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Development and microanatomy of the CNS Development of the CNS

Lamina terminalis Forebrain Midbrain Hindbrain Ventricular system


Cerebral hemispheres Thalamus and hypothalamus Midbrain Pons and cerebellum Medulla

Rhomb Forebrain

Temporal lobe

Types of CNS cells Astrocytes Types Protoplasmic astrocytes found around cell body and processes Fibrous astrocytes found around axons Functions Help form blood-brain barrier by way of endfeet that reinforce capillary tight junctions Enclose the environment of the synapse and remove neurotransmitter As radial glia during development, guide migrating neurons to their appropriate locations and help direct axonal outgrowth In the cause of trauma, help wall off remaining intact CNS from blood and infection Oligodendrocytes myelinate multiple axons in the CNS Schwann cells myelinate a single PNS axon Microglia Originate from bone-marrow derived monocytes React to pathological processes in CNS phagocytose degenerating cells, help remodel CNS during development, change morphology and upregulate monocytes and macrophages in response to infection 1

Cerebrospinal fluid Production by choroid plexus of lateral ventricle Ependyma (lining of ventricle) + pia = tela choroidea Tela choroidea + blood vessels = choroid plexus

Circulation, resorption by arachnoid granulations/villi of superior sagittal sinus int. jugular vein Lateral interventricular foramen 3rd cerebral aqueduct 4th medial and lateral apertures sinuses spinal cord

CNS morphology Cerebellar cortex Outermost layer molecular layer (just below the pia) Middle layer Purkinje cell layer Inner layer granule cell layer Incoming fibers project to Purkinje cells & granule cells Output is via Purkinje fibers

Cerebral cortex (neocortex)

I = outside; VI = inside layer Receptive layers II and IV granule cells Projection layers III and V pyramidal cells

Hippocampus (archicortex) Hippocampus proper (Ammons horn) contains pyramidal cells Dentate gyrus contains granule cells that project to other cells within the structure

Response to damage Regeneration In the PNS, axons can normally regrow to the target following transection, particularly if the neural sheath is still intact and Schwann cells are present to facilitate growth In the CNS, there is usually no functional reinnervation due to glial scarring and secretion of growth inhibitors axon degenerations toward the axon terminal Sprouting adjacent cells may sprout new terminals to synapse on targets that have been deafferented in both PNS and CNS Internal anatomy of the brain (see lecture slides) Ventricular system

Caudate-putamen system (deep to cerebral cortex)

Hippocampus-fornix system The fornix arises from the hippocampus as a thin flap on its medial surface. After descending through the wall of the 3rd ventricle, it terminates in the mamillary bodies of the hypothalamus. Temporal horn of lateral ventricle separates the amygdala from the hippocampus.

Brainstem landmarks Midbrain

Open Medulla


Caudal medulla

The reticular formation, EEG, and normal sleep Reticular formation Anatomy Reticular formation is a network of highly interconnected nuclei that are most prominent in the central core (tegmentum) of the brainstem. Caudally, it is continuous with the intermediate zone of spinal cord control of autonomic functions Rostrally, it is continuous with several thalamic nuclei and projects widely to the cerebral cortex 4

control of consciousness and arousal Functions Control of consciousness ascending reticular activating system (ARAS) of rostral nuclei Control of motor function involved in posture and movement Control of autonomic function (HR, BP, respiration, digestion, etc.) in dorsal nuclei Control of sensory function (ex. neurons in PAG or raphe nuclei) Solicits input from other (often higher) brain regions that may be needed to produce specific responses acts as a sorting facility Generates EEG rhythms and controls timing mechanisms responsible for switching between sleep and wakefulness and between different stages of sleep EEG measures changes in electrical potential of the superficial cortex near the measuring electrodes EEG rhythms Alpha rhythm slow, large voltage wages adult at rest with eyes closed Beta rhythm faster (18-30 per second), lower amplitude Theta rhythm 4-7 per second, large amplitude Delta rhythm <4 per second, large amplitude deep sleep, coma Mental activity or stimuli replace waves with fast, irregular, low voltage activity (desynchrony) Normal sleep Non REM sleep (75%) 1. Drowsy transitional state characterized by decreased muscle tone, slow rolling eye movements, and mixed EEG waves 2. -like sleep spindles appear, wave frequency decreases 3. EEG activity becomes higher in amplitude/voltage, but slower in frequency (theta waves) 4. EEG activity becomes the slowest (delta waves) REM sleep (25%) rapid eye movement, decreased muscle tone, changes in heart and respiratory rate, fluctuations in body temperature, dreams; EEG similar to stage 1 **Transitions between sleep stages are controlled by reticular formation

Arterial supply to the brain Regulation of cerebral blood flow The brain is able to maintain fairly constant blood flow and pressure. Such autoregulation occurs in response to local metabolic conditions, and causes changes in blood vessel diameter by way of autonomic neurons. CO2, blood flow (major regulator) O2, blood flow Autoregulation can only go so far, however. When BP < 50-70 mmHg, autoregulation fails and there is decreased blood flow to the brain. When BP > 140 mmHg, capillary destruction may occur. After 8-10 second of hypoxia, brain dysfunction begins (ex. syncope/fainting) After 3-4 minutes of hypoxia, neuronal damage ensues Arterial routes supplying the brain Internal carotid system branches from common carotid artery Ant. cerebral artery (ACA) supplies of the medial surface of frontal and parietal lobes Middle cerebral artery (MCA) travels in the lateral fissure and supplies most of the lateral 5

surface of cerebral hemispheres + anterior pole of temporal lobe + orbital cortex Posterior communicating artery (Pcomm) proceeds posteriorly and joins with arteries of the vertebral-basilar system Vertebral-basilar system Vertebral arteries branch from subclavian artery, ascend through the transverse foramina of the cervical vertebra, & enter the cranial vault through the foramen magnum Anterior spinal artery (ASA) fuse together at midline and descend along ventral spinal cord Posterior spinal artery (PSA) descend independently along the dorsal spinal cord Posterior inferior cerebellar artery (PICA) independently supply inferomedial cerebellum and the medulla Basilar artery formed by the merging of the two vertebral arteries at the pontomedullary junction, after they have given off ASA, PSA, and PICA Anterior inferior cerebellar artery (AICA) supplies inferolateral cerebellum + pons Superior cerebellar artery (SCA) supplies sup. cerebellum + inf. colliculus + midbrain Posterior cerebral artery (PCA) supplies posterior & inferior parts of cerebral hemispheres + superior colliculus

Circle of Willis

Somatosensory pathways from the body Overview Dorsal column / medial lemniscus 2 point discrimination, vibration/pressure, conscious proprioception Anterolateral spinothalamic pathway pain localization and nature/quality (sharp, dull, etc.) Anterolateral spinoreticular pathway emotional & autonomic responses to pain DC/ML

SS1 = Brodman areas 3,1,2 SS2 = 5-7




Medulla (crossing in caudal medulla)

Cervical spinal Lumbar spinal

Anterolateral spinothalamic and spinoreticular tracts

Propriospinal/Spino-spinal tract minor pathway; very aversive visceral pain, crude touch, itch

Sensory components of mixed cranial nerves

Sensation from the head Main sensory nucleus of V 2 point discrimination Vibration Spinal nucleus of V pain (Mesencephalic and motor of V jaw proprioception; next page) Spinal nucleus extends to C2-C3 and merges with the substantia gelatinosa in the dorsal horn. V anterior face VII, IX and X pain from meninges, inner ear, external ear, posterior and anterior pharynx

Control of jaw proprioception The neurons of the mesencephalic nucleus are equivalent to DRG neurons in the periphery: they have a peripheral process that travels in the V nerve and a central process that provides input to the Motor nucleus of V. There is NO cell body in the Trigeminal Ganglion, and NO synapse in the Mesencephalic Nucleus.


Visceral sensory information

Motor neuron and spinal reflexes

Muscle spindle detects stretch myotactic reflex (monosynaptic) Muscle spindles are composed of intrafusal fibers that lie in parallel to the contractile extrafusal fibers. When the muscle is stretched, the Ia sensory fibers are distorted and generate receptor potentials that sum to produce action potentials. The Ia sensory fibers synapse directly onto the motor neurons and cause contraction of the extrafusal fibers. resting length is restored When the muscle shortens, the spindle is relieved of tension, and Ia fibers are no longer stimulated. In the absence of Ia input, motor neurons are stimulated and cause contraction of the intrafusal fibers muscle spindle remains sensitive If the passive stretch is of sufficient degree, Ia fibers may interact with interneurons and inhibit antagonistic muscles to facilitate contraction Golgi-Tendon Organ detects force inverse myotactic reflex (polysynaptic) The GTO lies in series with the muscle. Its Ib afferent terminals intertwine with the collagen network of the tendon. Stimulation of the Ib fiber by a very large change in force results in stimulation of an inhibitory interneuron that relaxes the muscle.


Withdrawal reflex response to noxious stimulus to subcutaneous tissue or muscle (polysynaptic)

Inhibition of extensor muscle + stimulation of flexor muscle pulling away from noxious stimulus Crossed extensor reflex: When the stimulus is strong enough, the reflexive response may go so far as to include excitation of the extensor musculature in the contralateral limb and inhibition of the contralateral flexors

Other local influences on motor neurons Inhibitory input by Renshaw cells Excitatory input of recurrent collaterals

LMN and UMN Pathways Cortical areas involved in motor activity 1o motor cortex directly contacts lower motor neurons or interneurons, which in turn target LMNs Posterior parietal cortex (BA 5-7) generates an internal model of the movement before it is made Premotor cortex (BA6, inferior) produces movements guided by external stimuli Supplementary motor area (BA6, superior) planning of internally generated movements Mirror neurons (parietal and premotor cortex) fire both when an action is performed and when it is observed in another person


Corticospinal tract (pyramidal tract)

Corticospinal tract, along with the corticorubral and corticoreticular tracts, travels within the middle 3/5 of the crus cerebri.

Corticorubrospinal and Corticoreticulospinal tracts As noted above, corticorubral and corticoreticular tracts travel with the corticospinal tract until they reach their destination. Rubrospinal tract decussates in midbrain and descends only to cervical cord levels. Reticulospinal tracts descend the length of the cord. Pontine reticulospinal medial tract Medullary reticulospinal lateral tract

Vestibulospinal tract Vestibular nuclei (sup, inf, lat, med) are present at the pontomedullary junction Medial longitudinal fasciculus (MLF) and medial vestibulospinal tract (MVST) originate from all 4 vestibular nuclei. They travel down to the cervical level. Lateral vestibulospinal tract originates from just the lateral nucleus. It travels all the way down the spinal cord.


(ponine) Vestibulospinal output is not under cortical control but is under cerebellar control. Motor tracts in the cervical spine

Effect of motor lesions LMN LESIONS No conscious control No monosynaptic reflex Areflexia or hyporeflexia Flaccid paralysis or paresis Denervation atrophy profound, very rapid onset

UMN LESIONS No conscious control Monosynaptic reflex intact Hyperreflexic (no inhibitory control) Babinski sign, Hoffmans sign, posturing Spastic paralysis Disuse atrophy (slow)

Decorticate vs. decerebrate posturing Decorticate movement (flexor) transection above the red nucleus Corticorubral tract severed, no inhibition of rubrospinal tract flexion of upper limb Intact reticulospinal and vestibulospinal tracts cause extension of lower limb Decerebrate movement (extensor) transection below the red nucleus Corticoreticular tract is severed Reticulospinal and vestibulospinal tracts cause extensor movement of upper and lower limbs


The autonomic nervous system Divisions of ANS Sympathetic arises in the lateral grey of the thoracolumbar region (T1-L2) fight or flight response Parasympathetic arises in brainstem and sacral region rest and digest response

Monitoring of ANS by higher brain centers The hypothalamus controls autonomic responses via descending fiber tracts that synapse with reticular formation cells involved in homeostasis Medial forebrain bundle Dorsal longitudinal fasciculus Mammillotegmental tract Preganglionic parasympathetics from CN III (papillary constriction), VII (lacrimal and salivary glands except parotid), IX (parotid gland), and X (thoracic and abdominal viscera) receive inputs from: Hypothalamus directly From reticular formation centers ( e.g., respiration, cardiac, etc.) that are controlled both locally and by the hypothalamus Reflexes via sensory cranial nerves containing visceral afferents Significance of ANS function or dysfunction Autonomic dysfunction occurs in association with many neurological diseases or syndromes, including Parkinsons, Huntingtons, spinal cord and head injury, multiple sclerosis, and tumors. Horners syndrome sympathetic dysfunction Symptoms Ptosis (upper eyelid drooping) Miosis (pupillary constriction) due to unopposed parasympathetic innervation 14

Facial anhydrosis (inability to sweat) Causes Peripheral lesions of preganglionic fibers in sympathetic trunk, or postganglionic fibers in superior cervical ganglion CNS lesions in reticular formation or cervical spinal cord, or preganglionic sympathetic nuclei in the spinal cord

Endogenous sensory modulation pathways Pain modulation may augment or suppress incoming sensory information Analgesia condition where nociceptive stimuli are perceived but not interpreted as pain Allodynia pain from stimuli which are not normally painful, or pain that occurs in a location away from the area stimulated (not the same as referred pain) Anesthesia loss of sensation Descending influences on pain modulation PAG can synapse on pontine and medullary raphe of the reticular formation, or synapse directly on the dorsal horn of the spinal cord. Raphe neurons themselves synapse on the dorsal horn of the spinal cord. 5-HT (from raphe nuclei) is the main neurotransmitter

Local pain modulation in the dorsal horn


Motor components of cranial nerves Control of extraocular movement III at level of superior colliculus Controls superior, medial, inferior rectus + inferior oblique + levator palpebrae superioris Oculomotor nucleus for somatomotor innervation Edinger-Westphal nucleus for para/pre MLF connects all Lesion to III results in: nerves involved in Deviation of eye laterally (strabismus) extraocular movement Diplopia (double vision) Inability to look , , or medially Drooping eyelid (ptosis) Pupillary dilation (mydriasis) due to unopposed sympathetic innervation

IV at level of inf. colliculus Innervates superior oblique intorsion of the eye Only CN that decussates within the brainstem before exiting Lesion results in: External strabismus Diplopia when looking (ex. going down stairs) Extortion of eye (since there is no intorsion) Patient may tilt head away from affected side to compensate VI at midpontine level (see next page) Innervates lateral rectus abduction of eye Lesion results in: Inability to look laterally Medial strabismus 16

Diplopia Control of the muscles of mastication CN V Lesion to V results in: Sensory deficits from the face Paralysis of muscles of mastication (V3) atrophy (produces facial asymmetry) Weakness on chewing if unilateral loss Protrusion of the jaw results in deviation toward side of lesion

VII (facial) control of facial muscles and glands (except parotid) Lesion to VII results in: Paralysis of muscles of facial expression (Bells palsy) Dryness of eyes (insufficient parasympathetic innervation of lacrimal gland)


Innervation of muscles of pharynx, larynx, palate (motor + para/pre) IX (Glossopharyngeal) Somatomotor innervation to stylopharyngeus muscles (nucleus ambiguus) Para/pre input to parotid gland (inferior salivatory nucleus) Lesion has little effect X (Vagus) Somatomotor innervation of all other muscles of pharynx, larynx, palate (nucleus ambiguus) Para/pre to thoracic and abdominal viscera (dorsal motor nucleus of V) Lesion results in: Dropped palate deviation of uvula away from affected side Hoarse voice General visceral dysfunction Bilateral lesion causes death by asphyxiation (occluded airway)

CN XI (Accessory) control of sternocleidomastoid and trapezius Lesion of XI results in: Depression and atrophy of shoulder Inability to shrug Paralyzed sternocleidomastoid inability to turn head away from affected side (since left SCM turns the head to the right)


CN XII (Hypoglossal) control of intrinsic and extrinsic muscles of tongue (ex. genioglossus) Lesion of XII results in: Paralysis and atrophy of tongue muscles difficulty speaking On protrusion, tongue deviates toward affected side


nerve oculomotor trochlear trigeminal abducens facial glosso. vagus accessory hypoglossal

motor nucleus oculomotor trochlear trigeminal abducens facial ambiguus ambiguus accessory hypoglossal

motor output extraocular muscles, levator palpebrae sup. superior oblique muscles of mastication lateral rectus muscles of facial expr. stylopharyngeus all other muscles of pharnynx, larynx, palate sternocleidomastoid and trapezius tongue muscles

para nucleus EdingerWestphal

para output constriction of pupil and muscles of ciliary body

brainstem level at exit midbrain midbrain pons pontomedullary jxn

superior salivatory inferior salivatory dorsal motor nucleus of X

glands except parotid parotid gland viscera of thorax and abdomen

pontomedullary jxn medulla medulla medulla, spinal cord medulla

Corticobulbar pathways Corticobulbar neurons are the UMNs for motor cranial nerves Corticobulbar input to motor cranial nerve nuclei Corticobulbar tract travels in the posterior limb of the internal capsule, rostral to CoSpTr. It gives off branches that affect the nuclei of cranial nerves. 19

Laterality of corticobulbar input to cranial nerve motor nuclei Lesion to areas with bilateral input result in transient weakness, not paralysis, of the innervated muscles.

Corticobulbar input to the facial nerve Rostral part of VII nucleus upper of face (bilateral input) Caudal part of VII nucleus lower of face (contralateral input) UMN lesion Total loss of input to caudal VII nucleus Ipsilateral input to rostral VII nucleus ok only lose 1 quandrant of motor function LMN lesion Loss of input from both caudal and rostral portions of VII nucleus motor loss to half of face (Bells Palsy)

Complex eye movements Eye movement systems Saccadic eye movements (conjugate) bring targets of interest rapidly into view via snapshots Horizontal eye movements are carried out by III and VI Vertical eye movements are carried out by III and IV Smooth pursuit (conjugate) tracking to allow stable view of a moving object Vergent movement Convergence when focusing on objects that are moving closer medial rectus Divergence when focusing on objects that are moving further lateral rectus Reflexic movement Vestibulo-ocular reflex allows images to remain in focus on retina as we move in space Nystagmus occurs when we turn our heads rapidly Rapid horizontal saccadic conjugate movement of the eyes toward the side were turning to Then, fixation on an object and tracking of that object to the opposite side as we continue making the turn


Control of eye movement systems Cortical centers initiate movement Both of the frontal eye fields project (via corticobulbar projections) to brainstem gaze centers.

Brainstem gaze centers control the coordinate movement of each eye only for saccades Horizontal gaze center Paramedian Pontine Reticular Formation (PPRF) controls horizontal conjugate gaze via connections in the MLF Vertical gaze center rostral Mesencephalic Reticular Formation (MRF) controls vertical movements of both eyes Dorsal part moves eyes up Ventral part moves eyes down Superior colliculus smooth pursuit and tracking INTERNUCLEAR OPHTHALMOPLEGIA destruction of the MLF disrupts control of III nucleus by the horizontal gaze center

With a lesion to the left MLF: If the person is asked to look to the right, the right eye moves Left eye cannot because PPRF cant activate the medial rectus of the left eye. With a lesion to right PPRF Left eye cant move, as just discussed Right eye cant move either


Basal ganglia General features Structures Caudate striatum Corpus striatum Putamen Lentiform nucleus Globus pallidus External segment Internal segment Substantia nigra Pars compacta (dorsal) Pars reticulata (ventral) analogous to GPi Subthalamic nucleus (nucleus accumbens where caudate and putamen merge anteriorly) Functions High order motor functioning Initiation of movement Prevents unwanted movement Permits desired movement and changes in muscle tone Cognitive and emotional functions Social and executive functions lesions produce personality changes, emotional disturbances, psychiatric problems Motivational drives Memory Circuitry Direct pathway reduces tonic inhibition motor output Indirect pathway increases inhibition suppresses movement DA promotes motion by stimulating direct pathway and inhibiting the indirect pathway


Disorders of the basal ganglia HYPOKINETIC DISORDERS due to increased inhibition on thalamus lack of stimulation to cortex Akinesia slowness in the initiation and execution of voluntary movement (ex. Parkinsons, due to loss of DA neurons in substantia nigra)

HYPERKINETIC DISORDERS due to inhibition on thalamus increased stimulation of cortex Chorea involuntary quick, jerky movements of head and limbs (ex. Huntingtons, due to loss of GABA neurons in striatum)

Athetosis slow, writhing, sinuous movements; seen in late stages of Huntingtons disease Hemiballismus violent involuntary movement involving the proximal musculature on one side of body; typical of lesions of subthalamic nucleus 23

Cerebellum Anatomy CEREBELLAR CORTEX Spinocerebellum = paramedian zone Cerebrocerebellum = lateral zone Vestibulocerebellum = median zone + flocculonodular lobe

DEEP NUCLEI Fastigial Globose Emboliform Dentate (looks like the inferior olivary nucleus) Dont Ever Get Fat

PEDUNCLES Superior peduncle is next to the ventricle Middle peduncle is huge


Functions of the cerebellum CEREBELLUM Coordination of motor functions to aid in producing smooth, synergistic movements balancing forces on all joints correct timing of contractions Comparison of ongoing movements with intended movements correction of errors Motor learning Maintenance of equilibrium, balance, and posture Preparation for acquisition of sensory info

BASAL GANGLIA Initiate complex movements Enhances desired movements Suppresses undesired movements Unlike the basal ganglia, the cerebellum directly receives sensory information from the body and head and integrates it with input from the association cortex. It also directly influences UMNs.

Input to the cerebellum Cortico-ponto-cerebellar tract coordinates fine movements of distal musculature (fingers and toes)

Spinocerebellar and cuneocerebellar tracts unconscious head and body proprioception


(Vestibular system involves fastigial nuclei) Olivocerebellar pathways motor learning Olive Oll deep nuclei Oll areas of cortex

Cerebellar processing


Output pathways (to all UMNs) Cerebellum influences all upper motor neuron pathways Corticospinal (+CoRu, CoRet) via the VA, VL Rubrospinal via direct output to red nucleus Reticulospinal via direct output to RF Vestibulospinal via direct output to vestibular nuclei Cerebellum receives input from and controls ipsilateral musculature. VA/VL of thalamus is needed for the cerebellum to communicate with the contralateral cortical regions that control those same muscles,

Cerebellar lesions In general, cerebellar lesions result in: Ataxia (lack of coordination of gait and limbs) Eye movement abnormalities (particularly saccades) Nausea, vomiting, vertigo Speech abnormalities (explosive, irregular in rate and volume) Unsteadiness Decreased muscle tone and pendular reflexes Important points Cerebellar lesions result in no (apparent) sensory deficits Lesions result in ipsilateral motor deficits Lateral lesions affect distal musculature more than proximal and medial lesions affect proximal axial musculature more than distal musculature. Lesions of the middle or inferior peduncle may have the same apparent result as lesions of the cerebellar cortex or whole cerebellum (since thats where the information comes in) Discrete lesions of cerebellar cortex may have a relatively mild result. Deep nuclear lesions, or lesions of the superior cerebellar peduncle, are usually much more severe and enduring than cerebellar cortical lesions. Syndromes Anterior lobe syndrome primarily affects legs, causing broad stance, staggering gait, and general lack of coordination (ex. alcohol) Posterior lobe syndrome lack of coordination of voluntary movement timing problems, intention tremor, difficulty with alternating movements (dysdiadochokinesis), disturbed speech Lesions of flocculo-nodular lobe disturbances in equilibrium and balance, and ability to perform conjugate eye movements during body movement


CNS Vasculature (see p. 5-6) Internal carotid system handles 80% of CNS blood flow. Aneurisms and cardiac emboli are more likely in the carotid circulation than in the vertebral circulation. Arterial supply to the internal structures of the cerebrum Anterior choroidal arteries branch from internal carotid; follow the contour of the optic tract Medial aspect of the temporal lobe Choroid plexus in the temporal horn Hippocampus Amygdala Optic tract to LGN of thalamus

Medial striate artery branch from ACA

Head of caudate Nucleus accumbens Adjacent anterior limb of int. capsule in the frontal lobe

Lateral striate arteries branch from MCA Globus pallidus Putamen Tail of caudate Posterior limb of internal capsule

Posterior choroidal arteries branch from PCA Posterior/dorsal thalamus Choroid plexus of 3rd ventricle


Arterial supply to lower brain structures Basilar artery Superior Cerebellar Artery **Inferior colliculus (PCA supplies superior colliculus) **Superior cerebellar peduncle Superior surface of cerebellum Deep nuclei of cerebellum CN III arises AICA between SCA **Middle cerebellar peduncle and PCA Dorsal pons Inferolateral surface of cerebellum Inner ear (labyrinthine arteries) Pontine branches of basilar artery basilar pons Vertebral artery PICA **Inferior cerebellar peduncle Inferomedial cerebellum Medulla Venous drainage of the CNS into dural sinuses internal jugular vein External veins


Internal veins

Vestibular system Structure of the inner ear (found within the petrous part of the temporal bone) PERILYMPH is found in the space between the bony and membranous labyrinths. high Na+, low K+ ENDOLYMPH is found within the membranous labyrinth low Na+, high K+

Sensory cells of the vestibular system UTRICLE AND SACCULUS Linear acceleration of the head Movement monitored: Maculae Hair cells contained in: Gelatinous membrane hair cells Otolith membrane* are embedded in: *Contains otoliths (CaCO3 stones) that help displace the hair cells

SEMICIRCULAR CANALS Angular acceleration of the head Ampulla (contain cristae) Cupula

In both systems, the hair cells have their basolateral surfaces in perilymph, and their apical surfaces exposed to endolymph. Movement of endolymph either directly causes movement of the stereocilia, or the gelatinous material they are embedded in. Displacement of the stereocilia toward the kinocilium depolarizes the sensory nerve Displacement away from the kinocilium hyperpolarizes the sensory nerve 30

Central connections of the vestibular system Vestibular information from the maculae and ampullae is transmitted to the brainstem as the vestibular nerve by bipolar neurons whose cell bodies are in the vestibular ganglion. Axons of the vestibular nerve terminate in the vestibular nuclei. They can then connect to: Cerebellum

MLF and MVST (particularly information about angular acceleration from the semicircular canals) reflexic movements of the eyes in response to head movement Lateral vestibulospinal tract (particularly information relating to linear acceleration) govern muscles that react to changes in gravity Nystagmus Nystagmus is the characteristic slow tracking of the eye to one side, followed by rapid saccade to the opposite side of the head during rotation of the head; may be horizontal, vertical, or rotatory. It is caused by the vestibulo-ocular reflex that allows one to maintain visual fixation on a target object while the head moves. direction of nystagmus is described according to the direction of the fast movement Vestibular nystagmus Corresponds to the deflection of the cupula in one direction at the onset of rotation and in the opposite direction at the end of rotation Not dependent on vision, and can be produced with the eyes open or closed Caloric nystagmus (diagnostic test) Putting cool water in the external auditory canal produces a nystagmus toward the opposite side Putting warm water in the canal produces a nystagmus toward the same side Optokinetic nystagmus Reflex eye movements that allow the eye to follow objects in motion when the head remains stationary (e.g. observing individual telephone poles on the side of the road as one travels by them in a car) Eyes follow a random pole for a bit, and then suddenly snap back to fixate on a new pole Oculocephalic reflex (Dolls Eye reflex) When the reflex is present, the eyes of the patient remain fixed on a single target while the head is moved; thus the eyes move in relation to the head. The presence of a reflex is normal. Absence of this reflex produces eyes that remain pointed in a constant forward direction


The auditory system Signal transduction in the ear

1. Incoming sound vibrates the tympanic membrane, causing the ossicles to vibrate 2. Stapes footplate presses in the oval window and creates pressure waves in the perilymph of the scala vestibuli (first part of the cochlea). Fluid flows from the scala vestibuli, though the helicotrema, and into the scala tympani; pressure is relieved by outward movement of the round window. 3. As fluid moves past the cochlear duct (scala media), its basilar membrane oscillates at a frequency corresponding to the frequency of fluid movement. 4. Outer hair cells (OHCs) sit atop the basilar membrane in the Organ of Corti. Oscillation of the cochlear duct deflects their stereocilia against the tectorial membrane. a. Deflection of the hair toward the tallest stereocilium opens K+ channels. b. Based on the large concentration gradient of K+ between the perilymph and endolymph, K+ flows out of the hair cell and depolarizes its membrane.

5. The OHCs then contract, thereby feeding additional energy into the basilar membrane. The inner hair cells are thus excited, and transmit information about pitch to the CNS through afferent branches of the cochlear nerve. a. High frequencies are detected nearest to the stapes (membrane is narrow and stiff) b. Low frequencies are detected near the apex (membrane wide and flexible).

Central auditory pathways 32

Afferent auditory input Dorsal and ventral cochlear nuclei Superior olivary nucleus optional synapse Inferior colliculus Medial geniculate nucleus of thalamus

Due to substantial decussation, information from both ears is carried on both sides of the brainstem

Efferent fibers controlling cochlear hair cells

Olivocochlear bundle is involved in controlling OHCs (cochlear amplifier cells) to allow for focus on desired frequencies Superior olivary nuclei are also important in sound localization


Central visual pathways Pathway from retina to visual cortex The nasal visual field is represented on the temporal retina and vice versa. The axons of the ganglion cells in the nasal retina cross at the optic chiasm Axons of the ganglion cells in the temporal retina stay on the same side. About 90% of the ganglion cells synapse in the LGN of the thalamus, and then project to the visual cortex via the optic radiation (geniculocalcarine tract). There is retinotopy throughout this pathway. The remaining 10% synapse in the pretectal area pupillary reflex (see next page) **The right portion of each visual fields (temporal R and nasal L) end up in the left cortex, and vice versa. Retinotopy in visual cortex Macula has a very large cortical representation relative to its physical size. It projects to the caudal-most region of V1. Peripheral regions of retina project more rostrally. Superior visual fields project below the calcarine sulcus. Inferior visual fields project above the sulcus. Structure of the visual cortex 6 layers LGN projects to layer 4 Stripe of Gennari (only in BA 17) Input from the right and left eyes is segregated into eye-specific ocular dominance columns, each of which responds to specific visual characteristics (orientation, movement, shape) Primary visual cortex projects to: BA 18 (which then projects to BA 19) visual association cortex Information from each eye remains separate from retina through primary visual cortex Only in BA 18 and 19 does information from both eyes converge. Back to the LGN to provide feedback To the pulvinar, superior colliculi, and pretectal regions to help modulate reflexes.


Lesions within the visual pathway named based on what part no longer works Hemianopsia of the visual field cannot be seen Quadrantic blindness of visual field cannot be seen Homononymous same visual field is affected in each eye Heteronymous opposite visual field is affected Pupillary light reflex As noted, 10% of the retinal fibers bypass the LGN and instead synapse in the pretectal nucleus. Each pretectal nucleus projects bilaterally to the Edinger-Westphal nuclei, thereby enabling a consensual response to light. Projection to the contralateral EW nucleus is through the post. commissure

Accommodation focus on near objects (para) Eyes converge due to contraction of medial rectus muscles Lenses thicken due to contraction of ciliary muscles (para) Pupils constrict (para)


Hypothalamus Anatomical features Rostral boundary optic chiasm Caudal boundary mammillary bodies (level of middle thalamus) Middle boundary Tuber cinereum the bulge of tissue between the optic chiasm and the mammillary bodies Infundibulum connects hypothalamus to pituitary gland Median eminence is an elevation of the rostral portion of the infundibulum where it emerges from the hypothalamus Blood supply from the circle of Willis

Functions of the hypothalamus **Due to significant overlap of function, lesions must be extensive or bilateral to cause symptoms Control of body temperature Anterior hypothalamic area heat loss (sweating, cutaneous vasodilation, thirst) Posterior hypothalamic area heat gain (shivering, cutaneous vasoconstriction, metabolism through TRH) Control of circadian rhythms suprachiasmatic nucleus

Control of fluid balance ADH, oxytocin Supraoptic nucleus (SON) primarily produces ADH in response to blood osmolarity Paraventricular nuclei (PVN) primarily produce oxytocin Control of feeding Ventromedial nucleus satiety Lateral hypothalamic area hunger Mammillary nuclei Control of autonomic function (especially sympathetic) via inputs from reticular formation (mammillotegmental tract) Consolidation of new memories via connections with hippocampus Control of endocrine function (arcuate fibers releasing hormones ant. pituitary) 36

Emotional responsiveness Mammillary nuclei, anterior thalamic nuclei, limbic cortex (via mammillothalamic tract) Dorsomedial nucleus of hypothalamus and thalamus, limbic cortex (via intrinsic hypothalamothalamic tracts) Medial forebrain bundle (MFB) connects hypothalamus with septal nuclei and cortex Ventral amygdalofugal pathway and stria terminalis connect hypothalamus to amygdala Hippocampus via the fornix Control of autonomic nervous system Parasympathetic Dorsal Longitudinal Fasciculus (DLF) Sympathetic: MFB/Hypothalamospinal tract (projects directly to intermedio-lateral spinal cord sympathetic neurons) Mammillotegmental tract (MTegT)

Thalamus and thalamocortical relations Sensory nuclei VPL pain and sensation from body VPM pain and sensation from head MGN auditory LGN visual Motor nuclei VA Input from globus pallidus and cerebellum Projects to premotor cortex and prefrontal association cortex (motor loop of basal ganglia) VL Input from dentate nucleus of cerebellum and all loops of basal ganglia Involved in regulation of movements as a link between basal ganglia and cortex CM (an intralaminar nucleus) feedback circuitry in basal ganglia 37

Association nuclei DM Reciprocal pathways with prefrontal cortex (anterior cingulate gyrus, orbitofrontal cortex, and frontal association cortex) Involved with integration of visceral information via connections with hypothalamus, amygdala, and olfactory cortex Involved in spinoreticular pain pathway emotional response to pain Pulvinar Reciprocal connections with association cortex of parietal, temporal, and occipital lobes Receives input from primary visual cortex, prectectal regions, and from the superior colliculi Lateral dorsal (LD) reciprocal connections with posterior cingulate gyrus Lateral posterior (LP) involved in integration of higher sensory information via reciprocal connections with somatosensory association cortex Anterior nuclei Input from mammillary bodies via mammillothalamic tract Major output is to anterior cingulate cortex Non-specific nuclei Reticular nucleus inhibition of other thalamic nuclei and reticular formation


The limbic system LIMBIC LOBE = cingulate gyrus, retrosplenial cortex, parahippocampal gyrus (including uncus and entorhinal cortex), hippocampus, dentate gyrus, and septal areas.

Olfaction Olfactory pathways

Odors are detected by bipolar neurons that are embedded in olfactory epithelium. They have a limited lifespan (30-60 days) and are continuously replaced throughout life These sensory neurons project as the olfactory nerve (CN I) to the olfactory bulb, which forms the olfactory tract. Olfactory tract then bifurcates into medial and lateral olfactory stria. Lateral olfactory stria projects to the ipsilateral primary olfactory cortex (BA 34), located near the uncus. There is no synapse in the thalamus. Entorhinal cortex (BA 28) in parahippocampal gyrus serves as olfactory association cortex Medial olfactory stria projects to the amygdala, the septal nuclei, and the hippocampus. Olfactory information is also shared between adjacent regions of olfactory cortex via projections in the anterior commissure Septal nuclei pleasant emotion The septal nuclei are found rostal to the anterior commissure at the base of the septum pellucidum


Connections Hippocampus (via the fornix) Hypothalamus (via medial forebrain bundle) Amygdala (via stria terminalis and ventral amygdalofugal pathway) Frontal cortex, cingulate gyrus, brainstem reticular formation Functions Thought to be involved in reward phenomena or pleasurable qualities of emotions Connections with hippocampus are thought to be important for establishing pleasant associations with some memories Amygdala unpleasant but essential emotions Amygdala is found in the rostral temporal lobe, deep to the uncus.

Connections Hypothalamus and septal nuclei via stria terminalis Hypothalamus, septal nuclei, striatum, olfactory cortex, thalamus, temporal lobes via ventral amygdalofugal pathway Functions Links conscious, cognitive aspects of feelings and experiences with somatic expression of those feelings (via autonomic nervous system) Helps to integrate appropriate visceral and somatic motor responses associated with drives Programs appropriate behavioral response required for basic drives Modulates hypothalamic activities, and also the activities of other limbic structures Involved in both innate and learned emotional responses, particularly fear and apprehension Bilateral amygdalectomy Kluver-Bucy syndrome Emotional flatness Compulsive hyper-attentiveness to sensory stimuli Psychic blindness (objects not recognized visually) Hypersexuality Changes in eating behavior


Hippocampus Located in medial temporal lobe; forms the floor of the temporal horn of the lateral ventricle

Connections Temporal lobe cortex and amygdala (via intrinsic connections) Hypothalamus primarily mammillary bodies (via fornix) Septal nuclei (via fornix) Function Essential for formation of new memories, especially declarative memory pathology is found in patients with Alzheimers disease and Korsakoffs syndrome Essential in learning Limbic system connections

Cerebral cortex Histology Types of cortex Neocortex constitutes 90% of cortex 6 layers Transitional cortex restricted to regions of limbic lobe 3-6 layers Archicortex hippocampus and dentate gyrus 2-3 layers Cells Granule cells receive incoming information Pyramidal cells are the chief efferents 41

Layers of neocortex I molecular layer II external granular layer input from association cortex III external pyramidal layer output to other regions of cortex IV internal granular layer input from thalamus V internal pyramidal layer output to spinal cord and brainstem (via Betz cells) VI fusiform/polymorphic layer

Sensory cortex has prominent II and IV Motor cortex has prominent III and V

Cortical connections Intracerebral association fibers connections between different gyri or lobes Short association fibers connect adjacent gyri Long association fibers connect gyri of different lobes Superior longitudinal fasciculus frontal, parietal, and occipital lobes Arcuate fasciculus -- frontal & temporal lobes; also connects Brocas area to Wernickes area Uncinate fasciculus frontal and temporal lobes Cingulum (on medial surface) septum and hippocampus

Intercerebral commissural fibers connection between homologous areas of the two hemispheres Corpus callosum Genu interconnects superior and lateral aspects of frontal lobes Body interconnects parietal lobes Splenium interconnects occipital lobes Anterior commissure interconnects inferior frontal lobes & temporal lobes Extracerebal projection fibers cortex and subcortical structures (travels within internal capsule) Corticospinal tract, corticobulbar tract, etc. Cortical deficits Aphasia inability to perform certain language functions Neglect disturbance of ones ability to recognize portions of the environment or self Right parietal lobe damage left-sided neglect Agnosia inability to recognize objects using a given sense, despite functional sensory mechanisms Apraxia inability to perform an action, despite the fact that relevant motor pathways are intact Agraphia inability to write Alexia inability to read Dementia decline in memory and other cognitive abilities impaired general function Loss of long projection neurons of cerebral cortex Loss of pyramidal neurons in CA1 and subiculum regions of hippocampus Loss of neurons in Nucleus Basalis of Meynert (ventral to globus pallidus; dorsal to optic tract) 42

Laterality Properties of functional hemispheric differences Ubiquity laterality occurs in many functional processing domains, from motor control to language and spatial cognition Subtlety most hemispheric asymmetry is mild, except for speech Complementarity both hemispheres normally play a role in complex activities Laterality of language Left identification of words Motor speech Brocas area Lesion non-fluent, labored, halting, difficult to start; writing is also impaired Receptive language Wernickes area Lesion person cannot understand their own words or the words of others; speech rate and intonation are normal, but speech is nonsensical Reading angular gyrus Right identification of emotional tone of speech and processing narrative-level linguistic information Laterality of perception and attention Neglect syndrome occurs after damage to R parietal lobe L side of body and visual field is ignored Prospagnosia damage to ventral occipitotemporal regions (esp. R) deficits in face recognition Visual processing posterior superior temporal areas L is dominant for extracting local details R is dominant for extracting global aspects of stimuli Laterality of emotion Experience of emotions (frontal lobe) L is dominant for positive emotions R is dominant for negative emotions Identification of emotion R is better Language Perception Emotion Left Motor and receptive speech Local details of stimuli Feeling positive emotions Right Emotional aspects of language Global aspects of stimuli Face recognition Feeling negative emotions Identifying emotion

Individual variation in hemispheric asymmetry Handedness 95% of righties are left-lateralized for language, vs. 65% of lefties Biological sex women are better with verbal fluency; men are better with spatial ability Age R hemisphere function declines more rapidly with age


Basics of sensory physiology Sensory receptors General principles Each receptor responds more readily to a particular modality than do other types of receptors (i.e. it takes less touch stimulus to excite a touch receptor than to excite a temperature receptor) Each receptor has a specialization that allows it to sense the modality of interest, a way to communicate changes in the stimulus to the nervous system, and a cell body the receptor is either itself an axon of a sensory neuron, or is a specialized cell that synapses with adjacent sensory neurons Sensory transduction Receptors transduce stimulus energy into graded generator/receptor potentials and transmit this information toward the central nervous system Adaptation allows sensory neurons to maintain their responsiveness as the mean level of the stimulus changes Phasic receptors respond very rapidly at the onset of the stimulus and then quickly adapt to the stimulus and stop responding Tonic receptors (such as those involved in proprioception, temperature, and pain) adapt very slowly and maintain their response to a stimulus over time

Sensory coding Sensory unit a sensory axon + all its peripheral branches Sensory modality the type of sensory information that is conveyed (ex. pain, temp, touch, sound) Stimulus intensity the frequency of action potentials sent to CNS + variation in # and type of receptor Within a particular receptive field, weak stimuli will activate receptors with low thresholds; strong stimuli activate receptors with higher thresholds As the strength of the stimulus is increased, it tends to spread over a larger area and activate sensory units in adjacent areas both of these are considered recruitment Stimulus location and acuity related to receptive fields Small receptive field, or overlap among adjacent fields, helps localize the stimulus Somatotopy receptive fields are conveyed to the CNS in an organized fashion that preserves the origin of a particular sensation Lateral inhibition receptors at the edge of a receptive field are inhibited by the receptors in the center of a receptive field enhanced boundaries of the stimulus Stimulus duration primarily related to adaptation/desensitization

Physiology of excitable cells: Membrane Potentials Membrane potentials Electrochemical equilibrium The equilibrium potential represents the voltage difference needed to exactly oppose a concentration gradient. It is given by the Nernst equation:
RT Cout = Vin Vout = E ln zF Cin

The further Vm is from Eion, the greater the ionic current: I = g (Vm E) When Vm = E, there is no net ion movement and the concentration gradient is maintained Resting potential The resting potential depends on the conductance of Na and K:
Vm = g Na gK EK + E Na g K + g Na g K + g Na

At rest, since GK > GNa, Vm is closer to EK Action potentials 1. Initial stimulus opens some voltage-gated sodium channels, allowing influx of Na+ ions. Because Vm is now further from Ek than at the resting potential, K+ efflux increases. 2. For weak stimuli, K+ efflux still exceeds Na+ influx. 3. As the stimulus strength increases, more and more Na channels open, leading to more Na+ influx 4. Once Na+ influx exceeds K+ efflux, a positive-feedback cycle starts and an action potential results Rapid increase in GNa drives the membrane potential toward ENa. Slower increase in GK repolarizes the membrane by driving Vm toward EK. Because GK remains elevated even after the membrane has returned to its resting potential, the membrane hyperpolarizes. 5. The action potential then propagates along the cell membrane with the same magnitude because local depolarization opens adjacent voltage-gated Na channels and maintains the inward Na current In myelinated axons, Na channels are found only at nodes of Ranvier. The myelin serves to insulate the axon and keep current from leaking out of the membrane so the action potential can jump from node to node saltatory conduction. Local/graded potentials electrotonic conduction In local responses, the magnitude of the depolarization is proportional to the stimulus. Because the currents induced by these potentials are too small to initiate an action potential, they propagate with decreasing magnitude until they dissipate (vs. action potentials, which have the same magnitude and travel the entire length of an axon).

Chemical neurotransmission Classes of neurotransmitters Acetylcholine Biogenic amines Catecholamines dopamine, norepinephrine, epinephrine (more of a hormone than NT) Serotonin Histamine Amino acids Excitatory glutamate, aspartate Inhibitory GABA, glycine Neuropeptides Endogenous opioids endorphins, enkephalins, dynorphins Substance P Gases nitric oxide Synaptic transmission at the neuromuscular junction Induction of the signal Action potential in the presynaptic cell depolarizes the presynaptic membrane, causing influx of Ca2+ through voltage-gated calcium channels Synaptic vesicles fuse with presynaptic membrane, and Ach is exocytosed into the synapse Ach diffuses across synaptic cleft and binds to nAChR, opening the ion channel and causing the end plate potential (EPP) Although GNa and GK both increase when the ion channel opens, GNa increases faster and there is a greater concentration gradient for sodium depolarization -bungarotoxin inhibits the function of nAChR Curare prevents ACh from binding to the receptor In the disease myasthenia gravis, there is decreased density of nAChR at the NMJ (probably due to autoimmune mechanisms). EPP extreme muscle weakness & rapid onset of fatigue EPP is transmitted electrotonically from the synapse toward the axon hillock, which has a high density of Na+ channels (and therefore a lower threshold) When EPP sums to threshold at the axon hillock, an action potential results Termination of the signal Acetylcholinesterase on the postsynaptic membrane hydrolyzes Ach to acetate and choline Anticholinesterases inhibit ACh-ase larger and prolonged EPP (but also desensitization) Hemicholiniums inhibit the reuptake of choline by the presynaptic cell ACh depletion ACh also diffuses out of the synapse Post-synaptic potentials PSPs represent 1-2 mV changes in membrane potential due to release of neurotransmitter from a single presynaptic cell. Integration of many synaptic inputs (temporally or spatially) can sum up to produce an action potential at the axon hillock. Excitatory PSP caused by neurotransmitters (Glu, Asp) that GNa or GK Inhibitory PSP caused by neurotransmitters (GABA, Gly) that GK or GCl 3

Microanatomy of the eye Anatomical structures Outer tunic Cornea No vessels (transparent) Nutrition from limbal vessels or aqueous humor Immune privilege to prevent inflammation and damage Sclera give the eye its shape and helps protect its inner parts Conjunctiva Vascular membrane that covers sclera and lines the inside of the eyelids Helps lubricate the eye by producing mucus and tears Uvea (vascular tunic) Choroid Vascular layer between retina and sclera Leaking choroid age-related macular degeneration Ciliary body and processes Produces aqueous humor Controls accommodation by changing the shape of the lens via zonules Iris sphincter around the pupil of the eye that is responsible for the papillary reflex Lens Focuses light onto the retina Protects against UV damage Thickens and becomes less elastic with age presbyopia (inability to accommodate) Involved in accommodation Hyperopia (farsighted) light focused behind retina convex lens Emmetropia normal vision Myopia (nearsighted) light focused in front of retina concave lens Vitreous humor Retina Cell types Pigment epithelium phagocytose shed outersegment disks, regenerate visual pigment; remove waste Photoreceptors transduce light 1st order neuron Bipolar cells 2nd order neuron Ganglion cells 3rd order neuron Horizontal cells enable lateral interactions between photoreceptors and bipolar cells Amacrine cells connect bipolar cells and ganglion cells Retinal glial cells Muller cells and microglia In the fovea, overlying cellular layers and blood vessels are displaced so there is a clear pathway to the densely-packed cones

Visual physiology Phototransduction Changes in membrane potential of the photoreceptors In the dark, there is a high [cGMP] in cytoplasm of photoreceptor. Na+ channels are open, and photoreceptor is depolarized Ca2+ can enter, and Glu is tonically release Light causes a conformational change in the opsin molecules (11-cis all-trans) that enables them to activate the transducin G-protein Transducin activates phosphodiesterase, which hydrolyzes cGMP Na+ channels close, membrane hyperpolarizes, less Glu released onto bipolar cells Deactivation of the photocascade requires phosphorylation of rhodopsin (catalyzed by rhodopsin kinase) and arrestin binding Regeneration of 11-cis retinal from all-trans retinal requires the enzymes present in the retinal pigment epithelium Transmission to the CNS Bipolar cells relay the signal from the photoreceptor to ganglion cells Ganglion cells form the optic nerve and project to the LGN of the thalamus and to other parts of the brain Concept of convergence In the rod system, many photoreceptors converge on a single ganglion cell In the cone system, few photoreceptors converge on a single ganglion cell better acuity Most ganglion cells have circular receptive fields with a center-surround orientation Surround has the opposite firing preference to the center for each type of ganglion cell On-center ganglion cells increase their discharge rate to luminance increments Off-center cells increase their discharge rate to luminance decrements.

Horizontal cells and amacrine cells mediate lateral inhibition in the outer and inner plexiform layers, respectively help detect edges Functional specialization of rod and cone systems SCOTOTOPIC VISIONvery low lightonly rods activated MESOPIC VISIONrods and cones activated PHOTOPIC VISIONbright lightrods saturated, only cones active red, green, and blue cones 5

Cell and tissue response to injury in CNS Pathologic reactions of neurons ISCHEMIC CELL CHANGE (RED NEURON) irreversible Between 8 and 24 hours after a hypoxic insult, the neuron shrinks and the cytoplasm becomes eosinophilic. The nucleus shrinks and becomes darkly stained. The intracellular changes involved include ATP depletion, acidosis, impaired reuptake of glutamate, accumulation of calcium, and generation of free radicals. WALLERIAN DEGENERATION When a PNS axon is transected, the axon and its myelin sheath degenerate distal to the site of injury. Eventually, the degenerating axon is broken up into short fragments that are phagocytosed. The axon may re-sprout in the PNS by way of central chromatolysis.

CENTRAL CHROMATOLYSIS After severe injury to the axon (particularly in motor neurons), the cell body swells, Nissl substance dissolves, and the nucleus migrates to the periphery of the cell. This sequence of events is an attempt by the neuron to increase protein synthesis and restore the integrity of its axon after injury; in the PNS, axonal regeneration occurs in most cases. INCLUSION BODIES Neurofibrillary tangle Alzeheimers:

Pick body Picks disease (a type of dementia)

Lewy body Parkinsons Negri body rabies Cowdry type A herpes, CMV Pathologic reactions of oligodendroglia round nuclei, no apparently cytoplasm on H & E MYELIN LOSS Multiple sclerosis (autoimmune) Progressive multifocal leukoencephalopathy (PML)

INCLUSIONS papova virus in PML produces a homogenous glassy nuclear inclusion

Pathologic reactions of astrocytes oval nuclei, many processes ASTROCYTOSIS (gliosis) secretion of GFAP produces hypertrophied astrocytes (gemistocytes)

INCLUSIONS Rosenthal fiber at end of astrocyte feet due to chronic gliosis

Pathologic reactions of microglia elongated nuclei; derived from mesoderm Reactive microglial cell Macrophage response (from differentiated microglia or monocyte) Microglial nodule response to low-grade infection

Multinucleated giant cell reaction HIV encephalitis, AIDS dementia

Pathologic reaction of ependymal cells Ependymal rosettes due to displacement of ependymal cells from ventricle during infection

Cerebral edema Cytotoxic edema due to Vasogenic edema due to disruption of blood-brain barrier; occurs predominantly in white matter

Congenital malformations and mental retardation Landmarks in the development of the nervous system Neural tube closure day 22 Starts at 2nd 7th somite and moves rostrally and caudally Rostral neuropore closes at day 24 Caudal neuropore closes between day 26-28 defects are more common in lumbosacral region because it closes later Outgrowth of telencephalic vesicles (future cerebral hemispheres) 5th week Proliferation in germinal matrix Cell migration cerebral cortex is formed inside out beginning about 7 weeks and finishes by 16 wks Gyration starts at 24 weeks Myelination begins about 20 wks in brainstem & spinal cord and progresses through 18 wks post-birth Axonal, dendritic, and synaptic development occurs throughout life (involved in learning & memory) Malformations Neural tube closure defects (dysraphism) most commonly caused by folic acid deficiency Spina bifida occulta a clinically-silent simple bony defect in the lumbosacral area that is often covered by a nevus, hairy patch, lipoma, or dimple; involves no neural tissue Meningocele involves protrusion of meninges and CSF through bony defect Myelomeningocele involves protrusion of meninges + spinal cord through the bony defect almost 80% of spinal meningoceles and meningomyeloceles are associated with hydrocephalus Encephalocele involves protrusion of meninges + brain Anencephaly lack of fusion of rostral neuropore results in deficient skull formation incidence currently 1/10,000 births Failure of diverticulation of telencephalic vesicles (holoprosencephaly) Involves incomplete development and septation of midline structures Failure of cerebrum to divide into left and right hemispheres Cyclopia, microcephaly, hypotelorism (close set eyes), single maxillary incisor Teratogens, chromosomal anomalies (ex. trisomy 13, defect in sonic hedgehog gene) have been described as causatory agents Incidence 1/250 during embryogenesis and 1/16,000 newborn infants 4

Migration defects Heterotopias groupes of neurons that have halted their migration and differentiated within the white matter proximal to their final destination in the cortex Gyration defects gyri may be absent, increased in number, or broader than usual Hydrocephalus increased amount of CSF Obstructive hydrocephalus (99% of cases) blockage of CSF flow Non-communicating hydrocephalus obstruction occurs within brain; caused by: Developmental malformation (ex. aqueduct stenosis) Ependymoma of IVth ventricle Fibrosis following chronic meningitis Communicating hydrocephalus obstruction occurs in subarachnoid space or within the arachnoid granulations (insufficient reabsorption); caused by: Subarachnoid hemorrhage Meningitis Dural sinus thrombosis Most cases of myelomeningocele are associated with Arnold-Chiari malformation that causes obstructive hydrocephalus Enlarged cerebellum, misplaced medulla and IVth ventricle obstruct foramen magnum Obstruction or agenesis of cerebral aqueduct Non-obstructive hydrocephalus (1%) due to excessive production of CSF from a choroid plexus papilloma Mental retardation Definition Significantly sub-average general intelligence (IQ < 70) with concurrent deficits in adaptive behavior (communication, social skills, home living) Onset during developmental period Etiology Prenatal factors Chromosomal abnormalities trisomy, deletion, sex chromosome abnormality, fragile X Metabolic peroxisomal and lysosomal diseases, neurological disorders Congenital infections rubella, CMV, toxoplasma, treponema Prenatal drug exposure Malnutrition Perinatal factors Prematurity (esp. < 28 weeks) Small for gestational age Germinal matrix hemorrhage (often rupture into lateral ventricles) Postnatal factors Severe infections of CNS encephalitis, meningitis Lead or mercury poisoning Asphyxia

Cerebral palsy Definition Group of chronic disorders impairing control of movement that appear in the first few years of life but generally do not worsen over time Disorders are caused by faulty development or damage to motor areas in the brain that disrupt the brains ability to control movement and posture Symptoms include difficulty with fine motor tasks, difficulty maintaining balance or walking, and involuntary movements Etiology May be congenital or acquired after birth Common causes include cerebral asphyxia or hemorrhage, head injury, jaundice, Rh incompatibility, and rubella A child who is at highest risk for developing cerebral palsy is premature, of low birth weight, requires mechanical ventilation for several weeks, and develops an intracranial hemorrhage

Neoplasms of the CNS Brain tumors comprise 9% of all primary neoplasms metastases are far more common They are the 2nd most common neoplasm in children, and 6th most common in adults General principles Site and type vary by age Children 70% are below tentorium medulloblastoma, ependymoma, cerebellar astrocytoma Adults 70% are above tentorium metastatic carcinoma, glioblastoma, astrocytoma, meningioma, pituitary adenoma Malignancy Benign tumors are very rare compared to other sites of the body Histological malignancy related to anaplasia, mitotic activity, and necrosis Clinical malignancy related to tumor site, since many regions are inoperable Growth patterns Local expansion (well-circumscribed) meningioma, Schwannoma, ependymoma Local infiltration malignant meningioma, astrocytoma, metastatic carcinoma Diffuse infiltration pontine glioma, astrocytoma, glioblastoma multiforme Multifocal primary lymphoma, glioblastoma multiforme, metastasis Metastasis Primary tumors only metastasize within the CNS spread through CSF pathways Metastasis outside CNS from a primary tumor is very rare Sites of growth Metastatic from other sites in the body (often at junction of white and grey matter) Intracranial, extracerebral (arise from meninges, nerve roots, pineal gland, pituitary) Intracranial, intracerebral Tumor presentation Intracerebral mass with focal neurological signs seizure, loss of function Metabolic encephalopathy Cranial nerve palsies

Tumor types
Tumor type Meningioma Presentation Intracranial pressure, seizure, twitching Compression, invasion, destruction of brain parenchyma; disturbed CNS function Severe headaches, papilledema cell of origin Arachnoid membrane cap cell common site of localization gross appearance Attached to dura Circumscribed lesion that compresses cortex and ventricles Cerebral Poorly defined, hemispheres homogenous microscopic appearance Whorls, mitotic figures prognosis 90% cure with complete excision


Immortalized astrocyte

Depends on grade


Glial cell with p53 mutation or EFG amplification

Motor cortex or Infiltrating mass, adjacent compression of subcortical ventricle region

Medulloblastoma Listless, headache, momiting, papilledema

Primitive neuronal cells

Vermis of cerebellum; seeds CSF due to proximity to IVth ventricle

Pallisading Bad necrosis, increased cellularity, pleomorphism, mitotic figures sheets of highly Depends on grade cellular discohesive primitive small cells with scant cytoplasm; mitotic figures; necrosis

Schwannoma tumor of Schwann cells compresses nerve Neurofibroma fibroblasts and other cells and structural elements infiltrate a peripheral nerve and destroy it (esp. VIII) Grading 3 tiered system Well differentiated astrocytoma/oligodendroglioma/ependymoma (low grade) Anaplastic astrocytoma/oligodendroglioma/ependymoma (malignant) Glioblastoma multiforme **WHO classification I (ex. juvenile pilocytic astrocytoma) low proliferative potential, discrete, circumscribed surgically curable II (astrocytoma) infiltrative tumors with cytologic aplasia but no mitotic figures slow progressing III (anaplastic astrocytoma) histologically malignant + cytologic atypia + mitotic activity 3-5 year survival IV (glioblastoma multiforme) mitotic activity + cytologic atypia + endothelial proliferation or tumor necrosis (often pallisaded by tumor cells) 9-18 month survival

Infectious diseases of the central nervous system General concepts BBB normally deters invasion of infectious agents, but hampers their clearance once penetrated. Thus, infections of the CNS are rare but life-threatening complications of systemic infections. Antibodies and immune cells are scarce in the brain and CSF, except in cases of infections. ** Antibodies found in the normal CNS are derived from serum; that is, they have leaked out from the blood into the CSF (no equilibrium between serum and CSF). Because diffusion across the CSF barrier is size-dependent, IgM is present at even lower levels than IgA and IgG. When inflammation disrupts the BBB, antibodies and immune cells leak into the CNS, along with other serum proteins. ** PMNs are the dominant inflammatory cells in acute bacterial infections of the CNS ** Mononuclear cells are the dominant inflammatory cells in viral infections and in subacute infections like TB and fungal infections Acute Meningitis Clinical manifestations **Headache, fever, and nuchal rigidity are the classic signs altered mental status If bacterial meningitis is not promptly treated, build-up of pus can cause cranial nerve palsies, hydrocephalus, vasculitis infarct death Causes Bacteria often causes permanent sequellae Birth 2 months enteric bacteria, strep, or listeria are the most common causes (immune system hasnt developed yet) 10% of acute meningitis but 50% of deaths 2 months 5 years H. influenzae was the most common cause, but is declining due to immunization; S. pneumo is still common Older child/adult N. meningitidis (epidemic disease) and S. pneumo are most common Virus enterovirus, mumps, HIV; infection is self-limiting and relatively benign; few sequallae

Pathogenesis Most bacteria and viruses invade the CNS from the blood, causing influx of immune cells and the formation of pus Bacteria multiply rapidly in CSF cerebral edema (vasogenic and cytotoxic) increased intracranial pressure herniation, hypoxia, infarct 8

Risk of CNS infection is related to magnitude and duration of bacteremia or viremia because pathogens are normally cleared by macrophages Intracellular bacteria (ex. M. tuberculosis) evade immune clearing by growing in RBCs Enteroviruses and arboviruses are cleared less effectively because of their small size

Treatment Mortality due to untreated bacterial disease approaches 100% need to treat early, and with agents that penetrate BBB; even with treatment, sequellae are frequent in survivors Viral meningitis requires only symptomatic treatment, since the disease is self-limiting Chronic meningitis (far less common; almost always associated with infection) Clinical picture fever, headache, stiff neck, mental status change, cranial nerve deficits Causes Bacteria M. Tuberculosis, spirochetes (syphilis, borrelia see below), Brucella Fungal cryptococcus, candida, coccidioides, histoplasma Parasitic cystercercosis, toxoplasmosis Viral retroviruses (HIV), enteroviruses CSF profile High pressure High protein Low glucose Mononuclear leukocytes Brain abscesses Pathogenesis Develop from a contiguous focus of infection (ears, sinuses or teeth), or by hematogenous spread from a distant focus of infection **Abscesses are thought to result from bacterial seeding of already devitalized tissue Many have mixed flora of aerobic and anaerobic bacteria strep (60-70%), staph, enterobacteria, and bacteroioides Fungi cause < 10% of brain abscesses Clinical manifestations Headache, focal signs, seizures CSF is usually sterile need to culture an aspirate of the abscess cavity Treatment Broad-spectrum antibiotics If there is encapsulation of the abscess, it should be drained to determine the specific infectious agent and to prevent rupture into the ventricles Spinal epidural and cerebral/spinal subdural abscesses are surgical emergencies can cause paralysis below the level of the abscess

Viral encephalitis/encephalomyelitis Acute viral encephalitis Clinical presentation fever, altered mental status, seizures Diagnosis CSF examination (profile similar to viral meningitis) Inflammatory response of mononuclear cells RBCs may be found in HSV encephalitis due to necrotizing pathology CSF protein is usually elevated; glucose is normal Other methods include viral culture, serology, antigen detection, MRI, EEG, brain biopsy Pathologic features Infection and destruction of neurons and glial cells Resulting inflammatory response produces neuronophagia (phagocytes surrounding neuronal debris), microglial nodules, astrocytosis, infiltration by mononuclear cells, and cerebral edema Etiologic agents Herpes (usually HSV-1) In neonates, disease is primarily due to HSV-2 and often becomes systemic In children and adults, disease is caused by HSV-1 and remains localized Arboviruses (hematogenous spread) West Nile virus spread to humans by mosquito bite Most people experience no or only mild flu-like symptoms 1/150 develop severe neurological symptoms Rabies produces characteristic Negri body in pyramidal cells Polio selectively infects motor neurons in spinal cord and brain stem Subacute encephalitis (ex. subacute sclerosing panencephalitis) Clinical presentation Occurs several years after an acute episode of measles, usually before 2 years of age 5-15 years later, symptoms set in behavioral changes seizures and motor problems coma and death Pathology Perivascular inflammation, astrocytosis, neuronophagia Viral nucleocapsid inclusions Postinfectious encephalitis Clinical presentation Follows mumps, measles, varicella, or other viruses as the viral syndrome is waning High fever, headache, vomiting, convulsions, coma, focal neurological signs Pathology Gross exam may be unremarkable or show some discoloration of white matter Microscopic exam shows perivenous foci of demyelination, with sparing of axons and a mononuclear cell infiltrate Virus cannot be isolated disease is immunologically mediated Neurosyphilis caused by Treponema pallidum (25% of untreated patients) Meningovascular syphilis a form of subacute or chronic meningitis Progressive fibrosis of meninges + chronic inflammatory infiltrate of meningeal vessels (particularly with plasma cells) Signs/symptoms depend on what part of the brain is affected and if cranial nerves are damaged General paresis chronic meningoencephalitis, with neuronal loss and gliosis Progressive mental and physical decline 10

Early dementia and personality changes predominate Tabes dorsalis myelopathy + degeneration of posterior columns Pain, ataxia, urinary incontinence Absent deep tendon reflexes, impaired vibratory and position sense in lower extremities Lyme borreliosis Early and late neurological involvement In 15% of untreated patients, subacute or recurrent meningitis, encephalitis, cranial nerve palsies, and peripheral neuropathies develop 1-9 months later. AIDS-related infections infect CNS soon after systemic infection Opportunistic infections CMV encephalitis Toxoplasmosis Primary CNS lymphoma (high grade B cell) Progressive multifocal leukoencephalopathy due to JC virus (a papova vrus) Other conditions (usually at the time of full-blown AIDS) Leukoencephalopathy cortical atrophy + areas of white matter pallor; often associated with giant cells Vacuolar myelopathy Spongiform encephalopathies Disease forms Kuru Creutzfeldt-Jakob disease Gerstmann-Sraussler syndrome Disease spread Growth hormone extracted from cadaveric pituitary glands Transplantation of corneas and grafts of dura Ingestion of infected neural (and other) tissue Parasites and neurological disease Acute encephalopathy or meningitis Malaria (esp. P. falciparum) Amebiasis Trichinosis Chronic neurological disease ** Taenia solium cystocercosis Trypanosoma sleeping sickness Schistosoma cerebral granulomas Toxoplasma gondii (immunodeficient patients) abscesses


Cerebrovascular diseases Ischemic injury Ischemia = reduced blood flow stagnant hypoxia Global ischemia involves the whole brain to approximately the same extent most common during cardiac arrest, during seizures, or as a result of intoxication (esp. with barbiturates) Neurons are more vulnerable than glia, microglia, and capillaries Cortical neurons, neurons in the globus pallidus and hippocampus (esp. Sommers sector), and cerebellar Purkinje cells are particularly susceptible Neurons of the brainstem and spinal cord are more resistant Watershed areas, at the interface between the distributions of major cerebral arteries, are also vulnerable because they are relatively hypoperfused to begin with Infarct = focal cell death due to prolonged ischemia Pathophysiology At the center of an infarct, cells are killed rapidly due to bioenergetic failure and ensuing breakdown of cell membranes and organelles Penumbra reversibly damaged brain parenchyma between the infracted zone and normal tissue; if the blood supply is not restored quickly, it progresses to infarct Infarction results in liquefactive necrosis of both neurons and glia, often accompanied by reactive gliosis to wall off the damage 12

Etiology **Cerebral atherosclerosis is the most common cause of ischemic infarction, either due to plaque occluding the vessel lumen, or by thrombus formation Most commonly occurs in middle cerebral artery or basilar artery Hydrocephalus ex-vacuo loss of necrotic tissue results in an enlarged ventricle Lacunar infarct microvascular occlusion, particularly in the basal ganglia and pons Embolus More commonly related to hemorrhagic infarcts because subsequent dislodgement or dissolution of the embolus allows reperfusion through vessels damaged by ischemia Vasculitis is linked to multiple embolic infarcts Microscopic features of infarcts Ischemic parenchyma is pale and vacuolated in appearance Neurons shrink, their cytoplasm becomes more eosinophilic, and nuclear detail is lost Macrophages then invade to clear the necrotic debris, leaving a cavity surrounded by gliosis Intracerebral hemorrhage Hypertensive hemorrhages Most often located in basal ganglia, thalamus, brainstem, or cerebellum Formation of a hematoma displaces brain tissue and obstructs the ventricles hydrocephalus Congophilic angiopathy Abnormal deposition of amyloid in cerebral vessels predisposes them to failure Hemorrhages are usually located in cerebral hemispheres Cerebral aneurysm subarachnoid hemorrhage Aneurysms commonly arise at the bifurcation of vessels, where blood flowing into the branchpoint produces an area of stress that ultimately bulges outward berry aneurysm. 80% of berry aneurysms occur in the portion of the Circle of Willis rostral to PComm 15% occur in basilar artery system Rupture commonly results in subarachnoid hemorrhage, but can also cause intracerebral or intraventricular bleeds They usually present with sudden onset of worst headache ever, followed by loss of consciousness. Upon waking up, patients may feel drowsy and confused, and complain of headache and neck stiffness. Vascular malformation Arteriovenous malformation is a congenital disorder in which arteries and veins are not easily distinguishable and form a tangle that lacks capillaries. They are usually superficial, often located over the cerebral convexity AVMs may be completely asymptomatic, or may cause symptoms (usually during the early 20s) Common presenting symptoms include headache, seizures, intracerebral hemorrhage, and focal neurological deficits Cavernous hemangiomas consist of a tightly packed collection of dilated venous channels. They are usually deeper, and there is less brain parenchyma between the vessels than in AVM. Usually asymptomatic, but may cause clinically significant hemorrhages, seizures, or focal neurological deficits


Visual loss Age-related macular degeneration (ARMD) Signs and symptoms Blurry vision Image distortion Central scotoma (area of lost visual acuity) Difficult reading may need magnifying glass Difficulty driving Epidemiology Most common in people > 75 yo Family history Smoking oxidative damage Non-exudative (dry) ARMD 90% Pathology Accumulation of drusen (extracellular material) between retinal pigment epithelium and Bruchs membrane in the region of the macula separation of photoreceptors from their source of nutrition (choroid) Atrophy of RPE + pigment clumping visual loss (including geographic atrophy if areas of atrophy coalesce) Management Amsler grid every day to track progression Eye exam every 6 months, or sooner if symptoms of visual loss change Antioxidant vitamins A, C, E, zinc Exudative (wet) ARMD Pathology New abnormal vessels grow from the choroidal circulation into the subretinal space and form choroidal neovascular membranes (CNVMs) These immature vessels leak, causing subretinal fluid and hemorrhage Management Photodynamic therapy to destroy CNVMs Anti-VEGF drugs to block angiogenesis Glaucoma common among African Americans Primary-open angle glaucoma (POAG) 95% of cases chronic, slowly progressing Pathology Blocked canal of Schlemm or adjacent tissue results in decreased outflow of aqueous humor Chronic increased IOP (25 vs. 22) damages retinal ganglion cells and their vascular supply Asymptomatic until late in the course of the disease, but produces significant visual field loss Signs and symptoms Visual field loss Blurry vision (late in disease state) Patient sees halos around lights due to corneal edema Management Observe IOP every 3-6 months; visual field exam every 6-12 months Decrease production of aqueous fluid with topical -blockers, -1 agonists, and carbonic anhydrase inhibitors Increase outflow of aqueous fluid with drugs (topical cholinergics and prostaglandin analogs), or surgically (trabeculoplasty, trabeculotomy) 14

Acute closed angle glaucoma 5% of cases Pathology Acute, abrupt blockage of aqueous outflow (IOP > 60) iris gets close to lens and blocks the path of fluid circulation Pupillary dilation can precipitate an attack because it increase the tightness of contact between the iris and the lens Signs and symptoms Visual field loss, blurry vision, halos (just like in POAG) Nausea, vomiting Intense pain Management Muscarinic agonists to contract the ciliary muscle and pull the iris out of the way Glycerol or mannitol as osmotic agents to decrease IOP Cataracts Pathology Cortical degeneration Opacities radiate from periphery of the lens Caused by swelling and liquefaction of younger cortical fiber cells Nuclear sclerosis Central opacity, often with lens discoloration Caused by deterioration of older cortical fiber cells Signs and symptoms Blurry vision (first a blur that progresses to failure of vision) Glare Monocular diplopia **Increasing myopia (near sightedness) need for reading glasses may disappear Management cataract extraction when visual symptoms interfere with daily living Diabetic retinopathy venous occlusive disease Pathology Non-proliferative retinopathy early stage Venous dilation A/V nicking Microaneurysms in venous capillary bed dot-blot appearance of retina Proliferative retinopathy later stages Areas of retinal neovascularization that spread into vitreous and bleed Exudates Retinal detachment may result from contraction of scar tissue Recurrent vitreous hemorrhage Signs and symptoms Blurry vision Floaters (in vitreous humor) Visual field loss (in regions of angiogenesis) Poor night vision Management Laser photocoagulation in peripheral retina to stop vitreous hemorrhages Pars plana vitrectomy (removal of vitreous) 15

Pathology of trauma and increased intracranial pressure Types of trauma Concussion transient neurological deficit induced by head trauma No structural abnormalities, but consciousness is altered Induces hypermetabolic state, retrograde amnesia, and Glu Contusion bruise of the brain due to deceleration injury, with ensuing structural injury Skull fracture Linear relatively straight; non-displaced Comminuted bone is broken into multiple fragments Depressed fragments are indented greater than the thickness of the surrounding skull Depressed fracture may need to be elevated if the dura is lacerated by the bone fragments in order to prevent seizure and focal deficits Open/compound overlying skin has been exposed (scalp laceration) predisposes to infection Management of increased intracranial pressure (normal is ~20 mmHg) Monroe-Kellie Doctrine Cranium has a fixed volume brain tissue + blood + CSF + interstitial fluid = constant If one of these constituents increases, another must decrease Large changes in volume of any of these constituents produces a rise in ICP Causes of increased ICP Cerebral edema often caused by trauma Hematoma Brain tumor General signs of ICP Headache, nausea, vomiting, altered level of consciousness, papilledema **Cushings Triad Hypertension Bradycardia Respiratory abnormalities Focal deficits if herniation occurs (see below) Treatment modalities Hyperventilation low CO2 constricts arterioles ( blood volume) Pharmacological diuresis (mannitol) interstitial fluid Ventriculostomy CSF volume Surgical removal of mass Removal of silent or injured areas of brain Craniotomy to remove part of the skull Barbiturates stop brain metabolism Herniation Subfalcine herniation Supratentorial edema in one hemisphere causes that hemisphere to escape to the opposite side by traveling under the falx cerebri Midline shift compression of ipsilateral anterior horn of lateral ventricle + possible compression of ACA weakness and sensory loss to lower limb Uncal herniation Supratentorial edema or mass effect can also push tissue downward, such that the uncus (parahippocampal gyrus) is pushed across the edge of the tentorium into the posterior fossa 16

Herniation displaces the midbrain compression of the contralateral CN III and PCA, causing: Ptosis, pupil dilation, lateral deviation of eye (contralateral to damaged side) Ischemic damage or infarct to occipital cortex Damage to descending motor pathways in the crus cerebri contralateral motor dysfxn **Kernohans notch = indentation in the crus cerebri from being displaced into the contralateral tentorium due to mass defect Duret hemorrhages in brainstem due to torsional injury associated with uncal herniation Tonsillar herniation Edema of cerebellum and brainstem (or downward displacement of supratentorial cerebral hemispheres) squeezes the tonsil through the foramen magnum The herniated tissue can compress the adjacent medulla impairment of respiration, consciousness, etc. Trans-defect herniation occurs through an acquired defect in the skull (often due to trauma or surgery) Contusions Localization Coup injury occurs in response to a blow to the surface of the brain only affects gyral crest Most common in occipital bone Contre-coup injury occurs when the brain rebounds within the skull after a coup injury Orbitofrontal cortex (due to rough areas within superior orbital plate) Tips of temporal lobes (due to confinement within wall of greater wing of sphenoid) Gross appearance Recent contusions small linear hemorrhages to the surface; only affect gyral crest Healed contusions cavities where macrophages have removed dead tissue; dark coloration due to residual hemosiderin Complications of contusions Can produce local deficits Can cause edema that can then cause brain herniation and death Old contusions may result in a seizure disorder Intracranial hemorrhage same complications as cerebral edema Epidural hematoma Caused by skull fractures of temporal bone that rupture middle meningeal artery trauma Produce a lens-shaped hemorrhage that takes up space as it grows Subdural hemorrhage Caused by torn bridging veins (which connect superficial veins with superior saggital sinus) Aging and degenerative brain diseases (ex. Alzheimers) increase the chance of a subdural bleed because an atrophic brain is smaller and stretches the bridging veins, making them more susceptible to rupture Patients with a propensity to bleed (low platelet count, decreased clotting factors) are more likely to develop subdural hemorrhages Falx provides a physical barrier that restricts a subdural hemorrhage to one side Chronic subdural hematoma results from organizing and rebleeding Outer areas of blood clot become organized and form membrane-like structures surrounding a central area that becomes liquefied by fibrinolysis Rebleeding of these neomembranes can cause an increase in the size of the clot


Subarachnoid hemorrhage Blood accumulates in subarachnoid space and fills the sulci Clinically significant SAH is associated with ruptured berry aneurysms Intracerebral hematoma Frequently associated with penetrating injury, but can be caused by bleeding from a contusion More commonly associated with focal neurological deficits Fat emboli Fatty acids from major bone fractures can enter the circulation, coalesce to form small globules, and get stuck in the capillaries of the brain most commonly occur at junction of grey and white matter Diffuse axonal injury Occurs after nonlinear twisting/shearing particularly affects corpus callosum If axons are severed, they retract and swell, causing microscopic visible axonal retraction bulbs Spinal cord lesions Spinal cord trauma causes Wallerian degeneration in both ascending and descending nerve fibers. Areas proximal to the lesion show degeneration of ascending pathways (sensation) Areas distal to the lesion show degeneration of descending pathways (motor)


Headache Pain sensitive structures in headache The brain itself has no pain fibers. Pain arises from strain/damage to the scalp, extracranial arteries, intracranial arteries near the circle of Willis, venous sinuses, large veins, basal dura, eye, mucosae of the nose, air sinuses, mouth, throat, ear, joints of the high cervical spine, CN II, II, V, IX, X, and C1-C3 spinal nerves. Painful stimuli from the anterior and middle fossa are referred mostly over the anterior part of the head and forehead. Painful stimuli from the posterior fossa are referred to the occipital region. Neurotransmitters involved in headache pain 5-HT trigeminal neurons and cranial blood vessels GABA sensory and central pain pathways Clinical syndromes of headache Acute Subarachnoid hemorrhage Sudden, severe, explosive pain Worst headache of my life Meningitis and encephalitis Buildup of headache over several hours Fever, stiff neck, and altered consciousness Subacute Giant cell arteritis (temporal arteritis) Severe headache that is present for weeks + tenderness of temporal artery jaw pain Caused by subacute granulomatous inflammation of external carotid artery system Brain tumor Dull headache (with or without vomiting) that is present for days or weeks Early morning awakening due to pain Headache worsened by laughing, coughing, or straining (reduced venous outflow) Pseudotumor cerebri (benign intracranial hypertension) Papilledema (optic nerve swelling) + reduced visual acuity Most often seen in young, obese women Chronic Migraine with aura (classic migraine) Abrupt onset of aura (most commonly visual disturbances) Totally blank area in central vision expands to the edges of the visual field and then disappears within 15-30 minutes Headache may or may not follow the aura Usually unilateral headache pain, but the affected side may differ from episode to episode Migraine without aura (common migraine) more frequent Pain appears in temporofrontal region and rapidly becomes a severe throbbing ache attended by nausea, vomiting, and dizziness Bright light, noise, and physical exertion exacerbate the pain Headache usually lasts between 4 and 24 hours 1

Tension headache Nonthrobbing, day and night, almost permanent headache + anxiety Can be episodic but is usually chronic Caused by tension of muscles of neck and shoulders Cluster headache Intense, nonthrobbing, burning, one-sided ache in the temporo-orbital region Patients pace around the room for the duration (2 hours) Bouts can recur several times a day, but also awaken the patient about 2 hours after he has fallen asleep Lithium can be a good preventative treatment Trigeminal neuralgia Brief excruciating jabs May be caused by a vascular structure irritating the trigeminal nerve Migraines Pathophysiology Familial/genetic factor, especially for migraine with aura Decrease in serotonin levels Vascular theory Aura resulted from arterial constriction Headache resulted from arterial dilation Spreading depression theory Primary disorder originates in some disturbance of brain function Arterial disturbances are a consequence Sterile inflammation/trigeminal dysfunction theory Release of neuropeptides from peripheral fibers innervating the meninges causes vasodilation and increased vascular permeability pain Treatment Abortive treatment simple analgesics, Triptan drugs (serotonin receptor agonists), narcotics Prophylaxis blockers, tricyclic antidepressants, CA2+ channel blockers, anti-seizure meds (depakote), B2, Mg, CoQ, trigger control, exercise

Neuromuscular diseases Localization within the motor unit Neurogenic disorders affect anterior horn cell or peripheral nerve (axonal part or myelin part) Junctional disorders affect NMG Myopathic disorders affect the muscle itself Laboratory tests Serum creatine phosphokinase (CPK) test Elevated in myopathic disorders Normal to slightly increased in neurogenic disorders Normal in junctional disorders Nerve conduction studies Repetitive stimulation tests (look for neuromuscular fatigability or facilitation) EMG Muscle or nerve biopsy 2

Anterior horn cell (motor neuron) disorders Amyotrophic lateral sclerosis Etiology is unknown 5% of cases are familial, with strong autosomal dominance 20% of familial cases are due to mutation in superoxide dismutase Age of onset most commonly during mid/late years of life Clinical features Purely motor (UMN + LMN) due to corticospinal tract degeneration Cramps and fasciculations Progressive muscle atrophy and wasting respiratory and swallowing impairment Extraocular and sphincter muscles are spared No pain or sensory symptoms No available treatment Peripheral nerve disorders affect motor and sensory neurons Demyelinating neuropathy Guillian Barre Syndrome Etiology immune-mediated destruction of myelin following infection Clinical features Rapid bilateral ascending demyelination produces predominantly motor weakness and disability, ultimately affecting respiratory muscles Autonomic symptoms are very common Monophasic illness, with recovery within 2-4 weeks after progression stops Lab tests Nerve conduction studies show slowed conduction velocity Nerve biopsy shows cellular infiltrates characteristic of an inflammatory disorder Blood tests for HIV/Campylobacter/Lyme help confirm preceding infection Treatment Plasmapheresis, IVIG to remove/neutralize antibodies ICU management to prevent respiratory and autonomic problems Axonal neuropathy (affects long nerves the most) Distal, symmetric muscle weakness, ultimately leading to atrophy Sensory loss (usually precedes motor symptoms) Hypo- or areflexia Decreased muscle tone Mononeuritis multiplex Affects only 1 nerve distribution Secondary to vasculitis Junctional disorders Post-synaptic Myasthenia gravis Etiology autoimmune destruction of nAChR abnormal thymus on x-ray Age of onset varies Clinical features descending fatigability and weakness, beginning in extraocular muscles Treatment ChE inhibitors to increase ACh in synapse Corticosteroids to suppress immune response Thymectomy 3

Pre-synaptic Lambert-Eaton Myasthenia Syndrome Etiology autoimmune, often paraneoplastic (esp. small cell lung cancer) Onset during mid-late years Presents with fatigue, proximal muscle weakness, and autonomic dysfunction Myopathic disorders Acquired inflammatory myopathy Etiology autoimmune Clinical presentation Purely motor symptoms and signs, particularly of proximal muscles Reflexes are lost late in the disease course Gait (waddling), trouble climbing stairs Diagnosis elevated CPK, characteristic EMG Treatment corticosteroids

Movement disorders Types of abnormal movement Hypokinesias too little movement Akinesia loss or absence of movement Bradykinesia slowness of movement Rigidity stiffness of muscle tone with passive movement of the joint Hyperkinesias/dyskinesias excess movement Tremor Chorea Dystonia Myoclonus Diseases and syndromes Parkinsonism a syndrome of bradykinesia/akinesia, resting tremor, rigidity, and postural instability Idiopathic Parkinsons Disease Clinical symptoms Tremor is usually 4-6 Hz, and is best seen at rest Patients have a generalized paucity and diminution of normal movements Shuffling gait with festination Caused by degeneration of dopaminergic neurons in the SNc Pathologic hallmark is the Lewy body in the substantia nigra Main treatment is L-DOPA, which crosses the BBB more easily than DA itself; it is given with carbadopa to inhibit conversion to DA in the peripheral circulation and minimize the resulting nausea and vomiting Long-term use can lead to motor complications such as wearing off and dyskinesias Hallucinations, agitation, paranoia, insomnia, and nightmares also occur with L-DOPA Other treatments include DA agonists, MAO-B inhibitor, antimuscarinics (since cholinergic neurons oppose effects of DA) pallidotomy, and deep brain stimulation of GPi or STN Other causes of parkinsonism ** Medications dopamine antagonists, such as neuroleptics (ex. haloperidol) or antiemetics may cause a tardive syndrome drug related choreiform movement Vascular parkinsonism due to strokes (ischemic damage to SN) 4

Hydrocephalus, frontal lobe masses Other neurodegenerative diseases Infections (postencephalitic effects) Tremor syndromes oscillatory, rhythmical, and regular movement affecting one or more body parts Essential tremor action tremor postural and kinetic (during voluntary movement) Action tremor (postural and kinetic elements), vs. resting for Parkinsons 6-10 Hz, vs. 4-6 for Parkinsons Physiologic tremor subclinical; induced by stress Intention tremor present during pursuit of a goal (ex. reaching a target) cerebellar disorder Chorea syndromes involuntary, purposeless, non-rhythmic movements that flow between body parts Huntingtons Disease Clinical features Progressive chorea involving all body parts Progressive dementia Psychiatric disturbances (personality changes, depression, schizophrenia) Symptoms begin between ages 30 and 50 HD is inherited as an autosomal dominant disease with complete penetrance Pathology demonstrates marked loss of GABAergic neurons in the striatum Ballism involves flinging limb movements; caused by lesion to STN Dystonia sydromes sustained patterned involuntary abnormal posturing (basal ganglia) Idiopathic torsion dystonia progressive generalized dystonia with no identifiable cause Begins during childhood in the lower extremities and gradually spreads to involve most parts of the body Mentation is usually spared Focal dystonia Adult onset Limited to 1-2 body areas (often cervical and upper limb) Myoclonus syndromes sudden, brief, twitch-like, involuntary movements Caused by hypoxic damage to cortex, brainstem, or spinal cord May be generalized or focal Tic disorders (ex. Tourettes) Semi-voluntary, repetitive, intermittent, stereotypic movements/sounds that are often preceded by an urge to perform the movement That urge is temporarily relieved after the tic is performed ---Wilsons Disease can present with any combination of abnormal movement types Defect in copper metabolism results in deposition of copper in brain, liver, kidney, and cornea Copper deposition in the putamen and globus pallidus results in movement disorders

Seizures and epilepsy Seizure sudden change in behavior characterized by changes in sensory perception or motor activity 5

caused by excitation of cortical neurons, with spread to, and recruitment of, adjacent neurons Epilepsy recurrent, unprovoked seizures Causes of epilepsy Birth 14 yo developmental or infection 15 24 yo trauma 25 44 tumor, trauma 45 64 tumor, vascular 65+ vascular Classification Partial seizures focal, localized Simple partial seizures sensations or motor activity, without loss of awareness Complex partial seizures (most common) involve loss of awareness/consciousness Aura loss of awareness automatic movements of face, hands, legs gradual recovery of awareness and function 1-3 minute duration 80% of complex partial seizures arise from temporal lobe Frontal lobe is 2nd most common site early motor activity, rapid recovery of awareness, occur in clusters Primary generalized seizures Absence epilepsy (petit mal) Usually occur between age 5 10; remit by adulthood Brief episodes of staring and eye fluttering, during which the patient is unresponsive 3/sec spike wave
Aura Duration Inherited EEG Post-ictal confusion Treatment Complex Partial Yes Minutes No Focal sharp waves Yes Carbamazepine, Phenytoin (Na channel blockers) Absence No Seconds Yes 3/sec, spike + wave No Valproate (increases GABA)

Juvenile myoclonic epilepsy Onset between 12-18 years of age; persist through adulthood unless treated with meds Individuals have brief jerks of the body, especially on awakening or falling asleep 4-6/sec spike and wave discharge Febrile seizures (most common seizure disorder) Occur in 5% of population upon a fast-rising fever, particularly between 3 months and 5 years Family history of febrile and other epilepsies is common Seizures may be simple or complex 2% risk of developing epilepsy EEG is usually normal, or may show excessive posterior slowing, or spike and wave Fever prophylaxis is recommended for children with history of febrile seizures Chronic daily treatment is only used in cases of recurrent or complex febrile seizures valproate or phenobarbital

Status epilepticus continuous seizure lasting longer than 30 minutes Most common causes are febrile illness in kids; drug withdrawal or chronic epilepsy in adults If allowed to persist longer than an hour, status can cause irreversible injury to the brain (particularly the hippocampus and cerebellum) Diagnostic evaluation for newly developed epilepsy EEG to help classify the seizure disorder MRI to screen for gliomas, sclerosis, AV malformation, cysticercosis, abscess, etc.

Stroke STROKE the development of a sustained, focal neurological deficit as a consequence of a local disturbance in the brains circulation. Ischemic infarction ~ 80% Hemorrhage (subarachnoid and intraparenchymal) ~ 20% TRANSIENT ISCHEMIC ATTACK the development of a reversible stroke-like syndrome that resolves within hours. Etiology of ischemic strokes Large vessel disease (30-40% of ischemic strokes) Atherosclerosis Ischemia may result from high-grade stenosis with compromised blood flow and thrombus formation, or from rupture of plaque with resultant embolization Plaque formation tends to occur the most at areas of high sheer stress and turbulent flow Arterial dissection (tear in lining of artery stenosis or aneurysm) Particularly affects internal carotid and vertebral arteries Very commonly presents with neck pain or headaches Vasculitis usually due to infection or drug use Vasospasm Prominent complication in 1/3 of subarachnoid hemorrhages, with onset days to weeks after the bleed May also be a complication of drug use (particularly cocaine) Other vasculopathies (ex. fibromuscular dysplasia and moyamoya) Small vessel (microvascular) disease lacunar infarct (20-25%) Result from occlusion of a single penetrating, small end-vessel with no collateral supply Typically occur in basal ganglia (lenticulostriate arteries), thalamus (thalamoperforant arteries), and in the pons Neurological dysfunction, including difficulty with motor functions and some degree of dementia, may occur with extensive occlusion Lacunar symptoms motor hemiparesis, ataxia (dyscoordination), clumsy-hand dysarthria, pure sensory strokes, and sensorimotor syndromes Embolic strokes (20-25%) Artery-to-artery emboli due to plaque rupture or dislodged thrombus Cardioembolic emboli due to atrial fibrillation, MI, or mitral stenosis, in which stagnation of blood leads to the formation of mural thrombi Bacterial endocarditis septic emboli Patent foramen ovale paradoxical emboli Cryptogenic (25-30%) 7

Risk factors for ischemic stroke **Previous stroke or TIA **Hypertension control of blood pressure helps prevent stroke However, once a vessel is occluded, high BP may lessen the extent of infarction by increasing perfusion through collateral circulation. Diabetes Smoking Hypercholesterolemia and hyperlipidemia (especially LDL) Elevated homocysteine levels Lack of physical activity Excessive alcohol consumption Treatment and prevention of ischemic stroke **Thrombolysis with tPA **Carotid endarterectomy vessel is opened surgically and internal plaque is removed Management of blood pressure Antiplatelet therapy (aspirin) Anticoagulation Statin therapy Intracranial hemorrhage Hypertensive hemorrhage Commonly due to vasculopathy involving deep penetrating arteries of the brain (particularly those supplying deep structures including the thalamus, pons, cerebellum, and basal ganglia) Blood may extend into the ventricular system, resulting in a poor prognosis Subarachnoid hemorrhage (SAH) 80% of non-traumatic SAHs are due to rupture of intracranial aneurysms Usually present with worst headache of a persons life, photophobia, meingismus (stiff neck), and low-grade fever need lumbar puncture to differentiate between hemorrhage and infection Tend to occur at branch points of intracranial vessels frequently located around the Circle of Willis, particularly involving AComm, PComm, MCA bifurcation, and tip of basilar artery. **Delayed morbidity (2-3 weeks after the bleed) due to vasospasm of major cerebral vessels Arteriovenous malformations (AVMs) AVMs are collections of abnormal arteries or veins with very little intervening brain parenchyma; no capillaries between arteries and veins Usually present with intermittent headaches and seizures Work-up of hemorrhagic stroke CT or MRI good for detecting hemorrhage if no hemorrhage, then can treat with tPA Lumbar puncture to look for blood in CSF (not always present)

Disorders of the ear Otalgia 8

Primary otalgia pain due to lesion in the ear (not inner ear, which lacks a sensory supply) Inflammatory due to infection of external or middle ear Auricular perichondritis bacterial infection of the cartilage of the auricle Otitis externa Bacteria localized (usually staph) or diffuse (polymicrobial) Virus often herpes Fungal aspergillus, mucor, candida Necrotizing pseudomonas in diabetic patients osteomyelitis of skull base Trauma bits, burns, frostbite, foreign-body, stab, gun shot, barotrauma Neoplastic basal cell, squamous cell, melanoma Referred (secondary) otalgia source of pain does not originate from the ear, where it is perceived Orofacial region teeth (infection), oral cavity, nose/sinuses, parotid gland (mumps), TMJ Pharynx tonsillitis, retropharyngeal abscess Larynx laryngitis, GERD, squamous cell carcinoma Other sources cervical muscle Thyroiditis Hearing loss Types of hearing loss Conductive lesion affects mechanism that transmits sound energy into cochlea Sensorineural lesion to cochlea or CN VIII noise, aging, ototoxicity, acoustic neuroma Mixed Tests to diagnose hearing loss Tuning fork test Rinne test (tuning fork on mastoid process) AC > BC normal or sensorineural hearing loss BC > AC conductive hearing loss Weber test (tuning fork on top of head) Conductive hearing loss sound heard in affected ear Sensorineural loss sound perceived in normal ear Audiogram Tympanogram Brainstem auditory evoked potentials Imaging CT better for assessing trauma; MRI better for looking at soft tissue Management of sudden hearing loss unilateral or bilateral; ranges from mild to total deafness Conductive loss management depends on cause removal of foreign body, antibiotics, etc. Sensorineural loss 60% spontaneous recovery rate prognosis for spontaneous recovery depends on age (young is better), degree of hearing loss, and onset of recovery Start medication immediately corticosteroid, acyclovir If needed, surgical exploration of middle ear for suspected oval/round window fistulae Treatment of chronic hearing loss usually bilateral, with gradual onset; complete deafness is very rare Otitis media Audiogram, otomicroscopic exam Antibiotics, analgesics Myringotomy incision in eardrum to relieve fluid pressure or drain pus Myringotomy + placement of pressure equalizing tube Tympanoplasty reconstruction of ruptured TM (often seen in chronic otitis media) 9

Otosclerosis (abnormal resorption and deposition of bone in middle ear) Audiogram Stapedectomy (removal of stapes) or stapedotomy + placement of prosthesis Sodium fluoride Hearing aids Tinnitus Pulsatile tinnitus noise in ear coincides with heartbeat life-threatening pathology (vascular) Nonpulsatile tinnitus ringing in the ear not coincident with heartbeat Onset between 40-70 years old 75% have hearing loss (mostly sensorineural) Vertigo a sense of spinning due to lesion in vestibular system Central vertigo caused by problems in brainstem Peripheral vertigo caused by problems in the bony labyrinth Benign paroxysmal positional vertigo Sudden onset, lasts for several seconds No hearing loss Caused by dislodged otoconia that improperly stimulate semicircular canals Menieres disease Spontaneous, episodic attacks of vertigo that last for minutes to hours Caused by overaccumulation of endolymph or distortion/rupture of membraneous labyrinth Vestibular neuritis Vertigo lasts for days Caused by vestibular nerve degeneration, often resulting from viral infection (ex. herpes)

Demyelinating diseases Common acquired and genetic CNS demyelinating diseases Multiple sclerosis (MS) MS variants Devics disease a progressive & severe disease that prevents as acute optic neuritis + myelitis Diffuse cerebral sclerosis of Schilder and concentric sclerosis of Balo -- very rare Acute and subacute necrotizing hemorrhagic encephalitis (Marburg disease) Acute disseminated encephalomyelitis a monophasic disease that occurs after an otherwise nondescript viral infection (or after administration of a vaccine) that produces symptoms similar to MS Non-inflammatory diseases in which demyelination is predominant Central pontine myelinolysis Progressive multifocal leukoencephalopathy polyoma virus in immunosuppressed host Subacute combined degeneration Genetic-metabolic progressive leukodystrophies Metachromatic leukodystrophy (arylsulfatide deficiency) Adrenal leukodystrophy (excess long-chain fatty acids) Krabbes leukodystrophy (galactocerebrosidosis) Multiple sclerosis 10

MS is a progressive inflammatory degenerative disease of the CNS, marked by recurrent multifocal attacks directed against myelin or oligodendroglia, that also results in axonal damage and loss. Epidemiology More frequent in adults than in kids age of onset usually in 20s and 30s Females are more affected than males (2-3:1 female:male) More common in people who live further from the equator Immigrants from high and low prevalence areas carry the risk of their region of origin if their immigration occurs after age 15 Has little impact on lifespan, but quality of life is significantly affected Disease syndromes Relapsing-remitting 45% acute onset of attacks of neurological dysfunction, which resolve and recur with an unpredictable frequency Primary-progressive 15% slow, inexorable worsening without identifiable relapses Secondary progressive initially follows a relapsing-remitting course, but then progresses with either a variable rate or with occasional relapses, remissions, & plateaus Progressive-relapsing disease

Clinical features highly variable depending on the location of the plaques Spinal tracts weakness or numbness; spasticity with hyperreflexia Cerebellum gait ataxia and nystabmus, intention tremor, and/or incoordination of arms and legs Brainstem nystagmus, diplopia, vertigo, dysarthria, Bells palsy Optic nerves optic or retrobulbar neuritis Hemispheric white matter (particularly the parts involved in executive functions) Fatigue and malaise Sleep disorders Laboratory findings Destruction of myelin sheath; other elements of nervous tissue are spared Breakdown of BBB + infiltration of inflammatory cells (macrophages, TH2 cells, B cells, activated glia) Evidence of re-myelination + high numbers of transected axons in MS plaques Plaques are found predominantly in periventricular white matter, cerebellum, brain stem, optic nerve and tract, and occasionally in interdigitating sheaths as they pass into gray matter Cortical atrophy develops over time, with diffuse ventricular enlargement Multiple ovoid, periventricular lesions (Dawsons fingers) on gadolinium contrast MRI Diagnosis 11

Abnormal neurologic exam (48 hours of dysfunction) MRI with gadolinium contrast to look for demyelination (although normal in 10% of patients) Evoked potentials Elevated IgG in CSF Fluctuating signs and symptoms Treatment Non-immunospecific therapies Corticosteroids help speed up recovery from acute attacks Pan-immunosuppression rescue drugs mitoxantrone (can cause cardiotoxicity), azanthioprine, methotrexate, cyclophosphamide, plasma exchange, IvIg, statis, sex hormones Treatments for relapsing disease -interferon reduce relapse rate, development of new MRI lesions, prevents brain atrophy Betaseron Avonex Refib Copaxone synthetic random polypeptide constituents of myelin that interfere with T cells and prevent them from destroying the myelin sheath Tysabri monoclonal antibody that prevents activated T cells from entering brain; limited use since there have been 3 cases of PML

Sleep disorders Obstructive sleep apnea OSA is a condition characterized by short periods of sleep during which no breathing takes place. At night, the muscles of the soft palate relax to a point where the airway collapses and becomes obstructed. When the airway closes, breathing stops, and the sleeper awakens to open the airway. Once normal breathing is restored, the person falls asleep, only to repeat the cycle throughout the night. These brief arousals disrupt continuous sleep and prevent the person from reaching REM Narcolepsy Classical features (often preceded by emotional excitement) Excessive daytime sleepiness, even after an adequate amount of nighttime sleep. As a result, people with narcolepsy are likely to fall asleep rapidly during the day without warning (and fall into almost immediate REM). treat with methylphenidate, dextroamphetamine, modafinil, sodium oxybate Cataplexy (loss of muscle tone) during sleep attacks treat with antidepressants or sodium oxybate Sleep paralysis temporary inability to talk or move upon waking Hypnagogic hallucinations dream-like experiences that happen as the person is falling asleep Insomnia inability to fall asleep or remain asleep (wake too early) next day consequences Transient insomnia lasts a few days; usually associated with an acutely stressful situation Short-term lasts up to 3 weeks; usually associated with acute or situational stress Long-term lasts more than 3 weeks Principles of good sleep hygiene 12

Regular time to bed/wake up Avoid daytime naps No heavy/spice food in the evening Use bedroom only for activities associated with sleep If not asleep in 30 minutes, move to another room and engage in a boring or relaxing activity Sleep only as much as needed to feel refreshed and alert during the day Avoid or minimize caffeine, alcohol, and tobacco Hypnotics Characteristics of the ideal hypnotic Rapid sleep induction Sufficient duration, with no hangover Lack of habituation/tolerance Normal sleep pattern High therapeutic index Lack of drug interactions Barbiturates decrease REM and sleep; REM rebound; tolerance develops Antidepressants highly sedating Antihistamines anticholinergic, can cause morning hangover Benzodiazepines little or no REM suppression, but do suppress sleep; possible rebound insomnia **BZD1-specific non-benzodiazepines fast acting; little effect on sleep stages; CNS side effects **Melatonin receptor agonist short acting; promote sleep and shift circadian phases

Stupor and coma Anatomical requirements for consciousness Ascending reticular activating system (RAS) Intralaminar nuclei and reticular nuclei (level of thalamus) Periaqueductal gray (level of midbrain) Tegmentum (central tegmental fasciculus at level of pons) RAS gets projections from sensory pathways and has diffuse projections to thalamus and cerebrum. Levels of consciousness Alert normal state of arousal Lethargic/obtunded patient is less than fully aroused at rest, but is readily arousable If hallucinations and agitation are also present delirium Stuporous patient is more unresponsive and requires vigorous and repeated stimuli to be aroused; without stimuli, the patient goes back to unresponsiveness Comatose (transient) state of unarousable psychologic unresponsiveness with the eyes closed Vegetative state psychologic unresponsiveness, but the patient is arousable (eyes open to auditory stimuli) and can have a sleep-wake cycle persistent vegetative state after 1 month permanent vegetative state after 12 months Differential diagnosis Locked in syndrome stroke of anterior pons involving motor tracts (but sparing RAS) causes motor paralysis of all extremities and lower cranial nerves patient is paralyzed but fully conscious Clinical assessment 13

Complete neurological exam, including mental status exam **Eye movement evaluation Oculocephalic reflex (Dolls Eye phenomenon) When the reflex is present (i.e. brainstem is intact), the eyes of the patient remain fixed on a single target while the head is moved; thus the eyes move in relation to the head In patients with dysfunction of vestibular/MLF pathway, their eyes remain fixed forward in the direction that the head is turned toward Oculovestibular reflex (ice water caloric) In a normal patient (intact brainstem), cold water in the ear causes slow movement toward the side stimulated, followed by fast correcting nystagmus toward the other side COWS cold opposite, warm same (refers to direction of nystagmus) Motor response Decorticate posturing lesion above brainstem (red nucleus) arms flex, legs extend Decerebrate posturing --- lesion in midbrain (below red nucleus) arms and legs extend Glasgow coma scale Used to objectively assess the conscious state of a person 3 parameters eye opening, motor responses, and verbal responses Scored from 3-15 3 = deep coma or death 8 = coma 15 = fully awake Measures to decrease intracranial pressure Elevate the head Keep the patient fluid restricted (and/or use diuretics) Administer Decadron (steroid) to reduce vasogenic edema Hyperventilate (CO2 causes vasoconstriction) Shunt to draw off CSF or blood Barbiturate anesthesia (decreases CNS metabolism) Mannitol (osmotic diuretic) if brain begins herniating Brain death irreversible loss of brain function, including brainstem Clinical diagnosis of: Coma or unresponsiveness Absence of brainstem reflexes (ex. nonreactive pupils, absent reflexes) Apnea Exclusionary criteria Complicating reversible medical condition (severe electrolyte or acid/base imbalance or endocrine disturbance) Drug intoxication or poisoning Hypothermia Confirmatory lab tests (optional in adults; required in newborns) **EEG looks for electrical activity **Technetium 99 brain scan looks for cerebral perfusion Cerebral angiography Transcranial Doppler ultrasound Dementia disorders 14

DEMENTIA a syndrome, characterized by acquired loss of intellectual abilities (memory, language, visual processing and orientation, mood, personality, social skills, executive functions), that occurs in a state of clear consciousness that causes inability to function independently Differential diagnosis of dementia Normal aging (ex. mild cognitive impairment) Severity of cognitive decline is greater with dementia In MCI, activities of daily living are still intact MCI may be a risk factor for dementia Delirium In dementia, consciousness is spared (at least until advanced stages) caused by CNS dysfxn In delirium, alertness and attention are impaired (due to underlying medical problem) Causes of dementia Neurodegenerative (60%) Alzheimers disease (AD) Accumulation of intracellular neurofibrillary tangles ( protein) causes progressive loss of neurons in the: Cerebral cortex (frontal, parietal, temporal lobes) loss of executive functions, personality change, impaired judgment, etc. Basal forebrain loss of ACh abnormalities in higher cognitive functions Hippocampus memory loss and anterograde amnesia -amyloid plaques (extracellular) destroy synapses Symptoms consistent with AD Insidious onset Preceding personality change Depression, withdrawal from activities Lack of insight (anosognosia) Physically healthy Typical behaviors paranoid delusions, wandering, social disinhibition Symptoms not consistent with AD Abrupt onset Rapid decline New focal neurological signs/symptoms speech disorder, parkinsonian features, seizures, falls in early stages Depression, anxiety, sleep disorders are also common in AD need to be treated Motor and sensory function are usually preserved, at least until the late stages of the disease Dementia with Lewy bodies (DLB) Part of clinical spectrum of Parkinsons disease DLB and PD emerge together Progressive cognitive decline particularly attention, visuo-spacial, and executive functions fluctuations in consciousness and visual hallucinations Lewy bodies are found in subcortical nuclei (substantia nigra, locus ceruleus, dorsal raphe, nucleus basalis) Fronto-temporal lobe dementia (FTLD) Substantial neuron loss in frontal and temporal lobes (AD also affects parietal lobe) Affects behavior more than memory disinhibition, apathy, hyper-orality, hypersexuality, dietary change, decline in hygiene/grooming Speech is also affected lack of spontaneity, echolalia, perseveration 15

Onset at an earlier age than AD Picks disease Pick bodies are apparent as inclusions within swollen (ballooned) neurons Usually confined to front parts of brain, particularly frontal and anterior temporal lobes First symptoms are personality change (apathy, indifference, disregard, poor social judgment, inappropriate sexual advances) and decline in function vs. memory loss in AD Onset after age 40 Progressive decline average disease course is 5 years Spongiform encephalopathies rapidly progressing dementia with myoclonic jerks Vascular (20%) Vascular dementia (pure) Multi-infarct dementia Onset between ages 60 and 75; affects men more than women Symptoms develop in a step-wise manner confusion, memory problems, incontinence, emotional problems As more small vessels are blocked, there is gradual mental decline Subcortical ischemic vascular dementia due to lacunar infarcts Vascular dementia with AD Toxic-metabolic Hypothyroidism B12 deficiency Medications anticholinergics, sedative-hypnotics, anti-histamines, anticonvulsants Misc dehydration, infection, heavy metal toxicity Inflammatory HIV and associated infections (toxoplasmosis, PML) Chronic fungal or TB meningitis Neurosyphilis Multiple sclerosis Other intracranial disorders Hydrocephalus Subdural hematoma Meningioma Traumatic brain injury Assessment of dementia Clinical diagnosis of AD Evidence of dementia documented by mental status or neuropsychological testing Slowly progressive loss of memory and other cognitive abilities Onset between ages 40-90 Exclusion of other causes of dementia Conclusive diagnosis can only be made at autopsy


The blood-brain barrier BBB isolates brain cells from variations in body fluid composition to provide a stable and fully controlled environment. Superimposed on it are a variety of transport mechanisms into and out of the brain Cellular and molecular basis of BBB Cerebral endothelial cells form tight junctions Tight junctions are established in the 4th month of fetal development; prior to the 6th month, fetal proteins and chemicals/neurotoxins have free access to the fetal CNS Astrocytes induce the formation of the tight junctions; their endfeet hold the endothelium together and help maintain its tubular form Posterior pituitary gland has no BBB Selective uptake Size limitations Lipid soluble molecules > 700 Da are excluded, as are water soluble molecules > 5000 Da Exceptions are molecules that bind to plasma proteins (hindered uptake) or molecules that have specific carriers to enhance their transport Gases (nitrous oxide), lipid soluble substances (insecticides) are readily permeable Glucose is taken up by a facilitated transport mechanism; galactose can inhibit glucose uptake Active uptake of AAs, essential fatty acids, vitamins, and cofactors Mannitol (used to dehydrate brain and reduce swelling) is poorly permeable Molecules bound to serum proteins are excluded (ex. conjugated bilirubin) Enzyme barriers (peptidases, esterases, decarboxylases) are found at the luminal side of the endothelium Toxic materials may destroy BBB Bordatella pertussis toxin destroys tight junctions Endotoxin causes inflammation elevated MMPs destruction of BBB Abuse of psychotropic drug abuse (LSD, speed) may lead to permanent BBB damage Aging and diabetes have negative effects on BBB Penetration of the barrier Antibodies to transferrin receptors or coupling to transferrin Selective cell adhesion molecules Autoimmune attack on CNS to allow sensitized lymphocytes to enter

Cholinergic synaptic communication ACh as a neurotransmitter Synthesis Phosphatidyl-ethanolamide phosphatidyl-choline acetyl coA ACh Choline is the rate-limiting component Storage and release Black widow spider venom causes massive release of ACh postsynaptic overstimulation Botulinum toxin prevents ACh release from motor neurons flaccid paralysis

Inactivation Acetylcholinesterase degrades ACh in the synapse Insecticides and nerve gases inhibit AChE respiratory failure Choline is transported back into neuron terminal Hemicholinium inhibits the choline uptake system ACh depletion ACh receptors Nicotinic receptor fast acting ion channel Pentameric structure, with ion channel in the middle Nicotine is a receptor agonist alertness Autoimmune destruction of nAChR produces myasthenia gravis Muscarinic receptor slower acting; coupled to G protein Control a number of second messenger pathways adenylyl cyclase, PLC, K+ channel, etc. Muscarine is an agonist Atropine is an antagonist Pharmacological manipulation of the cholinergic synapses ACh synthesis ACh transport into vesicles Release from presynaptic neurons Postsynaptic receptor modulation Presynaptic muscarinic receptor mediates the feedback mechanism ACh inhibition Choline uptake inhibition

Catecholamines Catecholamines have benzene rings with 2 adjacent hydroxyl residues + an amino group. Many psychotropic drugs have similar structures Metabolism Synthesis Phe phenylalanine hydroxylase tyrosine Tyrosine tyrosine hydroxylase L-DOPA DOPA decarboxylase DA NE E Amino acid analogs (-methyl-tyrosine), catechol derivatives, and iron chelators inhibit TH Long-term regulation of TH activity occurs through transcriptional regulation by extracellular stimuli from neurotransmitters, caffeine, and nicotine Storage and release Storage in granular synaptic vesicles also contain ATP, enzymes, and neuropeptides Membrane potential can be tuned by presynaptic receptors that monitor the catecholamine concentration in the synaptic region Dopamine transporter is involved in reuptake of DA by the presynaptic cell cocaine is an inhibitor of DAT Catabolism MAO, Catecholamine-O-methyltransferases (COMT), aldehyde reductase or dehydrogenase Homovanillic acid = DA metabolite MHPG = NE metabolite 2

Serotonin, histamine, GABA, glycine Serotonin (5-hydroxy-tryptamine) Because Trp levels vary according to the circadian rhythm, 5-HT levels do too Enterochromaffin cells, platelets, raphe nuclei, and pineal gland are rich in 5-HT Melatonin is released into the blood stream at night; it is involved in the regulation of circadian cycles P-chlorophenylalanine irreversibly inhibits tryptophan hydroxylase Reserpine intereferes with loading of 5-HT (along with NE and DA) into vesicles Autoreceptors (1D) reduce the amount of 5-HT released Hallucinogenic drugs are often associated with 5HT receptors

Histamine Within the brain, histamine appears to be produced exclusively in the tuberomammilary nucleus of the hypothalamus, which projects to regions of the cerebral cortex, hippocampus, basal ganglia, and amygdala. In the hypothalamus, histamine may alter food and water intake and influence thermoregulation.

GABA Decarboxylation of -ketoglutarate by glutamic acid decarboxylase (GAD) is the major regulatory event in the synthesis of GABA. Glial cells participate in GABA metabolism and recycling The subunit structure of the GABA receptors may change after alcohol consumption Overdose of GHB, a metabolite, can cause coma, seizures, vomiting, respiratory depression, and amnesia Glycine Gly is the major inhibitory neurotransmitter in the mammalian brainstem and spinal cord, and is used predominantly by short axon interneurons. It is synthesized from serine, and is destroyed by a glycine cleavage system at the neighboring astrocytes or recycled at the presynaptic membrane. GlyR is a chloride channel with subunits that are different than those in the GABA chloride channel. Mutation in the 1 subunit results in decreased Gly affinity human startle disease

Glutamate, opiates, anandamides, and neuromodulators Glutamate (and aspartate) excitatory NTs Metabolism Synthesized in the brain and released via a Ca-dependent mechanism from synaptic vesicles Specific re-uptake mechanisms, utilizing glial cells, are involved in their recycling process Excessive concentrations can produce excitotoxicity, anxiety, epilepsy, ischemic brain damage, and addiction Receptors Ionotropic AMPA mixed cation channel Kainate NMDA depolarization removes an Mg ion from the pore; Gly is a co-agonist Metabotropic = mGluR Opiates and other pain peptides Opiates = morphine + its derivatives (synthetic) Opioids = endogenous peptides endorphin, dynorphin, enkephalin derived from precursor large peptides, such as pro-opiomelancortin (part of ACTH) Opiate receptors (morphine), (dynorphins) , (enkephalins) Naloxone is an opiate receptor antagonist used to treat heroin overdose Opiate receptors on lymphocytes may regulate mechanisms of signal transmission and interleukin production opiate antagonists inhibit adhesion of certain lymphocytes 4

Nociceptin and nocistatin are endogenous ligands for opiate-type receptors they induce hyperalgesia and pain perception from non-noxious stimuli Opiates regulate the pre-synaptic release of tachykinins (including substance P), which are involved in pain sensation. capsaicin causes rapid release of substance P Anandamides endogenous cannabinoids Receptors G-linked CB1 in CNS CB2 in periphery, including white cells and in the testicles Effects of THC (exogenous anandamide) Antiemetic action by reducing gut motility and inhibiting DA input to vomiting center May cause birth defects (altered sperm morphology) Cognitive effects impairment of attention and executive functions, decreased memory, lowered motivation, decreased ability to filter out irrelevant information, slower processing rate Neuromodulators change the membranes ability to respond to signals E-type prostaglandins interfere with availability of Ca for presynaptic release of NE Nitric oxide synthesized on demand, affect cGMP vasodilation

Direct acting parasympathomimetics
Methacholine Bethanechol Carbachol Pilocarpine Therapeutic use supraventricular arrhythmias amotile gut and bladder glaucoma glaucoma Catabolism hydrolyzed by specific ChE shorter acting not hydrolyzed by ChE not hydrolyzed by ChE not hydrolyzed by ChE

Classification Direct acting parasympathomimetics (cholinomimetics) are mAChR agonists that produce effects similar to ACh (i.e. activate parasympathetic responses in smooth muscle, heart tissue, and glands). They do not require the presence of a cholinergic nerve to be effective. Pharmacological effects Arterioles Although arterioles do not have parasympathetic innervation, they do have mAChR Direct PSPs produce vasodilation lowered blood pressure Fall in blood pressure is sensed by baroreceptors (ex. in carotid sinus), which trigger sympathetic response (NE) to bring BP back into normal range Biphasic response initial PSP slows heart, NE stimulates it net stimulation of BP

Heart Since parasympathetic innervation is primarily supraventricular, direct PSPs can only act on SA node, AV node, and atria Slow rate of firing of the SA node (negative chronotropic effect) Decrease contractility of atria (negative inotropic effect) Slow conduction in AV node (negative dromotropic effect) No significant effect on ventricles Sweat glands Although sweat glands have sympathetic innervation, their symp/post fibers release ACh Use of direct PSPs therefore can cause sweating Gut increases gut motility Bladder causes voiding of urine (so direct PSPs are given at sub-threshold doses to enable voluntary voiding) Side effects Because the effects of direct PSPs are due to their pharmacological mechanism (activating parasympathetic responses), the distinction between therapeutic effect and side effect is arbitrary the therapeutic effect is the desired outcome, and the side effect is the unwanted effect. 1

Organ Eye Ciliary muscle Bladder GI tract Arterioles Heart Sweat glands Bronchioles

Effect miosis (pupil constriction) accommodation for near vision stimulated stimulated dilated bradycardia, slows AV conduction stimulated constricted

Therapeutic use glaucoma glaucoma atonic bladder atonic gut paroxysmal atrial tachycardia

Side effects impaired distal vision urinary frequency diarrhea fall in blood pressure cardiac standstill sweating difficulty breathing

Side effects requiring immediate medical attention Wheezing or tightness of the chest Light headedness or fainting spells change positions slowly (esp. in morning or after eating) take drug while supine or sitting Minor side effects that dont need immediate attention (dont trivialize; positive approach) Flushing, a feeling of warmth around the face Increased sweating Increased saliva Increased tears Symptoms of PSP poisoning Constricted pupils Marked lacrimation and salivation Low pulse Wheezing Watery bowel movements Involuntary urination Contraindications Urinary tract obstruction retrograde passage of urine would damage kidney Must not be given IV could cause cardiac arrest (rapid drop in blood pressure + decreased rate and strength of cardiac contraction) Asthma bronchoconstriction could trigger an attack Hypotension Bradycardia Cholinesterase inhibitors affect both specific and nonspecific ChE Receptor classification
Symp Effector organs ganglia adrenal gland sweat glands ganglia smooth muscle, heart, glands cortex, thalamus, etc. end plate mAChR nAChR x x x x x x

Para CNS Motor nerve

Cholinesterase Forms of ChE AChE terminates action of ACh in the synapse (very rapid removal) PseudoChE involved in metabolism of certain drugs (ex. cocaine) 2

Mechanism of action Active site of AChE consists of an anionic (binds N terminus of ACh) and esteratic site (binds ketone domain) Ester linkage in ACh is ruptured, releasing choline and acetylating the enzyme Acetylated enzyme then reacts with water to regenerate the native enzyme General properties of ChE inhibitors ChE inhibitors vs. direct acting PSPs Both stimulate glands, bowel and bladder; dilate pupils; slow heart rate; and cause bronchoconstriction Differences ChE inhibitors affect both nAChR and mAChR (vs. only mAChR for PSPs) ChE inhibitors only work when there is nerve input that provides ACh do not lower blood pressure because there is no para innervation of arterioles can cause skeletal muscle fasciculations have no impact on denervated organs (ex. transplanted heart) Reversible ChE inhibitors Mechanism of action block active site on ChE and prevent breakdown of ACh **Drugs Tertiary amines (can cross BBB) Physostigmine Quaternary amines (cannot cross BBB) Neostigmine Edrophonium very short acting Therapeutic uses Postoperative bowel dysfunction also treatable with PSPs (but if deficient para input Urinary retention to begin with, ChE inhibitors might not be effective) Glaucoma Myasthenia gravis (deficiency of nAChR) Reverse the effects of non-depolarizing neuromuscular blockers (quaternary only) see p. 7 Increase the effects of depolarizing neuromuscular blockers see p. 8 Irreversible ChE inhibitors (organophosphate insectides) Mechanism of action inactivate ChE at esteratic site need new enzyme (or PAM) to restore activity **Drugs Parathion Very lipid soluble crosses BBB, can have CNS effects in poisoned individuals Organophosphate poisoning Signs and symptoms Parasympathetic response (bronchoconstriction respiratory failure death) Fasciculations of skeletal muscle Convulsions (due to BBB permeation) Treatment Atropine (mAChR blocker) doesnt affect skeletal muscle Pralidoxime (PAM) to reactivate ChE doesnt penetrate CNS 3

Potentiation pharmacological effect of 2 drugs is greater than the sum of their independent actions methacholine (direct PSP hydrolyzed by ChE) is potentiated by ChE inhibitors Summation pharmacological effect of 2 drugs equals the sum of their independent actions 2 PSPs exhibit summation Intrinsic activity the pharmacological effect produced when a drug is combined with a receptor 0 = blocker 1 = full agonist

Muscarinic blockers Atropine Mechanism of action Broad spectrum competitive antagonist (zero intrinsic activity) of all mAChR subtypes M1 in CNS and ganglia M2 in heart M3 in glands and smooth muscle No effect on nAChR Effects loss of para input produces sympathetic-like response Eye Pupil dilation (midriasis) due to inhibition of light reflex Accommodation of eye for far vision (prevents ciliary muscle contraction) Heart Tachycardia No effect on blood pressure (since no para innervation) Therapeutic uses Dilate the pupil during eye exams & fix lens for more accurate refraction Anti-spasmotic agent decrease gut motility and bladder overactivity Anti-secretory agent (especially before surgery) Antidote for parasympathetic poisoning Atropine overdose Symptoms Dryness of mouth due to inhibition of salivary glands Botulinum toxin Blurred near vision due to lens accommodation (prevents ACh Photophobia due to loss of light reflex release) presents Dry skin due to inhibition of sweat glands with similar Tachycardia symptoms, but **Hyperthermia also affects Difficulty voiding urine skeletal muscles CNS confusion, mania, visual hallucinations, psychotic behavior Antidote tertiary ChE inhibitor physostigmine

Ganglionic blockers and stimulants Ganglionic blockers Drugs Hexamethonium Trimethaphan 4

Mechanism Competitive antagonist of nAChR in para and symp ganglia drug/receptor combination has zero intrinsic activity No effect on motor activity (specific to ganglia nAChR) Side effects Easily blinded by light loss of light reflex (para) Only can see far objects loss of accommodation (para) Dry mouth para Constipation para Urinary retention para Impotence para (needed for erection) + symp (needed for ejaculation) **Hypotension (BP = HR * SV * R) Decrease in sympathetic tone to arterioles (decreased peripheral resistance) Decrease in sympathetic tone to veins pooling of blood in venous bed decreased venous return decreased end diastolic volume decreased stroke volume (via Starling mechanism) Decreased sympathetic tone to heart decreased HR and SV Postural hypotension only due to veno-dilation Loss of reflex bradycardia after BP elevation para Loss of reflex tachycardia after BP lowereing symp
Light reflex Accomodation for near vision Blood pressure Reflex bradycardia from BP elevation Reflex tachycardia from BP lowering Atropine absent absent (no effect) absent (no effect) Hexamethonium absent absent hypotension absent absent Autonomic inhibition para para symp para symp

Hexamethonium inhibits para and symp. Atropine only inhibits para. Ganglionic stimulants Nicotine Mechanism nAChR agonist in ganglia (para and symp) + adrenal gland + skeletal muscle motor endplate Nerves are not required for this action (just like direct acting PSPs) Nicotine action is of longer duration and higher binding affinity because there is no enzymatic inactivation by cholinesterase Effects Ganglia depolarize ganglia Para action increased tone of intestine and bladder; stimulation of glands Symp action tachycardia; vasoconstriction of skin vessels and kidney vessels Adrenal gland causes production of epi and norepi Skeletal muscle causes contraction fasciculations CNS Stimulates vomiting center Stimulates cardiovascular centers in medulla tachycardia, hypertension Release of ADH from pituitary 5

Neuromuscular blockers Neuromuscular blockers made it possible to do surgery under light anesthesia. Non-depolarizing neuromuscular blockers Drugs Tubocurarine Atracurium shorter duration Mechanism conduction failure: Compete with ACh for nAChR in skeletal muscle endplates drug-receptor combination has zero intrinsic activity When there are not sufficient free receptors available to depolarize the muscle, conduction ceases Antagonism by quaternary ChE inhibitors Inhibition of ChE less ACh inactivated more ACh available to compete with the blocker for the receptor reversed neuromuscular block Only ChE inhibitors that are quaternary amines have this property Edrophonium Neostigmine Side effect tubocurarine causes release of histamine from mast cells Depolarizing blockers Drug succinylcholine Mechanism bind to nAChR in skeletal muscle depolarization block Sodium channel has 2 gates M (voltage-dependent activation) and H (inactivation) Prolonged depolarization closes the H gate, and the receptor cannot become reactivated

Side effects depolarization results in a release of intracellular K+ can cause arrythmias Facilitation of neuromuscular block by ChE inhibitors (since ChE also breaks down succinylcholine)
Drugs Produces NM block Effect of ChE inhibitors Side effects Non-depolarizing Tubocurarine, atracurium yes reversal of effect release of histamine Depolarizing succinylcholine yes facilitation of effect hyperkalemia, fasciculations

Direct acting sympathomimetics Direct acting sympathomimetic receptor agonists; active even in the absence of an adrenergic nerve Indirect acting require the adrenergic nerve to be active Classification of adrenergic receptors
Receptor -1 -2 -1 Location vasculature iris nerve terminals heart Action vasoconstriction pupil dilation (mydriasis) feedback inhibition of NE release SA node -- tachycardia AV node -- faster conduction of impulse Atria -- inotropic effect Ventricles -- inotropic effect vasodilation bronchodilation

Most vascular beds contain both 1 (constriction) and 2 (dilation)


skeletal muscle arterioles bronchial muscle

Effect of sympathomimetics on blood pressure BP = HR*SV*R Determinants of blood pressure Systolic pressure determined primarily by stroke volume 1 (inotropic effect) Diastolic pressure determined primarily by peripheral resistance Constriction of arterioles increases diastolic pressure 1 Dilation of arterioles decreases diastolic pressure decreased sympathetic tone Determinants of heart rate Positive chromotropic and dromotropic effect of 1 agonists Cardiac reflexes Elevation of mean blood pressure vagal response to slow heart rate Lowering of mean blood pressure sympathetic reflex to increase heart rate Drugs no pure 2 agonists
Agonist actions Effect on diastolic press. Effect on pulse pressure Effect on heart rate Effect on bronchioles Therapeutic use Phenylephrine 1 increase (1) Norepinephrine 1, 1 Increase (1) increase (1) Reflex bradycardia Bradycardia (vagal reflex > 1)* Epinephrine 1, 1, 2 decrease (2>1 low dose) increases - high dose increase (1) Tachycardia (1) Bronchodilation Isoproterenol** 1 = 2 Decrease (2) Increase (1) Tachycardia (1) + symp. reflex Bronchodilation Albuterol** 2 > 1

Nasal decongestant, Asthma Asthma (2) Asthma (2) pressor agent, Pressor agent Anaphylaxis (1, 1) Stimulate AV node (1) mydriatic * if atropine is administered to block the vagal reflex, tachycardia results ** -1 agonist action may precipitate an anginal attack or cardiac arrhythmia in susceptible individuals (less of a problem with albuterol)

Adrenergic blockers -AR blockers Drugs -1 specific blockers prazosin Broad spectrum (block -1 and -2 receptors equally) greater reflex tachycardia (blocked -2) Phentolamine (reversible) Phenoxybenzamine (irreversible) Therapeutic uses Lower BP (-1) Arterioles have sympathetic innervation to maintain their tone Blocking E/NE therefore causes vasodilation decreased blood pressure Amount of BP fall depends on the sympathetic tone In the supine position, blockers have little effect Blockers produce a marked fall in BP in the standing position because there is significant sympathetic tone needed to maintain BP against gravity postural (orthostatic) hypotension when changing from supine/sitting to standing due to veno-dilation, decreased venous return, and decreased stroke volume (see p. 5) Parasympathetic blockers have no impact on blood pressure because there is no parasympathetic innervation to the arterioles Facilitate voiding in patients with enlarged prostate (symp. inhibits bladder contraction) Side effects Miosis leave the iris solely under para control Nasal stuffiness lose inhibition of nasal glands + vasoconstriction of nasal arterioles Diarrhea Impotence (unable to ejaculate) Postural hypotension Reflex tachycardia (particularly with broad spectrum blockers) -AR blockers 1 is the desired therapeutic action Drugs Broad spectrum blocker propranolol (1 = 2) contraindicated in bronchial asthma Broad spectrum blocker with weak intrinsic activity pindolol Useful in treating asthma due to mild activation of 2 (bronchodilation) But, because it blocks all the -2 receptors, it prevents albuterol from being used Cardioselective blocker (1>2) atenolol and -1 blocker labetolol Therapeutic uses Angina pectoris 1 blockage rests the heart Cardiac arrhythmias Essential hypertension

Indirect-acting sympathomimetics facilitate release of NE Cocaine Mechanism Inhibits Uptake 1 system that terminates the action of NE potentiates NE Inhibits reuptake of DA euphoria Therapeutic uses Stop bleeding (-1 vasoconstriction) Diagnosis of post-ganglionic Horners syndrome (eye should dilate) Side effects Mydriasis Tachycardia Hypertension Hyperthermia (due to vasoconstriction) Tyramine Mechanism Enters nerve terminal via Uptake 1 drugs that inhibit Uptake 1 (ex. cocaine) inhibit tyramine Facilitates the release of NE from adrenergic neurons drugs that inhibit NE stores (ex. reserpine) inhibit tyramine Interaction with MAO inhibitors MAO is needed to inactivate tyramine When MAO is inhibited, the tyramine present in food (red wine, cheese, etc.) can attain concentrations sufficient to release NE from nerve terminals hypertensive crisis Therapeutic use dx of pre-ganglionic Horners syndrome (should cause release of NE mydriasis) Reserpine Mechanism Inhibits transport of NE (and DA) into synaptic vesicles, causing depletion of NE This prevents tyramine from being effective Ephedrine mixed sympathomimetic Mechanism Indirect action releases NE from adrenergic terminal 1, 1 effects Direct action agonist of adrenergic receptors (particularly 2) Therapeutic use Nasal decongestant Bronchial asthma (ineffective since its a weak agonist) Side effects Hypertension (1) Cardiac arrhythmias (1)

Sympatholytic drugs decrease sympathetic activity lower BP Methyldopa Mechanism Methyldopa is a pro-drug that is metabolized to methyl-NE (a false transmitter) Its therapeutic action is due to binding of -2 receptors in the CNS less NE released decreased BP In the peripheral circulation, it has the same intrinsic activity as NE Side effects Diarrhea (para input is unopposed) Impotence (need symp to ejaculate) Postural hypotension (loss of symp tone to veins) Clonidine Mechanism central -2 agonist Side effects Rebound hypertension after abrupt withdrawal Chronic use downregulates central -2 receptors but upregulates peripheral receptors Rapid cessation dis-inhibits NE NE is released onto sensitized periphery hypertension Avoid the problem by weaning off clonidine Treat the rebound with an -1 blocker (phentolamine, phenoxybenzamine, prazosin) Diarrhea, impotence, postural hypotension just like with methyldopa Guanethidine more effective than methyldopa or clonidine at lowering blood pressure Mechanism Transported into adrenergic terminal via Uptake 1, and displaces NE in the vesicle Upon release, it is pharmacologically inert competes with NE for receptors less vasoconstriction decreased BP Side effects Similar to methyldopa and clonidine, but more severe Guanethidine doesnt cross BBB no CNS side effects Metyrosine Mechanism inhibits tyrosine hydroxylase (converts tyrosine to dopa as part of NE synthesis) Therapeutic use treatment of pheochromocytoma (tumor secretes large amounts of E and NE) -1 antagonist (phentolamine, etc.) needed to prevent hypertension during surgical removal of the tumor

Pharmacology of the eye Autonomic innervation of the eye Pupil Parasympathetic constriction Sympathetic dilation (1 receptor) Lens Parasympathetic accommodation for near vision (ciliary muscles contract, less tension on suspensory ligaments, lens thickens) Cycloplegia = inability to accommodate for near vision; caused by muscarinic blocker Sympathetic no effect on accommodation 10

Treatment of glaucoma ANGLE CLOSURE GLAUCOMA iris mechanically obstructs the outflow of aqueous past the lens from the posterior to the anterior chamber decrease intraocular pressure by pulling iris away from lens OPEN ANGLE GLAUCOMA blocked Canal of Schlemm prevents aqueous outflow decrease aqueous humor formation increase aqeueous outflow
Drug PILOCARPINE PHYSOSTIGMINE DORZOLAMINE EPINEPHRINE DIPVEFRIN (epi analog) APRACLONIDINE TIMOLOL BETAXOL LATANOPROST Classification Muscarinic agonist ChE inhibitor* Carbonic anhydrase inhibitor Sympathomimetic -2 agonist blocker (1 = 2) blocker (1 > 2) Prostaglandin analog Angle Closure X X Open Angle X X X X X X X Comments Angle closure miotic (iris) Open angle ciliary muscle Angle closure miotic (iris) Open angle ciliary muscle Decreases formation of aqueous humor Decrease aqueous production; increase uveo-scleral outflow Decrease aqueous production; increase uveo-scleral outflow Betaxol has a lower risk of causing asthmatic attacks Increases uveo-scleral outflow

MARIJUANA X Mechanism unknown *Need reversible 3o amine (4o cant get through BBB; irreversible ChE-I (ex. isoflurophate) cause cataracts)

Opioids Endogenous opioids and opiate drugs Pharmacokinetics Distribution Endorphins in hypothalamus and pituitary Enkephalins in CNS, PNS, adrenal gland, and enteric nervous system Dynorphins are involved in spinal analgesia Heroin and codeine pass BBB much more easily than morphine Fentanyl has a short duration of action because it rapidly redistributes to peripheral tissues Synthesis Pre-pro-opiomelanocortin (POMC) - endorphin Pre-pro-enkephalin met- and leu-enkephalin Pre-pro-dynormphin dynorphin Absorption Parenteral absorption is generally good Methadone, codeine, oxycodone > meperidine, pentazocine > morphine by mouth Metabolism Most are metabolized in liver Morphine (and its derivatives heroin and codeine) are glucuronidated and excreted by kidney Pharmacodynamics Receptors morphine (and other synthetic opiates) analgesia, euphoria, respiratory depression (and ) spinal analgesia All are G-coupled and act to inhibit adenylyl cyclase less cAMP


Mechanism of action Presynaptic inhibition of spinal pain transmission (less substance P released) Postsynaptic hyperpolarization of pain neurons Increased firing rate of DA neurons euphoria Receptor occupation by opiate drugs may release endogenous opioids

Cardiovascular effects Little effect on HR or BP when supine, but can cause orthostatic hypertension Renal effects Depressed renal function Elevated ADH release (supraoptic hypothalamus) urinary retention GI effects Delayed stomach emptying, decreased gastric motility, decreased gastric acid secretion Inhibition of peristalsis due to anticholinergic effect constipation, anti-diarrheal effect Skin effects Vasodilation and flushing Itching and urticaria due to histamine release from mast cells (morphine breaks histamineheparin bond) Bronchial effects Histamine bronchoconstriction Direct bronchoconstriction via opioid receptors on smooth muscle Depressed respiration and cough reflex CNS effects **Analgesia (particularly dull pain) Euphoria Nausea, vomiting, dizziness **Respiratory depression, sedation Miosis ( receptor) can be blocked by adrenergic agonists or atropine no tolerance Antitussive effect (no isomeric preference) Convulsions may be produced by high doses of meperidine, codeine, propoxyphene **Symptoms of overdose miosis, respiratory depression, decreased mental status Drugs and their clinical use Opiate agonists Morphine pain; long duration of action because metabolies are also active opiates Codeine cough (less potent than morphine, so not as useful for pain) Heroin (strong CNS effects because of high lipid solubility) Meperidine (Demerol) acute, severe pain; short duration of action Methadone treatment of opiate dependence (longer acting and less potent than heroin) Fentanyl anesthesia (very short acting) Propoxyphene Opiate agonists-antagonists low abuse potential Butorphanol Pentazocine 12

Buprenorphine Special purpose opioids Loperamide anti-diarrheal effects; no CNS effects Dextromethorpan antitussive Contraindications Avoid combining pure agonists and mixed agonist-antagonists Avoid use in patients with head injuries opiates can increase intracranial pressure Avoid use in pregnancy opiates suppress respiration in fetus (except meperidine) Avoid use in patients with impaired lung function histamine and direct bronchoconstriction Reduce dose in patients with reduced hepatic or renal function (decreased metabolism) Reduce dose in patients with adrenal insufficiency or hypothyroidism (potentiate opioids) Avoid coadministration with typical anti-psychotics (potentiate depression of respiration) Avoid coadministration with MAO-I because of incidence of febrile coma Tolerance and withdrawal Rapid tolerance to euphoriant effects + cross-tolerance to other opiates All opiates produce similar withdrawal symptoms, which usually end within 5-10 days Withdrawal begins 8-10 hours after last dose autonomic hyperactivity, dysphoria, drug craving Treat with methadone to prevent abrupt withdrawal Clonidine to reduce sympathetic side effects during initial detoxification phase Narcotic antagonists naloxone, nalmefene, naltrexone Pharmacokinetics Absorption Naloxone short duration acute opiate overdose Nalmefene long-duration (IV only) acute opiate overdose Naltrexone long-duration maintenance drug for addicts in treatment programs Distribution pass BBB much easier than morphine Metabolism glucuronidation + excretion by kidney Pharmacodynamics Competitive blockade of receptor (to which most opiate drugs bind) Tolerance does not develop to these agents no withdrawal syndrome for chronic use

Stimulant drugs Convulsive stimulants

Drug Strychnine Mechanism Antagonist of GlyR Effects CNS excitation due to disinhibition Clinical use None Toxicity


Antagonism of GABA receptor

CNS excitation due to disinhibition CNS excitation due to disinhibition

Pentylenetetrazole Antagonism of GABA receptor (metrazole)

Treatment of CNS depressant overdose Activate EEG to diagnose seizures

tonic extension of body and limbs full tetanic convulsions with respiratory impairment hypoxia death uncoordinated tonic-clonic convulsions, sometimes followed by coma and death uncoordinated tonic-clonic convulsions, sometimes followed by coma and death 13

Toxicity treatment for all convulsive stimulants Central depressants (ex. diazepam) to control convulsions Support of respiration Lavage with charcoal, KMnO4, tannin Mood stimulants Xanthines caffeine, theophylline, theobromine Mechanism Non-specific blockage of A1 and A1 (adenosine) receptors [adenosine causes sleepiness] Blockage of phosphodiesterase elevated cAMP Effects Potent stimulation of CNS, particularly medullary respiratory centers alertness, reduction of drowsiness and fatigue Relaxation of bronchial smooth muscle Increase in gastric acid secretion Diuretic action BP and HR at high doses Clinical use Bronchodilator in asthma (theophylline) Apnea in premature infants Headache and migraine treatment (questionable efficacy) Toxicity (rare) Excitement progressing to delirium, emesis, and convulsions Tachycardia, arrhythmias, premature ventricular contractions Toxicity treatment Diazepam, in conjunction with barbiturates or anticonvulsants Lavage with activated charcoal Withdrawal Heavy drinkers who omit their morning coffee report irritability, inability to work effectively, nervousness, restlessness, lethargy, and headache Syndrome has an onset of 12-24 hours, peaks at 20-48 hours, and lasts 1 week or less Amphetamines Drugs Benzedrine racemic mixture Dexedrine D isomer Metamphetamine potent CNS stimulant with fewer peripheral effects Methylphenidate (Ritalin) Mechanism Stimulate release of NE and DA Block reuptake of NE and DA Metabolites are hallucinogenic Effects Sympathomimetic cardiovascular effects (BP, reflex bradycardia, arrhythmias) Mood elevation, euphoria, hyperactivity Insomnia Appetite reduction Stimulation of medullary respiratory center Clinical use 14

Narcolepsy ADHD Obesity Toxicity Acute effects nervousness, hyperactivity, insomnia, tremor, sweating, anorexia, euphoria + cardiovascular effects Chronic effects amphetamine psychosis (schizophrenia-like behaviors), motor stereotypy, necrotizing arteritis Dizziness, tremor, hyperreflexia, diaphoresis, tachycardia, tachypnea, hypertension are also common symptoms Overdose convulsions, cerebral infarcts, hemorrhages, arrhythmias, respiratory failure Toxicity treatment DA receptor antagonists -AR antagonists or sodium nitroprusside acidification of urine by NH4Cl to enhance elimination rate Tolerance and withdrawal Marked tolerance develops after both oral and IV use Crash manifests as drug craving and depression with hypersomnolence and hyperphagia, but produces neither seizures nor life-threatening symptoms, even in those patients who habitually consume large quantities Withdrawal is usually limited to a few days, and may be characterized by by apathy, depression, lethargy, anxiety, and disturbances in sleep Myalgias, abdominal pain, voracious appetite, and a profound depression with suicidal tendencies may complicate post-withdrawal period but peak in 2-3 days Symptoms are mildest with fenfluramine Nicotine Mechanism Increased release of DA in nucleus accumbens euphoric effect + addiction Increased release of NE, E stimulatory action Effects Increase in alertness/euphoria Muscle relaxation Appetite reduction Biphasic effects on respiration, HR, BP Increased GI motility Biphasic salivary response Clinical use Early stage Alzheimers disease compensation for loss of cholinergic neurons? Self-medication in schizophrenia and parkinsonism increased DA release? Toxicity Tremor proceeding to convulsions CNS depression and respiratory failure due to central paralysis and peripheral respiratory neuromuscular blockage Emesis due to activation of area postrema Toxicity treatment Induction of vomiting, followed by activated charcoal Respiratory assistance may be needed Tolerance and withdrawal **Most additive substance known 15

Tolerance develops rapidly and is long lasting (primarily cellular tolerance due to changes in receptor density) Withdrawal emerges soon after smoking cessation, peaks 24-48 hours, and may last for 10 days or more; cravings may continue for years Major symptoms of withdrawal are dysphoria, irritability, difficulty concentrating, fatigue, and sleep disturbances Cocaine Mechanism inhibits reuptake of NE and DA (see p. 8) Effects Hyperactivity Restlessness Increased BP and HR Euphoria Tolerance and withdrawal Tolerance and sensitization are common Withdrawal paranoia, insomnia, depression, fatigue, agitation, sweating, nausea, vomiting (but less severe symptoms than opiate or depressant withdrawal) No standard pharmacology, but DA agonists may reduce symptoms
Drug Strychnine Picrotoxin Pentylenetetrazole Caffeine Theophylline Theobromine Amphetamine Methylphenidate Modafanil Nicotine Mechanism glycine antagonist GABA antagonist GABA antagonist adenosine antagonist adenosine antagonist adenosine antagonist catecholamine release catecholamine release catecholamine release nAChR agonist Clinical use None None EEG activation to diagnose seizure asthma, apnea asthma, apnea None narcolepsy, ADHD, obesity ADHD Narcolepsy early stage Alzheimer's

Sedative-hypnotic and anxiolytic drugs Ethanol Metabolism mostly in liver (zero order kinetics) Ethanol alcohol dehydrogenase acetaldehyde acetaldehyde dehydrogenase acetate ** Disulfiram/Antabuse inhibits acetaldehyde dehydrogenase 3-8 days of hangover Mechanism potentiation of GABA-A receptor + inhibition of adenosine reuptake ( sleepiness) Effects Acute Paradoxical excitation due to disinhibition, followed by sedation, slurred speech, and ataxia Diuresis due to ADH inhibition Gastric acid secretion Chronic Korsakoff syndrome (thiamine deficiency) amnesia, confabulation, apathy, etc. Hypertension and cardiomyopathy Gynecomastia, testicular atrophy Cross-tolerance to other sedative-hypnotics and narcotics (all act on GABA-A receptor) 16

Clinical use Solvent and drug vehicle Topical use in poison ivy, fever, and as disinfectant Treat trigeminal neuralgia, methanol and ethylene glycol poisoning Toxicity treatment GI lavage, hemodialysis to remove alcohol from circulation Tolerance and withdrawal Early symptoms begin 8 - 9 hours after last drink, and peak between 24-36 hours. Autonomic hyperactivity (sweating, tachycardia), increased hand tremor, insomnia, nausea/vomiting, transient hallucinations or illusions Alcohol withdrawal seizures (grand mal) Occur 6-72 hrs after abstinence, peak incidence is 31-48 hrs Tend to occur in clusters and rarely progress to status epilepticus; intervening EEG is normal Delirium tremens Occurs 2-3 days after drinking stops; last 1-5 days True delirium, with altered levels of consciousness + autonomic instability, agitation, tremor, diaphoresis (sweating), and hallucination Visual and tactile hallucinations may be treated with antipsychotics Often associated with medical illness Detox Thiamine, multivitamins, and folate Correct fluid and metabolic disturbances from DTs Substitute a long-acting sedative-hypnotic (ex. benzo or barbiturate) for alcohol and then gradually taper off its dose Biological markers of alcohol abuse Elevated -glutamyl transferase (most sensitive test for assessing heavy alcohol use, independent of BAC) AST, ALT MCV, folate deficiency Barbiturates amobarbital, phenobarbital, pentobarbital Mechanism Prolongation of GABA channel opening enhanced synaptic inhibition Reduction of Glu AMPA receptor activation decreased synaptic excitation Depression of voltage-activated Na and Ca channels Effects Dose-dependent depression Anticonvulsant effect (Phenobarbital) Some anxiolytic and euphoriant effects at low doses Increase in total sleep, but decreased REM daytime drowsiness Cross-tolerance to other sedative-hypnotics Respiratory depression Potentiated by ethanol, antihistamines, MAO inhibitors Clinical use Emergency treatment of convulsions (Phenobarbital) Ultrashort acting IV anesthetic Narcoanalysis by carotid infusion to determine dominant speech hemisphere before neurosurgery Treatment of neonatal hyperbilirubinemia 17

Toxicity Effects similar to alcohol, but onset, severity, and duration of action depend on the half-life of the particular drug Respiratory acidosis + cerebral hypoxia due to suppressed respiration Depression of cardiac contractility, hypotension, and renal failure Toxicity treatment Maintain patent airway and ventilation Gastric lavage and activated charcoal Support blood pressure with DA if needed Tolerance and withdrawal (same for benzodiazepines) Tolerance may develop to sedative effect but not to the respiratory depressant effect Withdrawal anxiety, tremors, twitches, nausea, vomiting for 16 hours; convulsions may occur 16-48 hours after withdrawal 5-15% risk of seizures If short acting drugs have been abused, Phenobarbital or long-acting benzo is substituted If long acting drugs have been abused, same drug may be continued Taper drug of choice by 10-20% per day Benzodiazepines Mechanism GABA receptor agonist Diazepam class Lorazepam class Half life Longer Shorter Onset Rapid (very lipophilic) Slow (less lipophilic) Duration* Short (due to redistribution within CNS) Long * Only for single dosing does this pattern hold true. For chronic use, the diazepam class has a longer duration of actions. Lorazepam, Oxazepam, and Temazepam are metabolized by conjugation, rather than by oxidation less stress on liver. Adverse effects CNS depression sedation, ataxia, psychomotor impairment Anterograde amnesia Disinhibition Tolerance, dependence, withdrawal Drug interactions CNS depressants (ex. alcohol) can lead to overdose Cimetidine and disulfiram inhibit oxidative metabolism Clinical use Select based on pharmacokinetic profile (duration of action, single vs. chronic dosing, metabolism in patients with liver disease) Use the lowest dose with the shortest duration possible Dont prescribe to patients with substance abuse problems, suicidality, or pregnancy Gradual withdrawal after long-term, heavy use Tolerance and withdrawal same as for barbiturates (p. 17) Buspirone Mechanism 5-HT1A partial agonist that affects NE (vs. GABA agonist for benzos) Clinical use equal efficacy as benzos in treating generalized anxiety disorder; no other established uses 18

Adverse effects Dizziness, light-headedness, nervousness, headache, nausea Little potential for tolerance, dependence, withdrawal, or abuse Pharmacokinetics 10-14 day lag time to onset Antihistamines Histamine evokes arousal in the forebrain blocking histamine produces sedation 1st generation H1 antagonists (ex. diphenhydramine) No associated toxicity, but anti-cholinergic side effects H1 receptors brain H2 receptors gut H3 receptors presynaptic autoreceptors Melatonin Modulates circadian clock in suprachiasmatic nucleus of the hypothalamus Only clinical use is as a mild sedative (no toxicity) Less commonly used drugs Antipsychotics rarely used Clonidine (2 agonist) Carbamates Beta blockers Antidepressants


Drug abuse Diagnostic criteria Substance abuse non-dependent problem use 1 or more of the following in a 12 month period: Failure to fulfill a major role obligation Use in physically hazardous situations Recurrent legal problems Recurrent social problems Substance dependence loss of control + inability to abstain = addiction 3+ in a 12 month period: Tolerance Withdrawal Ingesting more than intended Unsuccessful efforts to cut down Use of drug takes precedence over all else Important activities are given up due to drug use Continued use despite negative consequences ** Substance abuse and dependence are mutually exclusive categories. Intoxication, per se, has nothing to do with either category. Treatment of drug abuse Withdrawal symptoms reflect physiological dependence Withdrawal from long-acting drugs has a delayed onset, is relatively mild, and may occur over many days or weeks Withdrawal from more rapidly metabolized/eliminated drugs produces shorter but more intense symptoms Cravings reflect psychological dependence (caused by sensitized receptors) Tolerance reduced drug effect with repeated use + requirement of higher doses to produce same effect Cross-tolerance to other drugs in the same class Metabolic tolerance rate of drug elimination increases with chronic use Cellular tolerance biochemical adaptation to the drug typically downregulation of receptors Withdrawal symptoms LSD and mescaline LSD is one of the most potent known pharmacologic agent Rapid and high degree of tolerance develops to behavioral effects + cross-tolerance with mescaline and psilocybin **No dependence or addiction PCP (agonist of NMDA) Some tolerance can develop during long-term PCP abuse, but dramatic dosage escalation is uncommon less physical dependence potential than opiates and depressants Marijuana Tolerance is only apparent among heavy long-term users Very mild withdrawal symptoms following chronic use at very high doses


Antipsychotic drugs Antipsychotic drugs block D2 receptors. Typical antipsychotics acute treatment of positive symptoms Low potency High potency Names Chlorpromazine (Thorazine) Fluphenazine Thioridazine (Mellaril) Trifluorperazine Thiothixene Haloperidol Side effects Anticholinergic (blocked mAChR) Extrapyramidal symptoms Postural hypotension (blocked 2) (other side effects minimized) Sedative effects (blocked H1) (few extrapyramidal symptoms) Extrapyramidal symptoms mimic disorders of basal ganglia Dystonic reaction acute spasm of a muscle group within first 72 hours of treatment Parkinsonian symptoms treatable with anticholinergics Akathisia motor restlessness, inability to sit still treatable with propranolol or benzos Tardive dyskinesia irreversible, untreatable involuntary rhythmic movements of lips, tongue, and jaw (due to DA hyperactivity in basal ganglia) Atypical antipsychotics chronic treatment of both positive and negative symptoms; also block 5HT2 Risperidone Extrapyramidal symptoms Postural hypotension Preferred antipsychotic in elderly SSRIs inhibit CYP Olanzapine Prominent weight gain Postural hypotension unlikely more aggressive dosing Most expensive Smoking induces CYP need higher doses Quetiapine Virtually no EPS or endocrine effects Highly sedating


Mental status examination Purposes Observe and evaluate a persons mental status at a specific time Systematic written record Provides essential diagnostic data Baseline for measurement of patient changes Major areas of MSE (mnemonic: ARTSMAJIC) General description Appearance age, race, sex, body habitus, clothes, self-care, posture, gait, movement disorders Behavior psychomotor activity, eye contact, mannerisms, gestures, inappropriate (ex. responding to internal stimulus) Rapport Mood the subjective report of patients own emotional tone Affect objective report by the clinician of the patients external expression euthymic/blunted/flat Speech quality, quantity, rate of production, volume, idiosyncrasies Thought processes normal, circumstantial, tangential, flight of ideas, looseness of association, nonsequitur, neologism, clanging/punning, word salad, thought blocking Thought content Hallucinations (false perceptions in the absence of an external stimulus) Delusions (fixed false beliefs outside cultural norms) paranoid, religious, somatic, erotomanic, jealous, bad/bizarre, grandiose First rank symptoms Ideas of reference getting messages from the TV, radio, computer, etc. Thought withdrawal/insertion/broadcasting Preoccupations obsessions, compulsions, phobias ego-dystonic Suicidal Ideation Homicidal Ideation Perceptual disturbances Hallucinations Illusion Depersonalization feeling detached from your own body Derealization feeling foreign in a familiar environment Judgment understanding the outcome of ones own behavior/actions Insight degree of awareness and understanding of illness + need for medication Cognition Alertness/attention Orientation Memory immediate, recent, remote Concentration test by serial 7s, simple calculations, spelling Abstraction ability to deal with concepts, similarities, proverbs Intelligence infer by vocabulary Intelligence

Mood disorders MOOD a sustained emotional tone (an internal state) AFFECT the external expression of present emotional content (normal = euthymic) MOOD DISORDER a prolonged and abnormal disturbance of mood, generally of a depressed, elated, or irritable nature, with syndromal features that result in significant subjective distress and/or objective disturbance in functioning Depression Disease syndromes Major depression causes significant social/occupational dysfunction Major depression with psychotic features Dysthymia mild chronic depression (>2 years), pessimistic worldview Adjustment disorder with depressive mood stress related phenomenon; symptoms resolve within 6 months after end of stressor/consequences Clinical features of major depression Depressed mood, sometimes with anxiety or tension Cognitive changes difficulty concentrating, indecisiveness, decreased self-esteem, guilt, pessimism, thoughts of helplessness and hopelessness Thoughts of death and suicide Psychotic features (<25%), usually congruent with mood Behavioral changes sad face, crying, psychomotor retardation/agitation, social withdrawal Physiological changes decreased energy or fatigue, sleep disturbance, appetite disturbance, weight change, decreased libido Epidemiology 10% men and 20% of women affected 15% overall incidence Mean age of onset ~40 >50% have 2nd episode 80% recover 15% commit suicide (risk comorbid with anxiety and substance abuse) Mania Disease syndromes Bipolar I manic episode, with or without depression Bipolar II hypomanic episode with major depression Cyclothymic disorder hypomanic episode with minor depression Bipolar NOS hypomanic episode without depression Clinical features Labile mood, often persistently elevated or irritable Cognitive changes rapid or racing thoughts, grandiosity, excessive optimism, sometimes psychotic features Behavioral changes increased talkativeness, increased activity level and sociability, increased sexuality, poor judgment Physiologic changes increased energy, increased libido, decreased need for sleep Epidemiology Affects males and females equally (1% for each) Mean age of onset is 30 Untreated episodes last 3 months 2

45% of people have multiple episodes; 40% become chronic Associated with psychotic features in 50% of individuals at some point in their illness may be confused with schizophrenia High risk of drug and alcohol abuse Etiologic theories Stress-diathesis model (biopsychosocial) Early life trauma may result in long term, if not permanent, hyperactivity of the CNS + CRF + NE systems Sensitization of the CRF circuits in adulthood leads to an exaggerated stress response Persistent elevations in CRF and cortisol secretion cause alterations in the glucocorticoid receptors in the hippocampus, resulting in decreased volume and cell production This is the basis for development of mood and anxiety disorders Treatment Antidepressants, antipsychotics, mood stabilizers ECT Psychotherapy Modifications to the environment Mood disorders caused by other medical conditions Neurological disorders Parkinsons, stroke, MS, dementia Metabolic electrolyte disturbances, toxins, heavy metals GI irritable bowel, cirrhosis, chronic pancreatitis Endocrine hypo and hyperthyroidism, Cushings, diabetes Cardiovascular heart attack, post-op from coronary artery bypass, angina, cardiomyopathies Pulmonary COPD, sleep apnea, reactive airway disease Heme/onc anemias, brain tumors, pancreatic cancer Autoimmune lupus, rheumatoid arthritis, fibromyalgia Mood disorders caused by drugs Alcohol Cocaine Amphetamine Opiate Hallucinogen

Antidepressants and mood stabilizers Treatment for major depression Psychotherapy (especially CBT) 70% efficacy, but not useful for psychotic depression Electroconvulsive therapy 70-95% effective in treating acute depression, particularly if psychotic symptoms or suicidal thoughts are present rapid effect Pharmacotherapy generally takes 4-6 weeks for response 60-80% effective in treating acute episodes; all antidepressants have similar efficacy rates Mechanism modulation of NT function on surface of the cell cAMP, CREB, BDNF intracellular neuron repair lifting of depression

Drug classes Tricyclics amitriptyline (Elavil) inhibit presynaptic reuptake of NE/5HT/DA **Cardiotoxicity in high doses Sedation blockage of H1 receptor Orthostatic hypertension blockage of -AR Dry mouth, constipation blockage of ACh SSRI fluoxetine (Prozac) inhibit presynaptic reuptake of 5HT **Little risk of overdose **Sexual dysfunction simulation of 5HT-2 Nausea, diarrhea stimulation of 5HT-3 Restlessness, insomnia due to moderate inhibition of DA transporter MAOI phenelzine (Nardil) inhibit breakdown of NE/5HT/DA Dizziness, insomnia Interaction with aged cheese and red wine Mirtazapine (Remeron) promotes release of NE and 5HT **Significant weight gain **Low nausea, headache, or sexual dysfunction Bupropion (Wellbutrin) inhibits DA reuptake (good for smoking cessation and ADHD) **Low sexual dysfunction and weight gain **Seizure risk Insomnia Upset stomach Treatment for bipolar disorder Drugs Lithium inhibits excitatory NT release **Narrow therapeutic range possible toxicity 1-3 week onset of effect Well-established relapse prevention Helps treat depression Valproate (anticonvulsant) facilitates GABA release Wide therapeutic range little risk of toxicity 2-7 day onset of effect Better for treating rapidly cycling mood Additional considerations When needed, anti-psychotics and benzodiazepines are used as adjuncts to mood stabilizers Care must be taken not to overtreat and send a depressed patient into mania

Delirium Delirium = acute confusional state = global encephalopathy = toxic psychosis 4

reversible disturbance of consciousness, cognition, and perception that cannot be accounted for by past or developing dementia DSM criteria Disturbance of consciousness, with reduced ability to focus, sustain, or shift attention Change in cognition, or perceptual disturbances Symptoms develop over a short period and tend to fluctuate Caused by the direct physiological consequences of a general medical condition Clinical presentation **Impaired attention Disorientation (particularly to time) Change in level of consciousness hypervigilant to stuporous Disturbance in sleep-wake cycle (due to brainstem and thalamic dysfunction) Behavior not goal-directed Fragmented, disjointed speech Variable emotional tone apathetic to agitated/irritated Impaired sensation misperceptions and hallucination **Rapid progression to acute delirium Symptoms worsen at night (less cognitive stimuli) Epidemiology Most common in the elderly, the young, and post-op patients 10-15% of general medical patients develop delirium during hospitalization High mortality 40-50% dead within 1 year 25% dead within 3 months 20% mortality in children and adolescents Sleep deprivation & sensory deprivation may contribute to severity of delirium, but they do not cause it. Etiology Anything that can make a person very sick can cause delirium (esp. hypoxia, head injury, and infection) Neurotransmitter changes NE (decreased awareness) ACh (decreased cognition, memory) GABA DA (hallucinations) 5-HT (anxiety) Delirium is usually reversible if the underlying disorder is treated promptly. If allowed to persist, it may result in permanent brain damage, fixed cognitive deficits, and behavioral changes. Treatment **Fix underlying medical condition Manage environment quiet, restful, well-lighted Facilitate orientation Reassurance by familiar people (especially family) Pharmacotherapy Avoid opioids, antihistamines (anti-cholinergics) 5

Avoid benzodiazepines (further increase GABA) risk of respiratory suppression May need to treat agitation with lose dose anti-psychotics

Child and adolescent psychiatry Evaluating children and adolescents Special consideration must be given to the patients developmental age and to age-appropriateness of the childs behaviors It is crucial to assess the entire family When medications are prescribed, the specifics of child metabolism must be taken into account (ex. proportionately greater liver mass than adults need higher doses). ADHD Assessment Interview parent and child Documentation from school about inattention/hyperactivity/impulsivity Behavioral problems must occur in two or more settings and cause impairment Clinical features Hyperactivity/impulsivity Subtypes hyperactive/impulsive, inattentive, combined Inattention Clinical outcome lifelong disease Etiology Impaired executive functions (dorsolateral prefrontal cortex) Perturbations in DA and NE systems glucose metabolism + abnormal DA function in PFC of adults Genetic component Co-morbid disorders Boys conduct disorder, oppositional defiant disorder Girls depressive disorders, anxiety disorders Adolescents substance abuse Conduct disorder a pattern of behavior that violates the rights of others; precursor to APD Clinical features Shallowness of relationships and attachments Lack of empathy Impaired capacity to feel guilt Aggression to people and animals, destruction of property, theft impairment Etiology Genetic Neurobiological serotonin deficiency, low autonomic arousal, intrauterine exposure to alcohol, head trauma Temperamental novelty-seeking personality Psychosocial abusive parenting, failed parent-child bonding, parental conflict, harsh/inconsistent discipline, early puberty for girls Clinical course and outcome High risk of substance abuse, incarceration, major psychiatric symptoms 6

Outcome depends on age of onset (< 10 has poorer outcome than > 10), degree of socialization, aggressiveness Co-morbidities ADHD Learning disorders (particularly reading and expressive language) Substance abuse PTSD and other dissociative disorders (particularly in incarcerated delinquent youth) Oppositional defiant disorder (mild version of CD no serious violations of the rights of others) Etiology Inconsistent parenting methods Modeling after a stubborn/impulsive parent Parents not investing time/energy in child Clinical course Some people with ODD progress to CD Risk factors for progression: Low IQ Physical fighting Resistance to discipline Poverty Inconsistent parenting, inadequate supervision, parent substance abuse, young first-time mom Autism Clinical features manifest most noticeably after age 3 **Qualitative impairments in reciprocal social interaction Communication and language impairment Restricted, repetitive, stereotyped patterns of behavior/interests/activities (including compulsions, motor mannerisms, and preoccupation with parts of objects) Co-morbidities Intelligence and cognitive deficits (most are retarded, which is associated with a worse prognosis and a higher prevalence of seizure disorders) Fragile X syndrome Tuberous sclerosis (TSC) Chromosome 15 abnormalities Aspergers disorder effectively a high-functioning form of autism, without mental retardation Separation anxiety disorder **One of the only mental disorders that affects males and females equally Clinical features Developmentally inappropriate/excessive anxiety concerning separation from home/attachment objects, which produces significant impairment to life functioning Clinical course Typically begins around school age, usually recognized in early/middle childhood Often recurrent, with acute exacerbations at beginning of school Risk factor for major depressive disorder in early to later adolescence Etiology modeling from parents, genetics, inborn temperament Comorbidities more than 92% have additional psychiatric disorders (particularly major depression) 7

Anxiety disorders ANXIETY a state of apprehension, uncertainty, and fear that impairs functioning Lifetime prevalence is 25% (vs. 20% for mood disorders) ANXIETY DISORDER excessive anxiety that lasts too long and affects daily function PHYSICAL SYMPTOMS tachycardia, sweating, other sympathetic responses PSYCHOLOGICAL SYMPTOMS preoccupation, poor concentration, impaired mental clarity, indecisiveness, mind going blank, irritability, agitation, panic, hypervigilence Disorders Generalized anxiety disorder anxiety that is not focused on any particular object or situation 4-7% prevalence Treatment CBT, benzodiazepines, SSRI Social anxiety disorder (social phobia) 16% prevalence (vs. 8% general phobia)

Schizophrenia Symptoms Positive symptoms hallucinations, delusions Negative symptoms affectual blunting, avolition (lack of motivation), alogia (poverty of speech, thought), disinterest, social withdrawal Active-phase psychosis Specific types of bizarre delusions and prominent hallucinations Marked loosening of associations Catatonic behavior Prodromal/residual phase symptoms Social withdrawal Impairment in role functions Peculiar behavior Neglect of hygiene and grooming Blunted or inappropriate affect Bizarre speech or ideation Unusual perceptual experiences Apathy Disease course Onset usually in adolescence or early adulthood; usually insidious Progression Deteriorating function, at least for the first few years May have course of exacerbations (positive sx) and partial remissions (negative sx) Social withdrawal, depression, and substance abuse lead to greater decline in functioning Treatment Anti-psychotic medications are effective during active phase of illness; can help prevent relapse Social and family therapies ameliorate the degree of disability during residual phases

Miscellaneous Neuroscience Lectures

Head and neck development (embryology) Fate of pharyngeal arch components

Development of cranial features Derivatives of pharyngeal arch cartilage 1st arch cartilage mandible, maxilla + malleus, incus 2nd arch cartilage supporting elements for jaw + stapes 3rd 6th arch cartilage supporting elements for neck and larynx Formation of head and face mostly from frontonasal process, maxillary, and mandibular processes Craniofacial muscles Derived from paraxial mesoderm Intermingle and migrate widely through the head and neck, but maintain their embryological innervation pattern Formation of nasal cavity evagination from surface ectoderm Formation of palate Interior part of intermaxillary segment from FNP is primary palate Palatine shelves on either side fuse to form the secondary palate Ossification of primary and secondary palates hard palate Remaining non-ossified part of 2nd palate soft palate Formation of tongue Anterior 2/3 of tongue forms from tongue buds in 1st arch (trigeminal innervation) Posterior 1/3 forms from 3rd arch (glossopharyngeal innervation) Very posterior terminal end is derived from 4th arch (vagal innervation) Formation of the ear External ear from 1st and 2nd arches Middle ear from 1st and 2nd arches Inner ear from arches 2 and 3 non-pharyngeal innervation by VIII Development of thyroid Forms from dorsal surface of what will become the tongue, behind junction of 1st and 3rd arches Originally is an endodermal invagination (thyroid diverticulum) that extends inwards (thryroglossal duct), descends through the tongue, and migrates to straddle the larynx 1

Neuroradiology Most important element in radiological diagnosis LOCATION recognize abnormality, locate abnormality, then make diagnosis Advantages Disadvantages Plain Xray Cost Very little useful information Speed CT Speed Uses ionizing radiation Good bony detail for fractures Less sensitive than MRI Lower cost than MRI Motion artifacts Doesnt disrupt pacemakers MRI Much more information Cost Multiplanar scanning capacity Takes a long time Cant use on patients with pacemakers or other implants Claustrophobia Angiogram Gold standard for evaluating Invasive vascular lesions Ionizing radiation Only 2D information Cost


T1 images look anatomic white matter is lighter T2 white matter is darker than grey matter