production that sensitise receptors to inflammatory mediators
The NSAIDs and COX-2 inhibitors in practice
No particular agent has been shown to be more effective than any other in pain and inflammation
If a patient does not respond to the first NSAID trialled, generally one or two other NSAIDs should be trialled before confirming non-response to NSAIDs.
Monitor response and do not continue if there is no benefit after trial of different NSAIDs
Topical NSAIDs are commonly used for the treatment of local musculoskeletal conditions
minimal systemic absorption –> safer than oral NSAIDs;
Only be useful for superficial sources of musculoskeletal pain.
Co-prescribing with paracetamol enables lower doses of NSAIDs
Use a PPI for patients on an NSAID who cannot stop therapy but are at risk of GI adverse effects
- Describ ledopa, moa-b, comt
Dopamine
Neurotransmitter
Precursor of noradrenaline
Once released it is recaptured by a dopamine transporter at nerve terminals and metabolised by monoamine oxidase (MOA) and catechol-O-methyltransferase (COMT)
Acts both pre and post-synaptically
Levodopa
Levodopa enters the brain and is converted to dopamine. It is broken down in the periphery bydopa decarboxylase and catechol - O - methyltransferase (COMT).
Indications
- Parkinsons Disease
Clincal benefits:
- There is significant benefit and less adverse effects compared with dopamine receptor agonists(particularly in patients over 70 years)
- Over time the effectiveness declines.
- Whilst motor function is improved with levodopa other symptoms such as dysphasia and cognitive decline are not improved.
Unwanted effects:
- involuntary movements (dyskinesia) develop over time.
- ‘on-off’ effect: probably related to the fluctuating plasma levels. Bradykinesia and rigidity will suddenly worsen and then improve (with varying time windows).
- Nausea and vomiting (treated with domperidone which is a dopamine antagonist that works in the chemoreceptor trigger zone but does not access the basal ganglia)
- psychological effects - schizophrenia like syndrome (due to increased dopamine activity in the brain) with hallucinations, confusion, insomnia and nightmares.
- postural hypotension especially in elderly patients.
Note: only available as combination with dopa decarboxylase inhibitor, and sometimes also a COMT, to prevent peripheral conversion to dopamine and therefore also reduce peripheral dopamine adverse effects e.g. nausea, vomiting, hypotension.
Peripherally acting dopa decarboxylase inhibitors e.g. cabidopa reduce the required dose of levodopa and reduce peripheral side effects, but they do not cross BBB, and therefore can’t have an effect once levo is in the brain.
The peripherally acting inhibitors prevent its breakdown by other enzymes e.g. COMT, MAO-B.
Pramipexole, rotigatine and apomorphine (non-ergot derivatives) bromocriptine and cabergoline
Agonists at dopamine receptors.
Indications:
- Parkinsons Disease (as monotherapy or in combination with levodopa)
- Some are also indicated for restless leg syndrome
Clincal benefits:
Pramipexol is a non-ergot derivative dopamine agonist that is D2 and D3 selective, better tolerated and less fluctuations than levodopa. Does cause somnolence, hallucinations and compulsive behaviours.
Improve bradykinesia and rigidity but less effective than levodopa, with more confusion and hallucinations (especially in the elderly and at high doses)
May be used as monotherapy in early disease (preferred in younger patients) but long term monotherapy is limited due to adverse effects such as impulse control disorders.
Unwanted effects:
- Nausea and vomiting (treated with domperidone which is a dopamine antagonist that works in the chemoreceptor trigger zone but does not access the basal ganglia) and other GI upset
- Impulse control disorders are common and can occur at any time during treatment
- psychiatriceffects - schizophrenia like syndromewith hallucinations, confusion, insomnia and nightmares.
- Withdrawal syndrome - need to very slowly taper if stopping treatment
Note:
- Useful if PD is severe or if patients can’t or don’t want to swallow to have different modes of possible administration
- topical e.g. patch for rotigatine
- subcutaneous e.g. apomorphine, highly emetogenic, requires pretreatment with dopa antagonist that does not cross BBB
Monoamine oxidase type B inhibitors - inhibit the breakdown of dopamine
_Rasagiline, selegiline, safinamide_
Irreversibly inhibit monoamine oxidase typeB (MAO‑B); they reduce breakdown of dopamine and may also block dopamine reuptake.
Indications
- Parkinson’s Disease
Clinical benefits
- When used with levodopa, MAO‑B inhibitors may increase dopaminergic adverse effects (eg dyskinesia, hallucinations, nausea, vomiting)
- Often used as an adjunct to levodopa.
Unwanted effects:
Hypotension, dyskinesia, headache, insomnia, vomiting, arthralgia
Non-selective MOAI are used to treat depression an havemore adverse effects.
COMT Inhibitors - inhibits the breakdown of levodopa
_Enatacapone_
Inhibits catechol-O‑methyltransferase (COMT), mainly in peripheral tissues; increases the amount of levodopa available to the brain and prolongs the clinical response to levodopa.
Indications:
- Parkinson’s disease as an adjunct to levodopa in patients with motor fluctuations
Clinical benefit
- increases the amount of levodopa available to the brain and prolongs the clinical response to levodopa.
Unwanted effects
- discoloured urine (reddish-brown, nausea, vomiting, dry mouth, diarrhoea, abdominal pain, constipation, hallucination, confusion, paranoia, dyskinesia,skin, hair or nail discolouration, rash, increase in liver enzymes, hepatitis, colitis
Amantadine
Increases dopamine release and blocks cholinergic receptors; acts as a N‑methyl-D‑aspartate (NMDA) antagonist in the glutamatergic pathway from subthalamic nucleus to globus pallidus.
An antiviral drug that treats some influenza (more in block 6)
Indications:
- Parkinson’s Disease
- Influenza (limited use)
Clinical benefit
- It is less effective than other treatments, however can reduce dyskinesias induced by levodopa
Unwanted effects:
- nervousness, depression, nightmares, hallucinations, insomnia, hypotension, blurred vision, peripheral oedema, dry mouth, GIT
- There are reports ofimpulse control disordersassociated with amantadine
- Explain why codeine is no longer prescribed
Codeine can cause opioid tolerance, dependence, addiction, poisoning and in high doses, death.
- Compare and contrast opioids on the basis of pharmacokinetics
Choice and dosing of opioids usually depends on the PK/PD considerations can you think of how some PK/PD considerations influence the choice and dosing of an opioid?
PK considerations
PD considerations
Absorption
If the patient has acute pain and cannot tolerate oral medications they may need an injection eg intravenous (quick and 100% bioavailable) so would need to chose an opioid that can be given IV
Specific target receptor activity
Some opioids have activity on other receptros such as serotonin. If a patient is taking a medication that is already active at that receptor one might want to aviod an opioid with that activity
Distribution
An opioid which is more lipid soluble (higher Vd) will more readily cross the BBB and therefore have a faster onset of action.
Tolerance
If a patient is usually on an opioid and they present with acute pain they will need a higher dose of the acute opioid due to the receptos being chronically occupied.
Metabolism
Most opioids are metabolised by CYP enzymes into either active or inactive metabolites. Codeine is a pro-drug that is metabolised to morphine - if a patient cannot metabolise the codeine they will not get the analgesic effect
Excretion
If a patient has renal impairment one would want to avoid an opioid that was cleared by the kidneys.
- Describe NSAIDs: examples, MoA, indications, side effects, contraindications etc
NSAIDs inhibit COX1, 2
The COX enzymes
COX-1
Expressed in most tissue
Also found in blood platelets
Primarily involved in tissue homeostasis
Responsible for production of prostaglandins involved in:
Gastric cytoprotection
Platelet aggregation
Renal blood flow autoregulation
Initiation of parturition
COX-2
Induced in many inflammatory cells
Responsible for prostinoid mediators of inflammation
Activated by:
Inflammatory cytokines
Interleukin-1
Tumour necrosis factor-⍺
Antipyretic effects: Temperature balance is regulated by hypothalamus, NSAIDs rest this control returning it to normal point when fever is present Do not alter normal temperature Achieved by inhibition of prostaglandin production in the hypothalamus
Analgesic effects:
Used for mild to moderate pain caused my inflammation or tissue damage
Peripherally ↓ prostaglandin production that sensitise receptors to inflammatory mediators
Side effects:
All NSAIDs and COX-2 inhibitors have side effects that relate the cardiovascular, gastrointestinal and renal systems.
Knowing the effects of COX - Have a go at describing the adverse effects of NSAIDs and COX-2 inhibitors
SYSTEM
ADVERSE EFFECTS
Cardiovascular
Rise in blood pressure, fluid retention, myocardial infarct, stroke (caution advised for patients with cardiovascular disease)
Gastrointestinal
**
Upper abdominal pain, gastric erosions, peptic ulcers, oesophageal ulcers, GI bleeding, perforation. (Relative risk varies between different NSAIDs and is dose related). Selective COX-2 have less (but not none) GI complications. If a NSAID must be used and there is concern about GI bleed a proton pump inhibitor (PPI) may be co-prescribed to prevent (or atleast reduce the risk) of GI complications.
Of the NSAIDs, Diclofenac and Ibuprofen appear to have the lowest risk of GI complications (and are commonly used in practice)
**
Renal
**
Renal impairment (risk is increased in elderly, perioperatively, pre-existing renal disease and coadministration with ACEI and diuretics (triple whammy) or co-administration with other nephrotoxic medications should be considered before prescribing.
**
Some of the other side effects that are common to both classes are skin and lung side effects.
Skin
Erythematous reactions
Urticaria
Photosensitivity
Stevens-Johnson Syndrome (rare)
Lungs
Aspirin-sensitive asthma (5% of asthmatics)
Bronchospasm (does not occur with coxibs)
Liver
NSAIDs should NOT be prescribed to patients with severe hepatic impairment!!
-Triple whammy
- Describe opioid antagonists: name, MoA, side effects, indications, contraindications etc
Opioid ANTAGONISTS
There are TWO opioid antagonists that are used in clinical practice.
Naloxone (via injection)- used for reversal of opioids particularly in opioid overdose
Naltexone (oral) - used for chronic managment of alcohol and opioid dependence
Naloxone
Naltrexone
Mechanism of action
Pure opioid antagonist
(competetive antagonist)
Rapidly reverses effects of opioids
Short acting (<1 hour), shorter than the duration of the opioid and therefore repeated doses (or continuous infusion) may be required.
Given intravenous or intramuscularly
Not absorbed orally
Reversibly blocks opioid receptors (for 24–72 hours), preventing opioid effects, eg euphoria. Reduces craving for alcohol and possibly reduces some of the pleasurable effects, by blocking the effects of endogenous opioids Given orally
Indication
Opioid overdose or intoxication:
as a diagnostic aid in suspected overdose
to avoid the need for assisted ventilation in opioid overdose
Reversal of opioid sedation:
as an aid to weaning from assisted ventilation in intensive care units
to reverse sedation/respiratory depression postoperatively
Adjunct in treatment of alcohol dependence Adjunct in maintenance of abstinence from opioids after opioid
\Note: naloxone not abdorbed orally, does not antagonise analgesic effect at mu receptor centrally, so does not reduce analgesic activyt, but if crushed and inhected it would. note: naloxine is actually in targin becuae it locallly antagonises opioid receptors in GIT and reduce GI side effects such as constipation
- Describe receptors according the modality
Exteroreceptors: receive info from outside the body (e.g. visual, tactile … etc)
Interoreceptors: receive info from inside the body (e.g. stomach pain …etc)
Proprioceptors: detect body position and movement (e.g. joint, tendons …etc)
Adaptation:
- Slowly adapting
- Rapidly adapting
Types of receptors:
- Anatomical location
- Cutaneous
- Muscle, tendon, joint
- Visceral
- Special senses
- Modality
- Mechanoreceptors
- Thermoreceptors
- Chemoreceptors
- Nociceptors
- Electromagnetic (photo)
Type of receptors according to modality:
- Mechanoreceptors—detect deformation
- Thermoreceptors—detect change in temperature
- Nociceptors—detect injury (pain receptors)
- Electromagnetic—detect light
- Chemoreceptors—taste, smell, CO2, O2, etc.
Structural variation confers ability to detect different stimuli
- Free nerve endings = pain
- Expanded tip endings e.g. Merkel’s discs
- Spray endings e.g. Ruffini’s endings
- Encapsulated endings e.g. Pacinian or Meissner’s corpuscles
- Describe adaptation or desensitisation
-
Receptor Adaptation
- Upon a stimulus of constatnt strength on a sensory receptor, the frequency of action potentials declines, known as receptor adaptation or desensitization.
- Receptors are categorized into rapidly adapting (phasic) and slowly adapting (tonic) receptors, each with different adaptation mechanisms.
- There are two general mechanisms
- readjustments in the structure of the receptor itself
- electrical type of accommodation in the terminal nerve fibril
- Describe the components of vision
Components of vision
Colour vision
** This refers to how well we can discriminate colours.
Defects in the light sensitive opsin in photoreceptors will affect how well light signals are transduced.
The most common defect in colour vision is red-green colour ‘blindness’
**
Your experience of colour will depend mainly on the wavelength of the light being reflected back at you by the object/s scene you are looking at. These wavelengths activate different cone populations to different degrees, because their ‘spectral sensitivities’ overlap, as indicated on the previous page.
The colours that you perceive depend on which photoreceptors are activated, and how strongly they respond.
Defects in the genes coding M- and L- opsin result in red green colour blindness (deuteranopia).
Visual acuity
Definition: Sharpness of vision, measured by the_abilityto discern letters or numbers at a given distance according to a fixedstandard._
**
Acuity is measured when you read letters from an eye chart, where each subsequent row has smaller and smaller letters. It is a measure of how well our visual systems resolve points / lines that are adjacent, but not touching.
Acuity is affected by how well light is focused onto the fovea, therefore problems with the cornea, lens, and a discrepancy in eye size, will affect acuity.
The limits to acuity are determined by cone photoreceptor spacing at the fovea.
**
Acuity is affected by:
- Quality of the media (air, cornea, aqueous, lens and vitreous) that light passes through
- Transparency of the retina
- Inter-cone spacing (smaller gaps between them, means better acuity)
- Physiological responses of photoreceptors and their transmission
Visual acuity varies with retinal location - or ‘eccentricity’ from the fovea centralis; that is the part of the retina that lies on the ‘visual axis’ at 0° eccentricity.
Measures of acuity are typically recorded as fractions or decimals.
20/20 OR 6/6 (that is, 1.0) is defined as ‘normal’ / standard acuity for people in ~6th decade. The fraction defines the smallest letter that can be read by a person at a distance of 20 ft / 6 metres.
Acuity of “6/12” indicates that the smallest letter that this eye can read is at 6m, but can be read by a ‘standard eye’ at 12m.
_An acuity of 6/60 (0.1) is the legal definition of blindness_.
Contrast
**
This is a measure of how well we can discriminate differences / changes in contrast, or shades of grey. Highest contrast is black vs white. Lower contrasts measure shades of grey on grey.
This is an important function that contributes to our ability to detect the motion of objects in our peripheral vision. Changes in contrast in our peripheral vision activate the attention systems in our brain, so we turn to look at them directly (it could be a sabre-toothed tiger, or another hominid!)
**
It is difficult to see an objectif it is the same colour, or same brightness / luminance as the background - hence theconcept of camouflage!
Contrast can be generated / lost:
- By choice of colour (e.g., yellow writing on a white background_versus_yellow writing on a blue background)
- By different levels of luminance (e.g., black writing /no luminanceon white background /maximum luminance)
- By varying both colour and brightness at the same time.
Why are these three the most significant components of vision?
Because these are the 3 most significant response characteristics of retinal neurons. The retina contains cells that
- encode colour (most important in the central retina]
- encode contrast (most important in the peripheral retina]
- encode acuity (most important in the fovea]
- Describe transduction of sensory stimuli into nerve impulses
- photoreceptor
- Both rods and cones have cell bodies in the outer nuclear layer, and axonal processes in the outer plexiform layer. The outer segments of photoreceptors are intimately associated with the retinal pigmented epithelial (RPE) cells. Light entering the retina passes though 5 layers of cells and connections before entering the outer segment of a photoreceptor.
- In the outer segment of the photoreceptor light is ‘transduced’ into an electrical signal, through a G-protein-mediated interaction with light sensitive ‘opsins’. Photoreceptors are the most highly metabolically active cells in the body (ie., they are very oxygen hungry).
- Disorders and diseases affecting photoreceptors:
- Retinal detachment.The molecular processes involved in visual transduction include reactions that take place in the RPE. In addition, the outer retina receives its nutrients (O2 and glucose) by diffusion, from the underlying choroid. During detachment, the distance between the outer retina and choroid increase, therefore nutrient delivery reduces (Fick’s law). Thus, detachment of the retina from the RPE (retinal detachment) results in vision loss. Photoreceptors can survive only for about 24 hours if detached from the RPE; therefore the condition of ‘retinal detachment’ requires urgent attention.
- Photoreceptor dystrophies are inheritable/genetic disorders that lead to progressivephotoreceptor death, and are a significant cause of vision loss in teenagers and young adults, who were normally sighted at birth (“retinitis pigmentosa”).
- bipolar cell: Bipolar cells are located in the middle layer of the retina (INL). Theyget synaptic input from photoreceptor dendrites (in the OPL) and pass information onto ganglion cells.In primates there are around 11 different types of bipolar cell, which process the inputs from photoreceptors in different ways.They play a critical role in ‘managing’ theinformation that is passed on from photoreceptors to ganglion cells.As far as we knowthere are no diseases that stem from problems with bipolar cells.
- ganglion cells: Ganglion cells pass visual information to the brain. This information is a distillation of data from various ganglion cell types that encodecolour, position/acuity or contrast.
- Theyhave long axons that form the innermost layer of the retina, the Nerve Fibre Layer, as they course across the retina, in a stereotypical pattern, towards the optic disc. There they make a 90° turn and leave the eye as the optic nerve (CNII). Their functional characteristics are determined largely by the way they wire up to bipolar cells, although ‘amacrine cells’ also interconnect the GC-bipolar synapses to modulate signal transmission.
- Diseases of GC: In glaucoma ganglion cell axons become compressed at the optic disc, which results in ganglion cell death, usually in the periphery, and in distinct patches of the retina.
- Peak GC density is about 30,000 cells / mm sq, at 1 mm eccentricity. This is 30x greater than the average GC density across the retina.
- Each GC represents a line of direct communication to the brain. There are about 100,000 direct lines of information coming out of the foveal region and going to the brain; in peripheral retina there would be <5,000. Thus, the brain gets more information, of better ‘quality’, from the fovea / macula, than it does from other parts of the retina.
Note:
##### The retina is not uniformly effective at the 3 key elements of vision (colour, acuity and contrast / motion)
Different regions of the retina are specialised for different functions. These functions are determined by
- Differences in photoreceptor distribution e.g. photoreceptor topography: there is a 1mm region where cones outnumber rods ^[note rods and cones generated in utero and do not regenerate]
- Differences in the components of the neuralcircuits that process the information coming from photoreceptors, and the way they are ‘wired’. - gnaglion cell topography (there is a 400 um region of the fovea where ganglion cells and rods are absent)
Macula layers
![[Pasted image 20240307091745.png]]
- macula lutea
- The high density of yellow xanthophyll pigment, filters damaging blue wavelengths of light, and has anti-oxidative qualities. Macula (=spot) lutea (=yellow).
- It is the part of the retina used in most of your minute-to-minute activities. It is approximately in the centre of the retina, and has a very high density of cells in all layers, and a relative absence of large retinal vessels coursing across it. Rather, retinal vessels tend to arch around the macula (as do the axons of ganglion cells).
- fovea centralis
- The ‘fovea’ (dip/depression) is in the centre of the macula (centralis) and is the part of the retina that has the highest capacity for resolving fine details (‘acuity’). The presence of a shallow depression is its most distinctive feature, but the depression itself does not contribute to acuity.
- At the location of the fovea there is the highest density of cone photoreceptors (no rods), and the least amount of neural convergence of signals from photoreceptors through to GC. That means that a single GC can get a signal from a single cone, at the fovea (but nowhere else in the retina).
- There are no retinal vessels at the fovea, and the depression itself it likely secondary to that important adaptation.
From light to electricity and to the brain
### Step 1: Some more anatomy.
The ‘vertical meridian’ is a virtual line that passes through the macula, and divides the retina (almost) in half.
GC axons from retina temporal to the vertical meridian project to the same side of the brain
GC axons from retina nasal to the vertical meridian cross the midline in the optic chiasm.
![[Pasted image 20240307093107.png]]
Step 2: This pattern of GC projections means that the left visual hemifield projects to the right side of the brain (and vice versa)
When you attend to an object each eye sees the object (represented by the white circle in the middle) in the centre of its visual field - so in the diagram, each retina sees both the green and red parts of the visual field (indicated by colouring on the ‘retinas’).
![[Pasted image 20240307093139.png]]
When both eyes are open, the 2 visual fields merge into one (Note the blending of green and red towards the centre of the visual field strip). This field is made up of two ‘hemifields’, on either side of the spot, shown here as green (right visual hemifield) and red (left hemifield).
Because of the pattern of retinal projections at the optic chiasma, the visual hemmifields are represented in the opposite cerebral hemisphere(ie.the right/green hemifield projects through the leftoptic tract, and on to the left cerebral hemisphere).
Step 3 : input from GC to brain
There are four key destinations for projections from the retina.
Suprachiasmatic nucleus
Part of the hypothalamus that regulates circadian rhythms or sleep/wake cycle. Further projections include the pineal gland, to regulate melatonin. The ganglion cells that project to the SCN are distinct from the 3 most commontypes of cells (midget, parasol, bistratified). Rather they expresstheir own photosensitive opsin, melanopsin, and do not rely solely on photoreceptors for excitation.
Pretectal area
This projection provides the input for the circuits that control the pupillary reflex and islargely derived from melanopsin-containing ganglion cells.Cells in the pretectal area project bilaterally to the Edinger-Westphal nucleus (CN III), which sends parasympathetic output to the ciliary ganglion, and thence the constrictor pupillae muscle.
Superior colliculus
These inputs are mapped onto the superficial SC, which receives corresponding, mapped inputs from the visual cortex. SC also receives mapped inputs from the auditory system, and somatosensory system. SC co-ordinates ‘saccadic’ eye movements towards novel stimuli (auditory / somatosensory) for rapid (self-preserving) responses.
dorsal LGN
All information destined for conscious perception must pass through the thalamus, before going to neocortex. the dLGN is the ‘visual nucleus’ of the thalamus, and projects directly to primary visual cortex / V1, also known as ‘striate cortex’.
Projections to the SC and dLGN are mapped
This means that adjacent points in the visual field are represented in adjacent parts of the brain target, preserving the relationship between points. Inthe dLGN there is a map of the visual field in each layer, in an approximately alternating (left eye/right eye) pattern.
Step 5: ### The dLGN sends a mapped projection to primary visual cortex - V1 / Striate cortex / Area 17
- Describe how pain is classified
Classification of pain
Pain can be classified according to:
- anatomic localisation
- etiology e.g. malignant or non-malignant
- duration and intensity: acute or chronic; mild, moderate or severe
- pathophysiological classification
- inflammatory
- nociceptive
- pain due to an event that stimulates nociceptors e.g. bone fracture
- special nerve endings (nociceptors) send pain signals to the CNS
- can be visceral or somatic
- neuropathic
- dysfunction in the nervous system or damage to the nerve itself –without nociceptor activation e.g. phantom limb pain
- can be peripheral or central
Note also neurogenic pain, due to primary damage of nociceptors or their fibres.
An example is CTS.
- Distinguish between acute and chronic pain; and somatic and visceral pain
Acute and Chronic Pain
Acute pain is typically characterised as having a short duration and is temporary and reversible.
It is localised and generally has a well-defined etiology
The pain is acute and declines with tissue healing.
It may ignite the SNS.
Chronic pain on the other hand has a longer duration, usually longer than three months. It is ongoing, long-lasting and may be irreversible.
It is often poorly localised and may not have a well-defined etiology.
The pain is gradual and persists and can be without identifiable injury or cause.
Chronic pain does not impact SNS function.
Somatic vs. Visceral Pain
- Somatic Pain is associated with brisk movements (flight), rise of pulse rate and is well localised i.e. to the skin
- Visceral Pain is associated with quiescence (rest and recover), slowing of pulse rate, falling of blood pressure, sweating, nausea, poorly localised and referred pain.
An aside:
The neospinothalamic tract conducts fast pain (via A delta fibers) and provides information of the exact location of the noxious stimulus, and the multisynaptic paleospinothalamic and archispinothalamic tracts conduct slow pain (via C fibers), a pain which is poorly localized in nature
- List and describe the types of nociceptors
Nociceptors
Nociceptors respond to mechanical, thermal, chemical stimuli and/or tissue damaging.
There are several types of nociceptors:
- mechanical
- strong stimuli e.g. pinch, sharp objects, squeeze or pinch the skin
- a mechanical deformation of the nociceptor membrane leading to depolarisation
- feels like a sharp or pricking pain, via Adelta fibres
- thermal
- noxious heat or cold
- produces hot pain, via Adelta fibres (it is faster compared to C fibres, and thus is more appropriate for the withdrawal refle)
- chemical
- chemical irritants e.g. histamine, capsaicin, acids
- produce itch sensation, and irritation, via C fibres
- C-polymodal
- 50% of C fibres
- stimulated mechanically, thermally, chemically
- produces slow dull burning pain, or aching pain or secondary pain
- percept persists long after the stimulus is removed
- mechanoheat-insensitive afferent
- transmitted by C fibres
- insensitive to noxious stimuli until sensitised
Note:
- faster transmission along Aδ fibres explains why the first pain is sharp and localised, while the second pain is dull, diffuse and burning as it is being transmitted along C fibres
An aside
- Receptors on nociceptive unmyelinated nerve terminals in the skin.
- Different channels at the end of the nerve determines what stimulus it will respond to
- Nociceptive stimuli can activate some receptors directly due to transduction of the stimulus energy by receptors (e.g., transient receptor potential (TRP) channel TRPV1) or indirectly by activation of TRP channels on keratinocytes (e.g., TRPV3). Nociceptors (e.g., mechanoreceptors) can also be activated by the release of intermediate molecules (e.g., ATP). (Ganong’s 25th edition)
- examples of mechano/chemo/themoreceptors include ASIC, P2X, P2Y
- Describe peripheral sensitisation
Peripheral Sensitization: nociceptor modulation
- Peripheral sensitisation decreases the threshold to increase the response
- Onset of injury results in the release of chemical mediators
- Several key chemical mediators include:
- bradykinin
- directly depolarises nociceptors by inducing a conformational change
- stimulates long-lasting intracellular changes making heat activated ion channels more sensitive
- prostaglandins
- generated by lipid membrane breakdown increases nociceptor sensitivity
- substance P
- released by nerve terminals
- has a role in neurogenic inflammation
- vasodilation of adjacent capillaries
- release of histamine from mast cells
- histamine
- increases the excitability of the nerve ending membrane
Terms for Related Pain States
- Hyperalgesia: Augmented sensations of pain from a noxious stimulus e.g. opioid overuse
- peripherally mediated and/or centrally mediated e.g. amplification of signal in the spinal cord
- primary i.e. from tissue damage, or secondary i.e. reactive to primary damage
Peripheral sensitisation refers to the increased excitability at nerve endings usually due to the inflammatory soup following injury.
Effective drugs include NSAIDs and COX inhibitors.
Neurogenic inflammationis the peripheral mechanism whereby inflammation is caused by the liberation of chemical mediators released from peripheral nerve terminals.
This inflammation leads to hyperalgesia, the increased sensitivity to noxious stimuli
Note:
The inflammatory soup or elements of peripheral sensitisation
- Describe central sensitisation
Central sensitisation refers to the increase in the excitability of neurons centrally. This results in the transmission of nociceptive signals elicited by sub‐thresholdactivation of nociceptive afferents and leads to increased pain sensitivity..
Multiple mechanisms have been demonstrated, including:
- increased ion channels and receptors on afferents
- long term potentiation or increased synaptic strength
- windup: constant stimulation of a fixed intensity leading to increased pain perception. This is NMDA receptor mediated
- reduced GABA or glycine activity in the dorsal horn
- disinhibition can enable non-nociceptive myelinated Aβ primary afferents to engage the pain transmission circuitry aka reorganisation of circuits after A-beta sprouting onto spinothalamic tract neurons (a proposed mechanism for allodynia)
- microglia or astrocytes release inflammatory mediators which augment neuronal excitability
- Describe affernet pain modulation and descending pain regulation
The gate control theory of pain is a spinal cord mechanism which explains how the activation of non-nociceptive inputs can mask pain.
Stimulation of Aα and Aβ fibres will
- excite inhibitory neurons
- release of GABA
- inhibition of post-synaptic spinothalamic tract neurons
The interneuron plays a gating role.
The PAG sends descending projections to the raphespinal neurons in the rostral medial medulla.
These cells inhibit spinothalamic tract neurons in the dorsal horn.
They have a profound analgesic effect, and are thought to explain why soldiers at war or athletes can suppress pain from horrific injuries during times of need.
- Describe the thalamus and its regions
Thalamus: The Gateway
Sensory experiences can either cause immediate reactions or memories of the experiences that can be stored in the brain and determine bodily reactions at some future date.
This information enters the CNS through peripheral nerves and is conducted immediately to multiple sensory areas in
- spinal cord, at all levels
- the reticular substance of medulla, pons and mesencephalon of the brain
- the cerebellum
- thalamus
- areas of the cerebral cortex
All sensory information going to thecortex must pass through the thalamus ^[except olfaction]. Thus the thalamus is the gateway to the cortex.
The cortex reciprocally innervates the thalamus (known as feedback).
The internal almina divides the thalamus into four nuclei groups
- anterior: attention and learning
- ventral anterior/alateral: motor
- lateral
- lateral geniculate: vision
- ventral
- ventral posterior: somatosensory. Contains VPL and VPM
- medial: planning and active memory
- medial geniculate: hearing
- intralaminar
Second-order sensory fibres synapse in the ventral posterior nucleus.
- VPL: medial lemniscus body and STT projecting to somatosensory cortex. Receives/transmits: vibration, pain, pressure, proprioception and light touch
- VPM: medial lemniscus face and trigeminal system, projecting to somatosensory cortex. Receives/transmits: face sensation and taste
Note: inputs from dorsal column and spinothalamic tract project to overlapping regions to S1 area of the neocortex.
- List skin sensory receptors (table)
see table
- Describe the components of sensory coding – relate sensory homunculus to this. Relate vision to this.
Sensory Coding:
Converting a receptor stimulus to a recognizable sensation.
A. Modality
B. Location
C. Intensity
D. time course
A. MODALITY
-
The Adequate Stimulus
- The particular form of energy to which a receptor is most sensitive is its adequate stimulus. Receptors can respond to other forms of energy, but with a much higher threshold.
- It is perceived by a corresponding region of sensory cortex, no matter what type of stimulus energy activated the receptor
-
The “Labeled Line” Principle (Law of Specific Nerve Energies)
- Specificity of nerve fibers for transmitting only one modality of sensation. For example, stimulation of a sensory nerve from a Pacinian corpuscle results in the sensation of touch, regardless of the stimulus’s nature (pressure at elbow, irritation from tumour in brachial plexus).
B. LOCATION (Acuity)
-
The Receptive Field
- The sensory area supplied by a sensory neuron. High density enables better two point discrimination e.g., at fingertips or on lips
- Lateral inhibition enhances contrast by inhibiting receptors at the peripheral edge of a stimulus, making the central stimulus more pronounced. Achieved by interneurons
- Another phenomenon: convergence; multiple primary neurons converging on a secondary neurons, producing one field of detection.
C. INTENSITY
-
Stimulus Intensity and Receptor Potential
- An increase in stimulus intensity leads to an increased receptor potential and a higher frequency of action potentials. Intensity also recruits more receptors within the receptive field, activating those with both low and high thresholds (weak stimuli recruit low thresholds, strong stimuli recruit high thresholds)
- as the strength of a stimulus is increased, it tends to spread over a large area and generally not only activates the sense organs immediately in contact with it but also ‘recruits’ those in the surrounding area
- Furthermore, weak stimuli activate the receptors with the lowest thresholds, and stronger stimuli also activate those with higher thresholds
- An increase in stimulus intensity leads to an increased receptor potential and a higher frequency of action potentials. Intensity also recruits more receptors within the receptive field, activating those with both low and high thresholds (weak stimuli recruit low thresholds, strong stimuli recruit high thresholds)
D. DURATION
-
Receptor Adaptation
- Upon a stimulus of constatnt strength on a sensory receptor, the frequency of action potentials declines, known as receptor adaptation or desensitization.
- Receptors are categorized into rapidly adapting (phasic) and slowly adapting (tonic) receptors, each with different adaptation mechanisms.
- There are two general mechanisms
- readjustments in the structure of the receptor itself
- electrical type of accommodation in the terminal nerve fibril
homunculus and vision, acuity
- Describe fibre types and their examples
seet able
- List endogenous neurotransmitters and briefly describe their role in pain modulation
Endogenous opioid-mediated analgesia
- Endogenous opioid peptides play a key role in centrally mediated analgesia
- Endogenous opioids have a variety of roles in the CNS, not just related to analgesia
- enkephalin
- dynorphin
- β-endorphin
- Enkephalin may act
- presynaptically to reduce the release of substance P
- postsynaptically by producing an IPSP
- The endogenous analgesic effects of enkephalin is blocked by naloxone, an opioid antagonist
Endogenous cannabinoids
- Endocannabinoids found in many regions throughout the CNS
- they act as retrograde neurotransmitters: released from the depolarised neurons and activate the CB1 receptor of presynaptic terminals; postsynaptic cells controls presynaptic cells
- decrease the release of presynaptic neurotransmitter e.g. GABA or Glutamate
- Cannabinoid and opioid systems may operate synergistically
- both receptors exist at various levels in the pain circuits
- THC and morphine have been shown to act synergistically, mutually potentiating their anti-nociceptive actions
- interestingly, this action is inhibited by either cannabinoid or opioid receptor antagonists separately
- Increasing exposure to noxious stimuli result in increased levels of endocannabinoids in the PAG
- Describe how EEG works and identify waves
Brain Rhythms
- Rhythms: Pattern of events that has a repeated predictive structure.
- Brain rhythms are generated by the coordinated activity of large populations of neurons firing together in synchrony.
- Neural oscillations, or brainwaves, are rhythmic or repetitive patterns of neural activity in the central nervous system.
- Brain rhythms are typically classified into five main categories based on their frequency bands:
- Delta
- Theta
- Alpha
- Beta
- Gamma
What is an EEG?
- Electroencephalography (EEG) is a non-invasive, relatively inexpensive, and objective method for assessing brain neurophysiological function.
- During the procedure, electrodes consisting of small metal discs with thin wires are pasted onto the scalp.
- The electrodes detect tiny electrical charges that result from the activity of a large population of neurons.
- The charges are amplified and appear as a graph on a computer screen, or as a recording that may be printed out on paper.
- The healthcare provider typically evaluates about 100 pages, or computer screens, of activity.
Measurements
- Amplitude varies from 2 to 200uV
- 1 Volt = 1.000.000 uV
- Alpha amplitude: 50 uV.
- Frequency = from 0.5 to 50 Hertz
- 1Hertz = 1 cycle/sec
- The paper is divided in second one second: 3 cm of paper
- We need a population of neurons corresponding 6 cm2 to create a measured wave.
- Are divided into 5 bands in terms of frequency
EEG – Five Bands Frequency
- In an electroencephalogram (EEG), the electrical activity of the brain is typically divided into several frequency bands, each associated with different states of brain activity.
- Delta waves (0.5 – 3 Hz) associated with deep sleep, unconsciousness, and certain neurological conditions.
- Theta waves (4 – 7 Hz) observed during drowsiness or light sleep.
- Alpha waves (8 - 12 Hz) prominent during wakeful relaxation with closed eyes. They go away with attention or stress.
- Beta waves (13 -25 Hz) observed when the brain is active and engaged in cognitive tasks, such as problem-solving, decision-making, and focused attention. Present also during motor activity.
- Gamma waves (>25 -100 Hz) associated with high-level cognitive functions. Often observed during intense mental activity and may play a role in coordinating information processing across different brain regions.
What EEG measures
- superficial activity
Brain Waves and EEG
- Main indications:
- **Seizures and Epilepsy
- Altered Consciousness (coma, stupor, or confusion) – it helps to differentiate clinical conditions from psychiatric disorders.
- Sleep disorders (polysomnography)
- Evaluation of brain function
- Monitoring during Surgery or Intensive Care (induce therapeutic coma, monitor the depth of anesthesia and prognostication of cardiac arrest)
- Assessment of Brain Development
- Evaluation of Neurological Disorders
- Research and Clinical Trials
EEG Advantage and Disadvantage
- Good for monitoring population-level neuronal activity
- Non-invasive
- High Temporal Resolution.
- Portable and Affordable
- Dynamic Information
- Resolution can be poor
- Cannot give information about the activity of a single neuron
- Susceptible to Artifacts
- Inability to Penetrate Deep Brain Structures:
- Interpretation Challenges
- Limited Functional Localization
Recording EEG
- Recording an EEG is relatively simple.
- No patient preparation.
- Fasting is not required.
- Hairs need to be clean and dry.
- 20 electrodes are connected.
- Exam. Duration: 20 – 40 min.
- The method is usually non-invasive and painless.
- The electrodes are wires taped to the scalp, along with conductive paste to ensure a low-resistance connection.
- Small voltage fluctuations, usually a few tens of microvolts (V) in amplitude, are measured between selected pairs of electrodes.
EEG Protocol
EEG - Step by Step
Step 1 – Understanding the Electrode Placement - Montage
- The is a standard method of measuring the head and placing electrodes named International 10–20 system.
- The first measurement is from the nasion to the Inion.
Step 2 – How is EEG Recorded?
- The EEG uses the technology of the differential amplifiers.
- It takes 2 inputs and creates an output by the differences of the 2 inputs.
- The output is simply the difference between them.
- All the other commonalities are canceled out.
- EEG is not absolute, IS RELATIVE because it is the difference between two Inputs.
Step 3 – How EEG is Displayed
- EEG can be displayed in different ways that are known as montage.
- The most common is bipolar montage.
- The single line between two electrodes is called a Channel or derivation.
- The string of records that is linked together = Chain
Different Types of Montage
- Average Reference Montage
Step 4 - Normal and Abnormal EEG - Artifacts
- Reading an EEG
- Abnormal EEG - Seizures
- Describe microcircuits
Microcircuits Concept
- The microcircuit concept is a theoretical framework in neuroscience that emphasizes the functional organization of neural circuits at the level of local microcircuits within the brain.
- Key aspects of the microcircuit concept include:
- Local Connectivity
- Functional Specialization
- Cell-Type Diversity:
- Feedback and Feedforward Loops
- Plasticity and Adaptation
Microcircuits and Oscillation
- Examples of Central Pattern Generator
Spinal Central Pattern Generator
- Paraplegic patient
- Stimuli of ~5 V intensity (0.2 - 0.5 ms width at 25 - 60 Hz) elicit knee movements (K.M.); alternating innervation: agonists / antagonist.
- A severed spinal cord can produce movement: segmental networks ± intact; but command signals↓ from higher control centres.
- Proof of concept for CPG.
- Location of cells/network currently unknown
- Which two CNs are responsible for the light reflex arc. Describe the arc. Describe how to test it
Pupillary reflex
The pupillary response or pupil reflex constricts the pupil in response to light ^[https://www.ncbi.nlm.nih.gov/books/NBK537180/].
The afferent segment of the pupillary response are the ganglion cells that form the optic nerve. They project from the retina to the midbrain. travels to the pretectal olivary nuclei. It decussates in the nasal retina but not in the temporal retina.
The interneuron segment of the pupillary response are the cells of the pretectal nucleus. They project bilaterally to the parasympathetic nuclei of CNIII, known as Edinger-Westphal nuclei (preganglionic parasympathetic nuclei in the midbrain.)
The efferent segment runs from the Edinger- Westphal nuclei to the pupillary constrictor muscle to constrict the pupil, via the ciliary ganglion, which sends postganglionic axons to directly innervate the iris sphincter muscles ^[https://www.ncbi.nlm.nih.gov/books/NBK537180/].
First order pre ganglionic parasympathetic fibres exit the mifbrain in the oculomotor nerve, without crossing, synapsing in ciliary ganglion.
Second order post ganglionic neurons send axons from the ciliary ganglion to the sphincter pupillae via short ciliary branches.
The direct response is constriction of pupil in the ipsilateral eye; the consensual response is constriction of pupil in the contralateral eye.
It is tested by shining a light into one pupil and looking for a response in the other pupil (which constricts as well).
The swinging lamp sign: move light to the contralateral pupil; the ipsilateral pupil will then dilate after light has moved away from it (this is called an afferent pupillary defect) ^[https://www.derangedphysiology.com/files/cranial%20nerve%20exam.pdf]
The pupillary reflex exam is considered part of a neurological exam.
- Describe the accommodation reflex
Accommodation reflex
When our attention moves from an object in the distance to another nearby, our eyes have to accommodate to the new distance. Both eyes converge (turn inward), the pupil constricts, and the lens accommodation (become rounder), to shorten its focal distance. If you compare the schematics for the light and accommodative refelxes in the picture above, you notice, that the latter needs the involvement of the visual cortex (i.e. you have to want to look at something nearby to initiate this reflex). The pupillary response uses the same pathway as in the light reflex. To make the lens rounder, the ciliary body needs to contract, which in turn, relaxes the zonular fibres to release the lens. For both the pupillary response and the lens accommodation, the efferents are the preganglionic parasympathethic fibres of the Edinger-Westphal nucleus, which synapse in the ciliary ganglion to the post-ganglionic fibres of the short ciliary nerve that terminates on the constrictor muscles of the iris and the ciliary muscles. For the convergence, the oculomotor nucleus (medial rectus subgroup) sends bilateral impulse to the medial rectus muscles of both eyes.
- Describe corneal reflex
Corneal reflex
The reflex is mediated by:
- the nasociliary branch of the ophthalmic branch (V1) of the trigeminal nerve (CN V) sensing the stimulus on the cornea only (afferent fiber).
- the temporal and zygomatic branches of the facial nerve (CN VII) initiating the motor response on orbicularis oculi muscles (efferent fiber).
- the center (nucleus) is located in the pons of the brainstem.
- spinal nucleus of V for sensation
- facial motor nucleus
![[Cornea__Reflex__AB.jpg]]
Pupillary reflex
- Describe the vestibular apparatus and how it conveys balance information to the cortex
Vestibular system
The vestibular apparatus picks up the sense of linear acceleration and rotation of the head in three dimensions. It sends information to the brain about the position of the head in relation to the environment.
It initiates reflexes that are responsible for stabilising the retinal image + adjusting the posture during head movement. These are the vestibulo-ocular and vestibulo-spinal reflexes.
![[Pasted image 20240307101106.png]]
Vestibular apparatus
In the inner ear, the bony labyrinth is lined with the membranous labyrinth, a series of membrane-walled sacs and ducts: 3 semicircular canals, utricle and saccule (in the vestibule), which are responsible for picking up the sensation of head movements. These are part of the vestibular system.
The semicircular canals detect rotatory movements, when the cupula, containing sensory receptors are distorted by the movement of the endolymph.
![[Pasted image 20240307101156.png]]
Maculae in the utricle and saccule detect linear movement. During forward acceleration of flexion of the neck, otoliths tumble around, move the underlying gelatin layer. In turn, the cilia of vestibular nerve receptor cell are distorted, to initiate electrical signals.
![[Pasted image 20240307101209.png]]
### Vestibulo-ocular reflex
It activates during head movement to move the eyes in the opposite direction. I.e. when you visit a gallery, and you are looking at a picture on the wall while moving past, VOR will allow you to see the picture clearly as it stabilises the image on your retina.
![[Pasted image 20240307101241.png]]
Vestibulo-spinal reflex
The vestibulospinal reflexes are responsible for stabilising/adjusting the body during head movement. The vestibulospinal tracts are initiated in the medial and lateral vestibular nuclei. The medial vestibulospinal tract runs bilaterally close to the midline, joins in the medial longitudinal fasciculus (MLF) and terminates at the cervical levels of the spinal cord. In the spinal cord, the tract is located in the anterior funiculus, and axons synapse in Rexed laminae VII & VIII, to control neck muscles.The lateral vestibulospinal tract runs ipsilaterally along the whole length of the spinal cord, in the anterior funiculus. Axons terminate on motor neurons to activate extensor muscles (anti-gravity muscles), and inhibit flexor muscles.
![[Pasted image 20240307101316.png]]
Central connections of vestibular system
Receptors e.g. macualr hair cells and or cupula trasmit information to the vestibular ganglion, which passes information to the vestibular nerve.
There are four vestibular nuclei that receive information from the vestibular nerve (Superior, inferior, lateral, medial). The information is passed on to thalamus before being projecting to cortex.
The primary vestibular cortex is not well defined.
However it is suggested that is located in the area of the insula and Sylvian fissure in the right hemisphere.
It does seem that multiple cortical areas are involved in detection of movement and body position.
Cortical regions of the brain known to be involved with vestibular processing.
- The frontal eye fields control eye movements and receive vestibular motion information.
- Areas 2v and 3a are somatosensory areas that map body location and movement signals.
- Area PIVC (parietoinsular vestibular cortex) responds to body and head motion information.
- The posterior parietal cortex is involved with motion perception and responds to both visual and vestibular motion cues.
- The hippocampus and parahippocampal regions are involved with spatial orientation and navigation functions.
- All receive vestibular signals regarding body and head motion. (VIP: ventral intraparietal region; MST: medial superior temporal region; MIP: medial intraparietal area)
not: otoliths, vs
Describe the basal ganglia circuits and associated pathology
Basal Ganglia – Provides feedback to the
cortex regarding planned movement (to refine)
Components
(Dorsal) Striatum
Caudate – connected to frontal and pre-
frontal areas. Influence on social/moral
behaviours, active during the acquisition
of new motor skills.
Putamen – mainly connected to somatic
cortical areas. Mapped representation of body.
Output to globus pallidus. Cells are GABAergic (inhibitory)
Pallidum – globus pallidus – medial and lateral.
Regulators
Subthalamic nucleus
Substantia Nigra – pars compacta. Dopaminergic (excitatory)
Action Loops
Cognitive – learning new motor skills
Limbic – memory, motivational behaviour, facial expressions
Oculomotor – connected to frontal eye fields, eye movement
Pathologies
Parkinson’s: DA loss in the substantia nigra cells. Direct pathway disengages and indirect
pathway prevails by default. Results in enhanced inhibition of the thalamus -> hypokinesis. Also
may suffer tremor, rigidity, poor facial expression, saccades and impulse control.
Huntington’s: Chromosome 4 defect causing GABAergic cell death in the striatum. D2 MSNs
affected early, D1 later. Brakes applied harder to STN -> reduced basal inhibition on thalamus.
Leads to execution of otherwise suppressed motor behaviours (chorea, athetosis) -> hyperkinesis.
Athetosis – slow writhing movements\\
he direct pathway starts with cells in the striatum that make inhibitory connections with cells in the GPint. The GPint cells in turn make inhibitory connections on cells in the thalamus. Thus, the firing of GPint neurons inhibits the thalamus, making the thalamus less likely to excite the neocortex. When the direct pathway striatal neurons fire, however, they inhibit the activity of the GPint neurons. This inhibition releases the thalamic neurons from inhibition (i.e., it disinhibits the thalamic neurons), allowing them to fire to excite the cortex. Thus, because of the “double negative” in the pathway between the striatum and GPint and the GPint and thalamus, the net result of exciting the direct pathway striatal neurons is to excite motor cortex.
Indirect pathway. The indirect pathway starts with a different set of cells in the striatum. These neurons make inhibitory connections to the external segment of the globus pallidus (GPext). The GPext neurons make inhibitory connections to cells in the subthalamic nucleus, which in turn make excitatory connections to cells in the GPint. (Remember that the subthalamic-GPint pathway is the only purely excitatory pathway within the intrinsic basal ganglia circuitry.) As we saw before, the GPint neurons make inhibitory connections on the thalamic neurons. To see the net effects of activation of the indirect pathway, let us work backwards from the GPint. When the GPint cells are active, they inhibit thalamic neurons, thus making cortex less active. When the subthalamic neurons are firing, they increase the firing rate of GPint neurons, thus increasing the net inhibition on cortex. Firing of the GPext neurons inhibits the subthalamic neurons, thus making the GPint neurons less active and disinhibiting the thalamus. However, when the indirect pathway striatal neurons are active, they inhibit the GPext neurons, thus disinhibiting the subthalamic neurons. With the subthalamic neurons free to fire, the GPint neurons inhibit the thalamus, thereby producing a net inhibition on the motor cortex.
cog
Example loop:
- prefrontal and PPC
- Putamen, caudate and GP
- VA/MD thalamus
- SMA
oculomotor
- Connected to the ‘frontal eye fields’ and parietal association cortex
- Returns to Cx via VA & MD nuclei of thalamus
- During fixation, SNr tonically inhibits cells in the superior colliculus (SC)
- When a deliberate saccade is about to be made, SNr activity stops, to disinhibit SC.
Example loop
- frontal eye fields and PC to caudate and SNr (inhibits SC)
- VA/MD thalamus
- frontal eye fields
- frontal eye fields and PC directly to SC
limbic
Example loop:
- Limbic Cx
- N. Accumbens
- MD Thalamus
- Inf. Prefrontal Cx
!!! did not show on MCQs
Discuss anti-epileptics, their MoA, adverse effects and contraindications
GABA enhancers
e.g. benzodiazepines (midazolam and clonazepam), barbiturates (phenobarbitone)
### Mechanism of action
May have varying modes of action but ultimately increase the activity of GABA
Benzodiazepines: (eg Midazolam, clonazepam) - 1st line for seizure termination in emergencies
- Bind to allosteric modulatory site on GABAA receptor (distinct from GABA binding site) ->increase the affinity of GABA to the receptor
- Main effects:
- reduced anxiety (alpha-2subunit activity) - eg diazepam, alprazolam
- induction of sleep (alpha-1subunit) eg temazepam
- anticonvulsant - (can be used in an emergency to terminate a seizure) eg midazolam, cloncazepam
Barbiturates: (eg Phenobarbitone,Primidone)
- Prolong inhibitory postsynaptic potential by increasing the mean chloride channel opening time and hence the duration of GABA-induced cell membrane hyperpolarisation
- Not routinely used in practice due to long half-life
Role in therapy
Benzodiazepines are first line therapies for seizure termination in emergencies.
### Side effects
- sedation
- respiratory depression
- dependence
- confusion
- anterograde amnesia
- reduced muscle tone
Precautions and contraindications
- Barbiturates are not routinely used due to long half life
Sodium channel blockers
e.g. Phenytoin, valproate, carbamazepine, oxcarbamazepine, lamotrigine, lacosamide
Mechanism of action
- Prevents repetitive neuronal discharge by blocking voltage-dependent and use-dependent sodium channels.
- Preferentiallyblock excitation of cells that fire repetitively
- Many of the sodium channel blockers have other (additional) mechanisms of action, and many aren’t entirely understood.
Sodium Valproate - First line for many seizures (both acute and chronic management)
Prevents repetitive neuronal discharge by blocking voltage‑ and use-dependent sodium channels. Other actions include enhancement of GABA(competitive inhibition prevents GABA reuptake by glial cells and axonal terminals), inhibition of glutamate and blockade of T-type calcium channels.
Phenytoin - (sometimes used for status epilepticus but not often used chronically)
Blocks voltage and use dependent sodium channels
Carbamazepine: Used for chronic management
- Enhances sodium channel activation by reducing high-frequency repetitive firing of action potentials
- acts on synaptic transmission
Topiramate: Chronic management (not acute)
- Stabilises presynaptic neuronal membranes by blocking voltage-dependent sodium channels. Enhances activity of GABA on postsynaptic chloride channels.
### Role in therapy
- sodium valproate indicated in seizures — first line both for acute and chronic, bipolar disorder and migraine
- phenytoin indicated in seizures; sometimes used for status epilepticus but not often used chronically
- carbamazepine for chronic management; indicated in seizures, neuropathic pain, and bipolar or mania
- topiramate for chronic management; indicated in focal seizures, generalised tonic-clonic seizures, and migraine prevention
Side effects
- sodium valproate: drowsiness, tremors, nausea, paraesthesia, hair thinning usu. temp, weight gain, hepatotoxicity
- phenytoin: drowsiness, dizziness, confusion, gingival hyperplasia, hirsutism
- carbamazepine: CNS depression, hypersensitivity reactions, depressed white cell counts, GIT disorders, fluid retention
- topiramate: somnolence, fatigue, psychiatric effects: depression, emotional lability, nervousness, agitation, hallucinations, psychosis, suicidal ideation, nephrolithiasis, metabolic acidosis: weakly inhibits renal carbonic anhydrase, leads to a dose-related decrease in serum bicarbonate concentrations and rarely to hyperchloraemic, normal anion gap, metabolic acidosis
Calcium channel modulators
### how modulation reduces excitatory neurotransmitter release (e.g., glutamate)
(1) Action potential travels down to the nerve terminal
(2) Voltage-sensitive sodium channel senses the change in voltage, which triggers the channel to open and allows Na+into the cell
(3) Voltage-sensitive calcium channel senses the change in voltage, which triggers the channel to open and allowsCa2+into the cell
(4) Voltage-sensitive calcium channels are associated with a SNARE protein, which essentially mediate vesicular neurotransmitter release
The voltage-sensitive calcium channel contains 5 subunits: namelyα1(pore-forming unit),α2, andδ.
Binding of pregabalin and gabapentin to the α2-δ modulatory site decreases the voltage-induced Ca2+influx, which prevents the release of excitatory neurotransmitters, such as glutamate, therefore decreasing neuronal excitability.
The ‘unknown’ or ‘other’ mechanisms… Becoming increasingly common in practice due to predictable PK and less side effects and drug interactions.
- Antagonismat post-synaptic AMPA glutamate receptors (perampanel)
- Bindingto synaptic vesicle protein2A which may modulate neurotransmitter (glutamate) release (Levetiracetam andBrivaracetam)
- All 3 drugs have been associated with behaviour changes such as aggression and psychiatric effects.
Mechanism of action
- ethosuximide: Reduces low threshold voltage-dependent calcium conductance in thalamic neurones
- gabapentin and pregabalin: Bind to alpha‑2 delta protein subunit of high threshold voltage-dependent calcium channels, reducing calcium influx and neurotransmitter release. Although structurally related to the neurotransmitter GABA, they are not known to significantly affect GABA or its receptors.
-
### Role in therapy
- ethosuximide:?
- gabapentin and pregabalin indicated mainly in neuropathic pain, less common for partial seizures
Side effects
- gabapentin and pregabalin: CNS depression, weight gain, oedema, sedation
Levetiracetam
- mechanism of action unknown - May modulate neurotransmission (glutatmate) by binding to synaptic vesicle protein2A in the pre-synaptic neuron
- indicated in Seizures - Increasingly common in practice due to being better tolerated than other antiepileptics with less drug interactions.
- side effects: slight sedation, somnolence, headache, altered behaviours inc aggression
Special prescribing considerations for antiepileptic drugs
Women of child bearing age - contraception
Several antiepileptic drugs (eg phenytoin) induce CYP3A4 and may reduce the efficacy of drugs metabolised by this enzyme:
- Includingcontraceptives,
- Can use levonorgestrel IUD, medroxyprogesterone depot or copper IUD(unaffected by CYP3A4 inducers).
- It is important to look-up drug interactions when prescribing antiepileptic drugs
Pregnancy
- Consider and discuss the possibility of pregnancy before selecting a specific antiepileptic drug
- Some AEDs are potentially teratogenic or can affect cognitive development
- seizure control is high priority during pregnancy as they pose a greater risk to mother and foetus as compared to the adverse effects
- effects of antiepileptics can change during pregnancy due to altered PK
What options are there for managing antiepilectic therapy during pregnancy or for patients planning pregnancy?:
- Consider withdrawal of antiepileptic treatment in women planning pregnancy who have been seizure-free for at least 2years
- Lower the dose of sodium valproatein woman of childbearing age which decreases the teratogenic risk
- Less risk associated with some second generation AEDs
- Tiagabine, Gabapentin, Levetiracetam
- Increase intake of folic acid to 5mg per day commencing at least 1-3 months prior to conception
- Minimises risk of spina bifida
- Shown to have positive outcome on cognitive performance in children
- Some AEDs can impair absorption of folic acid
- PK considerations for phenytoin: - Saturable metabolism (zero-order) non-linear kinetics
- Requires plasma monitoring
- dose plasma concentration relationship non-linear (small rise in dose can cause unexpectedly large rise in drug plasma levels)
- EG: Dose can be increased by 100mg per day if the serum level is less than 5mg/L but only by 30mg per day if the level is above 5mg/L
- Steady state 7-10 days
- Loading dose usually required
- CYPenzyme inducer - many drug interactions
- Highly protein bound (on albumin)
- Toxicity phenytoin: leads to blurred or double vision, slurred speech, clumsiness, dizziness, confusion, hallucinations, cardiovascular collapse
- Monitoring of phenytoin:
- Phenytoin levels are related to efficacy - dose adjustment based on levels can be difficult eg: Dose can be increased by 100mg per day if the serum level is less than 5mg/L but only by 30mg per day if the level is above 5mg/L
- Phenytoin monitoring and dose adjustment are complicated by the drug’s nonlinear pharmacokinetics
- in patients with hypoalbuminaemia (eg in kidney disease, malnutrition, advanced chronic liver disease), a greater proportion of the phenytoin is free (because of lower protein binding) for the same total concentration
Dopamine antagonists
Antipsychotics
Antipsychotic actions are thought to be mediated (at least in part) by blockade of dopaminergic transmission in various parts of the brain (it was previously though that the hyperdopaminergia in the mesolimbic pathway was responsible for the positive symptoms in psychosis; however, it is now thought to also involve the striatum).
- all effective antipsychotics block D2receptors or are partial agonists at D2receptors(with the exception of pimavanserin, which is not yet available in Australia)
- differential blockade of other dopamine receptors (eg D1) may influence therapeutic and adverse effects
- antagonism of other receptors may influence antipsychotic activity, eg 5HT2Aantagonism with some agents
Typical (first generation):
eg chlorpromazine, haloperidol
- significant motor side efffects via the extrapyramidal system (EPSE)
- only effective against positive symptoms
Atypical (second generation):
eg olanzapine, clozapine, risperidone, quetiapine
- Fewer side effects compared with typical antipsychotics
- More commonly used in practice
- Some are often used in the treatment of depression (i.e., olanzapine + fluoxetine in treatment-resistant depression)
Cautions:
Neurological
- Parkinsons Disease: Antipsychotics aggravate PD as they oppose the action of the dopamine agonists
- Lewy body dementia:Antipsychotics (even low doses) can cause deterioration in cognitive and motor function
Cardiovascular
- Antipsychotics may increase the QT interval, increasing the risk of arrhythmia and sudden death
Elderly
- Use of antipsychotics in older people is associated with an increased risk of stroke and death.
Adverse effects of the antipsychotics
Extrapyramidal side effects (EPSE): (Dystonia, akathisia, parkinsonism, tardive dyskinesia)
- Much more common with the typical (first generation) antipsychotics
- Incidence is dose related and highest with haloperidol and trifluoperazine
- May require an anticholinergic (eg benzatropine)
More on the extrapyramidal side effects
Dystonias
Symptoms:
Involuntary movements
- Restlessness
- Muscle spasms
- Protruding tongue
- Fixed upwards gaze
- Neck muscle spasm
Details – onset and treatment
- Commonly occur in the first days to weeks of treatment
- Reversible upon cessation of drug (may be possbile to reintroduce at lower dose or alternative agent)
- Treatment with anticholinergic (eg bezatropine) is effective
Akathisia
Symptoms
Feeling of restlessness (difficult to differentiate from agitation related to psychosis)
Details – onset and treatment
- Occurs 2-3 days (up to several weeks) with increasing cummulative risk and may subside spontaneously
- Improves with dose reduction and worsens with dose increase (opposite to psychosis related agitation)
- Much lower incidence with the “Atypical (2nd generation) agents”
Parkinsonism
Tremor, rigidity, bradykinesia
- Occurs within weeks to months
- Usually reversible although short term symptomatic treatment with anticholinergic (benzatropine) may help
- If persists, may reduce dose or consider alternative antipsychotic
Tardive dyskinesia
Involuntary movements of face and tongue (can also be trunk and limbs)
Tardive dyskinesia is thought to occur from chronic antagonism of D2 receptors leading to upregulation of D2 receptors and, therefore, dopamine hypersensitivity in a pathway in the brain that mediates movement.
- Develops after months or years of treatment, or on sudden cessation
- Often irreversible, although a slow improvement after cessation (in young patient’s identified early)
Other side effects
Neuroleptic malignant syndrome
- Potentially fatal
- fever, marked muscle rigidity, altered consciousness and autonomic instability
- Progresses rapidly over 24-72 hours
- Elevated creatine kinase (CK) and leucocytosis often occur
- May occur at any time
- Cessation of therapy and supportive care (cooling, volume replacement etc and occasionally medical treatment with bromocriptine or dantrolene) are required
Endocrine effects
- Antagonising D2 receptors can ↑ prolactin secretion
- Breast swelling, pain and lactation (galactorrhoea) -Can occur in men and women
- ↓ growth hormone secretion
Sexual dysfunction
- ↓ libido and arousal
- Erection and ejaculation difficulties
Metabolic effects
- Weight gain - associated with increased triglycerides, cholesterol and blood glucose
- ↑ risk of diabetes and CVD
- more common with “atypical” agents
- Weight gain associated with H1 and 5HT2Cantagonism
Drowsiness and sedation
- Less common with the atypical antipsychotics
-
##### Dopamine Pathways, Positive Symptoms, Negative Symptoms, and Associated Side Effects
Note: there a three main theories for the etiology of schizophrenia/psychosis:
- Hyperactive dopamine in the mesolimbic/mesostriatal pathway
- NMDA receptor hypofunction
- 5HT2Areceptor hyperfunction in the cortex
The main dopamine pathways relevant to psychosis and schizophrenia are:
(1) Mesolimbic (mesostriatal) pathway - positive symptoms (e.g., delusions, hallucinations, etc.)
- It is hypothesised that increased dopamine transmission (hyperdopaminergia) in the mesolimbic/striatal pathway causes the positive symptoms of schizophrenia
- Therefore, blockade of dopamine in this pathway (via antipsychotics) reduces positive symptoms
(2) Mesocortical pathway - negative symptoms (e.g.,anhedonia, social withdrawal, alogia etc.)
- It is hypothesised that decreased dopamine transmission in the mesocortical pathway mediates the negative symptoms
- Therefore, blockade of dopamine receptors in this pathway canworsennegative symptoms
- This may account for why clozapine works well on negative symptoms, as it has low dopamine blockade
(3) Nigrostriatal pathway - parkinsonism
- Destruction of this pathway occurs in Parkinson’s disease
- Blockade of dopamine receptors in the nigrostriatal pathway, therefore, mimics Parkinson’s disease and leads to similar symptoms.
(4) Tuberoinfundibular pathway -hyperprolactinemia, sexual dysfunction
- Dopamine blockade in the tuberoinfundibular pathway is responsible for increase prolactin and sexual dysfunction/side effects
- Prolactin is produced by lactotrophcells in the pituitary:
- D2 agonism inhibits prolactin release
- 5HT2A stimulates prolactin release
- Therefore, D2 antagonism/partial agonism disinhibits prolactin release (i.e., increases prolactin); however, many atypical antipsychotics are 5HT2A antagonists, which blocks prolactin release (i.e., decreases prolactin). As a result, many atypical antipsychotics have a neutral effect of prolactin release (this is not true for all antipsychotics)
-
Clozapine
- S_uggested to be more effective than all other antipsychotics_
- Reserved for treatment-resistant schizophrenia due to side effects and special monitoring requirements
- Less likely to experience EPSE
- The only antipsychotic to reduce suicide in schizophrenia
- Associated with significant side effects and therefore requires special monitoringfor -neutropenia, agranulocytosis, seizures, cardiomyopathies and potentially life-threatening constipation (paralytic ileus)
Lithium
It has a lot of largelyunknown mechanisms and is used for bipolar and mania; its actions include
- Inhibition of dopamine release
- Enhancement of serotonin release
- Downregulation of NMDA (excitory) glutamate receptors
- Promotion of GABA (inhibitory) neurotransmission
- Inhibition of second messenger systems
Adverse effects - Therapeutic drug monitoring (TDM) is used to reduce adverse effects
- metallic taste, nausea, diarrhoea, epigastric discomfort, weight gain
- fatigue, headache, vertigo, tremor,hypothyroidism
- Hyponatraemia increases lithium toxicity
- Nephrotoxicity:
- Nephrogenic diabetes insipidus with polydipsia and polyuria is frequent (may be reversible on stopping).
- Lithium treatment is associated with reduced glomerular filtration rate; and lithium is renally cleared
- Nephrotic syndrome rarely occurs and can resolve after stopping lithium.
- Long-term lithium treatment (>10years) increases the risk of renal tumours, eg cancers and oncocytomas.
Provide differential diagnoses of migraine
Bad ie with migraine, meningism signs
- SAH
- tumour
- migraine
- sagital sinus thrombosis
- bac viral meningitis
- intraparenchymal/IC blled
- idiopathic intracranial hypertension
Describe dural venous sinuses
Venous Drainage of the Cerebral Hemispheres
- Dural sinuses constitute the superficial system
- Include superior and inferior sagittals, straight, right and left transverse, sigmoid, cavernous, confluence
- Venous dural sinuses are contained between two layers of dura mater.
- They drain venous blood from the brain, with virtually all the outflow from the cranium via the sigmoid sinus to the internal jugular vein (at the jugular foramen).
- The cavernous sinus also drains blood from the central face and orbit, acting as a potential source of infection.
Venous Drainage of the Cerebrum
- Involves cerebral veins and venous dural sinuses.
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Cavernous Sinus
- Acts as a venous “hub” with multiple “spokes” including:
- Superior ophthalmic vein
- Superior and inferior petrosal sinus
- Intercavernous sinuses
- Sphenoparietal vein/sinus
- Contains C4 +/− C5 segments of the carotid artery, CN VI; and CN III, IV, V in the wall.
- Sympathetic nerves to the orbit leave the carotid and pass to ciliary nerves.
Anterior
Sphenoparietal sinuses Cavernous sinuses
Cavernous sinus Superior and inferior petrosal sinuses
Midline
Superior sagittal sinus Typically becomes right transverse sinus or confluence of sinuses
Inferior sagittal sinus Straight sinus
Straight sinus Typically becomes left transverse sinus or confluence of sinuses
Posterior
Occipital sinus Confluence of sinuses
Confluence of sinuses Right and left transverse sinuses
Lateral
Superior petrosal sinus Transverse sinuses
Transverse sinuses Sigmoid sinus
Inferior petrosal sinus Internal jugular vein
Sigmoid sinuses Internal jugular vein
