Colin Haile Neuroscience Winter 2004 Lecture Notes: IV
LECTURE 36: Olfaction and Gustation Olfactory System • The olfactory system mediates the special visceral afferent (SVA) modality of smell via the olfactory nerve (CN I). • It is the only sensory system that has no pre-cortical relay in the thalamus. • It eventually projects to the thalamus, hypothalamus, amygdala and hippocampal formation. Olfactory Pathway • Olfactory cells are chemoreceptors numbering about 25 million on each side of the nose. • They are replaced throughout life and regenerate. • Olfactory cells are found in the nasal mucosa and are first-order neurons in the olfactory pathway. • They are unmyelinated bipolar neurons whose central processes are CN I. • They have axons that enter the olfactory bulb and synapse in the olfactory glomeruli with mitral and tufted cells. • Cribriform plate of the ethmoid bone, as seen from inside a human skull. • Olfactory fila pass through small holes (arrows) in the plate to reach the olfactory bulb. The Vomeronasal Organ – menstrual synchronization Location of Olfactory Epithelium • Olfactory epithelium is located on the lateral wall of the nasal cavity and continues across the roof of the cavity into a patch of similar size on the nasal septum. • Odorants can reach this epithelium either through the nostrils or by way of the oropharynx. CN I: Olfaction • Axons of the olfactory nerves are unmyelinated C fibers and are among the smallest and slowest in the nervous system. • Olfactory epithelium is also innervated by CN V (trigeminal) which detects noxious or painful stimuli such as ammonia. Chemosensory Transduction in Olfactory Receptor Cells • Odorant molecules bind to receptors located on cilia of the olfactory receptor neurons. • When the receptors are activated, they activate G-proteins (Golf) which activates adenylate cyclase. • There is an increase in intracellular cAMP that opens Na+ channels in the olfactory receptor membrane and produces a depolarizing receptor potential.

The receptor potential depolarizes the initial segment of the axon to threshold, and action potentials are generated. Glomeruli and Neurons of the Olfactory Bulb • Most glomeruli in this drawing contain only one type of neural process, either axon terminals of olfactory receptor neurons (go), dendrites of mitral cells (gm), or dendrites of tufted cells (gt). • In reality, each glomerulus contains all of these, together with processes of interneurons. Sorting of Olfactory Nerve Fibers Among Glomeruli • Olfactory receptors are of different types, each type characterized by one or a few receptor proteins and a restricted range of odor sensitivities (represented as different colors), are intermingled with each other in a given area of olfactory epithelium. • The axon terminals of any given type all converge on one or two glomeruli (which in reality would contain thousands of axon terminals and the dendrites of dozens of mitral and tufted cells). Olfactory Pathway • The olfactory bulb lies on the cribriform plate of the ethmoid bone and receives the olfactory nerve. • It contains mitral and tufted cells (second-order neurons) that project via the olfactory tract and the lateral olfactory stria to the primary olfactory cortex and the amygdaloid nucleus. Olfactory Pathway • Olfactory tract contains the anterior olfactory nucleus which gives rise to the medial and lateral olfactory striae. • It projects to the contralateral olfactory tract via the anterior commissure. • The lateral olfactory stria projects to the primary olfactory cortex and the amygdaloid nucleus. • The primary olfactory cortex overlies the uncus of the parahippocampal gyrus (area 34). • It receives input from the lateral olfactory stria and consists of prepiriform and periamygdaloid cortices. • The olfactory cortex projects to the medial dorsal nucleus of the thalamus, via the amygdaloid nucleus to the hypothalamus and via the entorhinal cortex (area 28) to the hippocampal formation. • The mediodorsal nucleus of the thalamus projects to the orbitofrontal cortex, where the conscious perception of smell takes place. Clinical Correlations • Anosmia: the loss of smell may occur as a result of a lesion of the olfactory nerve (anosmia is unilateral). • Olfactory nerves may be damaged by fractures of the cribriform plate, by meningitis, meningiomas, gliomas, or by abscesses of the frontal lobes. • Olfactory hallucinations may be a consequence of lesions of the parahippocampal uncus. • Foster Kennedy Syndrome results from a meningioma of the olfactory groove, which compresses the olfactory tract and the optic nerve.

It results in ipsilateral anosmia, optic atrophy, and contralateral papilledema. • Fractures of the cribriform plate of the ethmoid bone may result in anosmia and cerebrospinal rhinorrhea. Gustatory System • The gustatory system mediates the somatic visceral afferent (SVA) modality of taste. • It mediates gustation, which like olfaction, is a chemical sense. • Taste receptor cells line the taste buds that are located on specialized papillae. • The receptor cells are covered with microvilli, which increase the surface area for binding taste chemicals. • In contrast to olfactory receptor cells, taste receptors are not neurons. Distribution of Taste Buds and Innervation • The anterior two-thirds of the tongue: – detects salty and sweet sensations. – Is innervated by CN VII (chorda tympani). • The posterior one-third of the tongue: – Has circumvallate and foliate papillae. – Detects sour and bitter sensations. – Is innervated by CNIX (glossopharyngeal). • The back of the throat and the epiglottis are innervated by CNX. Morphology of Taste Buds Transduction in Taste Receptor Cells • (A) Tastant molecules activate the transduction machinery in the apical microvilli of a taste cell (1) cause production of a depolarizing receptor potential • (2) entry of Ca2+ through voltage-gated CA2+ channels (3) release of transmitter onto a peripheral nerve ending (4) and increased firing of the nerve fiber (5). • (B) Na+ ions (salty taste) flow directly into Na+ channels. (C), Protons (sour taste, H+) either flow through Na+ channels (1) or cause normally open K+ channels (2) to close (3). • The decreased K+ conductance causes the membrane potential to move toward the Na+ equilibrium potential (i.e. depolarize). • (D) Sweet substances all bind to G protein-coupled receptors (1). • Dissociation of the G-protein from some of these receptors (3) activates an enzyme (4) whose product (cAMP) leads to the closing of K+ channels (5) that are normally open (2). • (E) Some bitter substances bind (2) to normally open K+ channels (1), causing them to close (3). • Other bitter substances bind to G protein-coupled receptors (4). • Dissociation of the G-protein (5) activates an enzyme (6) whose product leads to the release of Ca2+ (8) from intracellular stores (7). Gustatory Pathway

Taste receptor cells are chemoreceptors; modified epithelia cells, not neurons. • They are continuously being regenerated and are located in the taste buds of the tongue, epiglottis and palate. • Taste receptor cells are innervated by SVA fibers of the facial nerve (CN VII), the glossopharyngeal nerve (CNIX) and the vagal nerve (CN X). • Taste buds on the tongue detect certain sensations: • sweetness at the apex of the tongue • saltiness posterolateral to the apex of the tongue • bitterness on the circumvallate papillae • sourness on the anterior two-thirds of the dorsal surface of the tongue Innervation of Taste Buds • Innervation of taste buds in different parts of the oral cavity by the facial (VII), glossopharyngeal (IX) and vagus (X) nerves. • The central processes of all three terminate in rostral parts of the nucleus of the solitary tract. CT, Chorda tympani nerve; GG, geniculate ganglion; GP, greater petrosal nerve; IG IX, inferior ganglion of the glossopharyngeal nerve; IG X, inferior ganglion of the vagus. Taste Pathway in the CNS • Second-order neurons are located in the nucleus of the solitary tract. • Second-order neurons feed into reflexes both by direct projection (e.g. to the nearby dorsal motor nucleus of the vagus, DMN X) and by connections with the reticular formation (RF). The projection from the parabrachial nucleus to the hypothalamus (H) and amygdala (A) is dashed because, although it is present in most mammals, its presence in primates is doubtful. Firing Patterns of Neurons and Taste • Information about taste is coded by the pattern of activity in populations of neurons. • Responses of a single gustatory neurons in the nucleus of the solitary tract (A) and the orbital cortex (B) of monkeys to tastants applied at the time indicated by the vertical dashed lines. • The brainstem neuron responds to multiple tastants, but the cortical neuron is more selective. Clinical Correlation • Ageusia (gustatory anesthesia or lack of the sense of taste) is most commonly caused by heavy smoking. • Ageusia is most frequently associated with peripheral lesions of CN VII (Bell’s palsy and diseases of the middle ear) and CN IX. LECTURE 37: Hearing and Balance The Auditory System • The auditory system detects sound frequencies from 20 to 20,000 Hz. • Ordinary conversation ranges between 300 and 3000 Hz. • There is a loss of high frequency tones with advanced age. • The outer ear consists of an auricle and an external auditory meatus.

• It is separated from the middle ear by the tympanic membrane. • The outer ear conducts sound waves to the tympanic membrane. • Blockage (wax) causes conduction deafness. Outer, Middle and Inner Ear • The middle ear (tympanic cavity) is located within the temporal bone. • It serves as an amplifier and impedance matching device. • The middle ear communicates with the nasopharynx via the auditory tube. • The blood supply to the middle ear comes from the stylomastoid branch of the occipital or posterior auricular artery. • Sensory innervation is mediated by the glossopharyngeal nerve (CN IX). • The middle ear contains the chorda tympani of CN VII, which mediates taste sensation and parasympathetic input into the submandibular and sublingual glands. • Pathology to the middle ear results in conduction deafness. • The middle ear is air-filled and contains the following structures: • Tympanic membrane: receives airborne sound vibrations and transmits energy to the middle ear ossicles. • Middle ear ossicles: consists of the malleus, incus and stapes. • Vibration of the tympanic membrane forces the footplate of the stapes into the oval window, triggering a traveling wave in the perilymph-filled scala vestibuli. Otitis Media • A bulging red tympanic membrane may indicate pus or fluid in the middle ear, a sign of otitis media. • Infection of the middle ear is often secondary to upper respiratory infections. • Inflammation and swelling of the mucous membrane lining the tympanic cavity may cause partial or complete blockage of the pharyngotympanic tube. • Tensor tympani and stapedius muscles: • These muscles are innervated by the trigeminal and facial nerves (CNV and CNVII). • They dampen vibrations of the ossicular chain, thus protecting the cochlear from loud low-frequency sounds (<1000 Hz). Inner Ear • The inner ear is fluid-filled and contains the semicircular canals, cochlea and vestibule. • The cochlea contains: • Scala vestibuli which contains perilymph. – The scala vestibuli transmits traveling waves toward the helicotrema, scala tympani and the round window. Labyrinth • Labyrinth of the left ear as seen through an outline of the bony labyrinth. Pale green areas indicate the locations of patches or strips of hair cells in the wall of the membranous labyrinth. • The endolymphatic sac is located beneath the dura on the surface of the temporal bone.

It contains no receptor cells but rather is the principle site of absorption of endolymph. • In addition to the bony labyrinth, there are a series of ducts called the membranous labyrinth. • The fluid outside the ducts is perilymph, the fluid inside the ducts is endolymph. • Cochlear duct (scala media) contains the organ of Corti and has endolymph. • It lies between the scala vestibuli and scala tympani which contain perilymph. • Organ of Corti contains hair cells and the tectorial membrane. • It rests on and is supported by the basilar membrane and functions as a frequency analyzer. Organ of Corti • The organ of Corti contains the receptor cells (inner and outer hair cells) that respond to auditory stimuli. • Cilia protrude from the hair cells and are embedded in the tectorial membrane. • Inner hair cells are arranged in single rows and are few in number. • Outer hair cells are arranged in parallel rows an and are greater in number than the inner hair cells. • The spiral ganglion contains the cell bodies of the auditory nerve (VIII) which synapse on the hair cells. Auditory Transduction by the Organ of Corti • Sound waves cause vibration of the organ of Corti. • Because the basilar membrane is more elastic than the tectorial membrane, vibration of the basilar membrane causes the hair cells to bend by a shearing force as they push against the tectorial membrane. Auditory Transduction by the Organ of Corti • Bending of the cilia causes changes in K+ conductance of the hair cell membrane. • Bending in one direction causes depolarization; bending in the other direction causes hyperpolarization. • The oscillating potential of the hair cells causes intermittent firing of the cochlear nerves. Hair Cells • Hair cells are auditory receptor cells that have stereocilia (microvilli). • The stereocilia are embedded in the overlying tectorial membrane. • They are mechanoreceptors that transduce mechanical (sound) energy into generator potentials. • Hair cells are stimulated by vibrations of the basilar membrane and are innervated by bipolar neurons of the spiral ganglion. • They receive efferent input via the olivocochlear bundle. Stereocilia • Each stereocilium is connected to its next taller neighbor by a filamentous tip link.

C, longitudinal micrograph showing two stereocilia and the actin filaments interconnecting them. • D, Deflecting the hair bundle toward the tallest stereocilia stretches the tip links. • E, This stretch increases the probability of cation channels at one or both ends of the tip links being open. Encoding Sound: Basilar Membrane • The frequency that activates a particular hair cell depends on the location of the hair cell along the basilar membrane. • The base of the basilar membrane (near the oval and round windows) is narrow and stiff: responding best to high frequencies. • The apex of the basilar membrane (near the helicotrema) is wide and compliant: responding best to low frequencies. The Basilar Membrane: Tonotopic Organization Inner Ear • The basilar membrane separates the cochlear duct from the scala tympani and has a pitch localization along its length: – 20 Hz at the apex and 20,000 Hz at the base of the cochlea. – Vibration results in deformation of the hair cells microvilli against the tectorial membrane. • Spiral ganglion (of CN VIII) is located in the body modiolus of the cochlea. – It consists of bipolar neurons of the cochlear division of the vestibulocochlear nerve (CN VIII). Simply, the spiral ganglion contains the cell bodies of the auditory primary afferent fibers. Auditory Pathway • The auditory pathway is characterized by reciprocal connections throughout its caudo-rostral extent and by multiple decussations at all levels. Hearing Defects • Hearing defects are classified into conduction deafness and nerve deafness. • Conduction deafness is caused by interruption of the passage of sound waves through the external or middle ear. – Conduction deafness can be caused by obstruction by wax (cerumen) or a foreign body in the external auditory meatus. – Otosclerosis is produced by neogenesis of the labyrinthine spongy bone around the oval window, resulting in fixation of the stapes. – Otosclerosis is the most frequent cause of progressive conduction deafness. – Otitis media is an inflammation of the middle ear. • It is the most common cause of meningitis (excluding meningococcus) and the most common cause of brain abscesses. • Nerve deafness (sensorineural or perceptive deafness) is due to disease of the cochlea, cochlear nerve, or central auditory connections (acoustic neuroma). – It may result from the action of drugs and toxins (e.g. quinine, aspirin, streptomycin).

Nerve deafness may also result from prolonged exposure to loud noise (industrial noise or rock music [yea!]; high frequency loss). • Rubella infection in utero, cytomegalovirus, and syphilis may also cause nerve deafness. • Nerve deafness includes presbycusis which is hearing loss occurring with aging. – It results from degenerative disease of the organ of Corti in the first few millimeters of the basal coil of the cochlea (high-frequency loss of 4000 Hz to 8000 Hz). • Presbycusis is the most common cause of hearing loss. • Acoustic neuroma (schwannoma or neurilemoma) consists of a peripheral nerve tumor of the vestibulocochlear nerve (CN VIII). – Acoustic neuromas are usually located in the internal auditory meatus or in the cerebellopontine angle of the posterior cranial fossa. – Symptoms include unilateral deafness and tinnitus (ear ringing). • Tuning fork tests are used to distinguish between conduction deafness and nerve deafness (sensorineural deafness). • Tuning fork tests simply compare air conduction with bone conduction. • Weber test is performed by placing a vibrating tuning fork on the vertex of the skull. – A normal subject hears equally on both sides. – A patient with unilateral conduction deafness hears the vibration louder in the diseased ear. – A patient with unilateral partial nerve deafness hears the vibration louder in the normal ear. • Rinne test compares air and bone conduction. – It is performed by placing a vibrating tuning fork on the mastoid process until it is no longer heard then it is held in front of the ear. • A normal subject hears vibration in the air after bone conduction is gone. • A patient with unilateral conduction deafness fails to hear vibrations in the air after bone conduction is gone. • A patient with unilateral partial nerve deafness hears vibrations in the air after bone conduction is gone. The Vestibular System • The vestibular system is a special somatic afferent (SSA) proprioceptive system. • This system maintains posture and equilibrium and coordinates head and eye movements. • It functions in concert with the cerebellum and the visual system. • It contains receptors (hair cells) that are located in the labyrinth of the temporal bone. Labyrinth • The labyrinth constitutes the inner ear (auris interna) of the temporal bone. • The bony part of the labyrinth is a series of cavities (cochlea, vestibule, and semicircular canals) that house the membranous labyrinth.

The membranous labyrinth is suspended within the bony labyrinth and is filled with endolymph. • It is a closed system: endolymph and perilymph do not mix. • It contains receptor (or hair) cells that are bathed in endolymph. • The labyrinth functions by way of a semicircular canal system (kinetic labyrinth) which detects and responds to angular acceleration and deceleration of the head. • It consists of three semicircular canals, three semicircular ducts and hair cells. • The three semicircular ducts consist of anterior, posterior, and lateral structures that lie in mutually perpendicular planes. • Each semicircular duct lies within a semicircular canal and contains hair cells. • Hair cells are embedded in the cupula of the cristae ampullares and are bathed in endolymph. • Hair cells contain one kinocilium and many stereocilia and are innervated by bipolar cells of the vestibular ganglion (Scarpa ganglion). Vestibular Apparatus • The receptors are hair cells located at the end of each semicircular canal. • Cilia on the hair cells are embedded in a gelatinous structure called the cupula. • A single long cilium is called the kinocilium; smaller cilia are called stereocilia. Stereocilia • Hair cells receive inhibitory input from vestibular nuclei and are stimulated by endolymphatic flow. • Flow toward the kinocilium and the utricle is excitatory. • Flow away from the kinocilium is inhibitory. Vestibular Transduction • During counterclockwise (left) rotation of the head, the horizontal semicircular canal and its attached cupula also rotate to the left. • Initially, the cupula moves more quickly than the endolymph fluid. • Thus, the cupula is dragged through the endolymph; as a result, the cilia on the hair cells bend. • If the stereocilia are bent toward the kinocilium, the hair cell depolarizes (excitation). • If the stereocilia are bent away from the kinocilium, the hair cell hyperpolarizes (inhibition). • Therefore, during the initial counterclockwise (left) rotation, the left horizontal canal is excited and the right horizontal canal is inhibited. • After several seconds, the endolymph “catches up” with the movement of the head and the cupula. • The cilia return to their upright position and are no longer depolarized or hyperpolarized. Hair cells of the Utricle and saccule

Hair cells are embedded in the gelatinous otolithic membrane, which contains calcareous otolith crystals. • They are stimulated by the shearing effect of the otolithic membrane during head movements. • They receive efferent innervation from the vestibular nuclei of the brainstem. Vestibular Pathways • Bipolar neurons of the vestibular ganglion are located in the fundus of the internal auditory meatus. • They project, via their peripheral processes, to hair cells. • Bipolar neurons of the vestibular ganglion project their central processes, as the vestibular nerve, to the vestibular nuclei of the medulla and pons and then to the flocculonodular lobe of the cerebellum. • Vestibular nuclei include the inferior, medial, superior and lateral nuclei. • They RECEIVE input from: • bipolar neurons of the vestibular ganglion • flocculonodular lobe of the cerebellum • uvula of the cerebellum • vermis of the anterior lobe of the cerebellum • vestibular nuclei of the contralateral side • fastigial nuclei of the cerebellum • The vestibular nuclei PROJECT fibers to the • flocculonodular lobe and uvula of the cerebellum • vestibular nuclei of the contralateral side • inferior olivary nucleus • Abducent, trochlear, and oculomotor nuclei receive input via the medial longitudinal fasciculus (MLF). • Ventral horn motor neurons receive vestibular input from the MLF and the vestibulospinal tract. • The MLF (medial longitudinal fasciculus) contains fibers from the medial vestibular nucleus that terminate in cervical and upper thoracic levels. • It coordinates head, neck, and eye movements. Testing Vestibulo-Ocular Reflexes • Doll’s head eye phenomenon (oculocephalic reflex) is not present in normal alert people unless they voluntarily fix vision. • The test consists of rapid movement of the head in horizontal or vertical planes. • With intact proprioception and brainstem (vestibular nuclei), the eyes move conjugately in the opposite direction. • Doll’s head eye movements are absent or abnormal when lesions of the vestibular nuclei and MLFs are present. • A vestibular nystagmus results from the stimulation of hair cells within the semicircular ducts on rotation or after caloric irrigation of the external auditory meatus with hot or cold water. Clinical Correlation • Vertigo is a sensation of irregular or whirling motion, it is an illusion of movement.

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Meniere disease is an inner ear disease associated with an increase in endolymphatic fluid pressure. – It is characterized by episodic attacks of vertigo, tinnitus, hearing loss, nausea, vomiting, and a sensation of fullness and pressure in the ear. Labyrinthitis is characterized by inflammation of the labyrinth, which may result from bacterial, viral, or toxic (e.g. alcohol, quinine, salicylates) causes. Labyrinthitis exhibits the same symptoms seen in Meniere disease. Labyrinthectomy: Unilateral labyrinthectomy results in predominantly horizontal nystagmus directed to the opposite side. Bilateral simultaneous labyrinthectomy does not give rise to nystagmus. Benign positional vertigo is the most common cause of recurrent vertigo. It is elicited by certain head positions, the paroxysm of vertigo is accompanied by nystagmus (involuntary rhythmic oscillation of the eyeballs, either pendular or with a slow and fast component). Benign positional vertigo is not associated with hearing loss or tinnitus. • It is due presumably to cuprolithiasis of the posterior semicircular duct (dislocation of the utricular macular otoliths). MLF syndrome: internuclear ophthalmoplegia (INO) consists of medial rectus paresis on attempted lateral gaze. MLF syndrome is usually the result of a demyelinating plaque. It is the most commonly seen in multiple sclerosis. Acoustic schwannoma (vestibular schwannoma) arises from the vestibular nerve of CN VIII within the internal auditory canal. It usually involves CNs V, VII, and VIII causing symptoms such as unilateral loss of hearing, tinnitus, and vertigo. It is marked by a lack of response to caloric stimulation “dead labyrinth”. Incidence of acoustic schwannoma is highest in individuals 40-50 years of age.

LECTURE 38: Basal Ganglia In 1817 James Parkinson, an English country physician, published a brief monograph entitled An Essay on the Shaking Palsy, in which he described the symptoms of several individuals who had the disease that now bears his name. • Parkinsonian patients are characterized by tremor, generally increased muscle tone, and difficulty initiating voluntary movements, which are unusually slow once begun. • Disorders of this sort whose signs typically include involuntary movements and generalized alteration in muscle tone, have come to be associated with damage to the basal ganglia. • They were long referred to as extrapyramidal disorders to distinguish them from disorders involving the corticospinal system. • This terminology is no longer used because the two systems are ultimately integrated.

The term basal nuclei (or basal ganglia) is applied to a collection of masses of gray matter situated within each cerebral hemisphere. • They are the corpus striatum, the amygdaloid nucleus and the claustrum. • The use of the term “Basal Ganglia” still varies but most people mean the combination of caudate nucleus, putamen, globus pallidus, subthalamic nucleus, and substantia nigra (both compacta and reticular parts). Corpus Striatum The corpus striatum is situated lateral to the thalamus and is almost completely divided by the internal capsule, into the caudate nucleus and lentiform nucleus. The term striatum is used because of the striated appearance produced by the strands of gray matter passing through the internal capsule and connecting the caudate nucleus to the putamen of the lentiform nucleus. Caudate Nucleus • The caudate nucleus is a large C-shaped mass of gray matter that is closely related to the lateral ventricle and lies lateral to the thalamus. • The lateral surface of the nucleus is related to the internal capsule, which separates it from the lentiform nucleus. • It is divided into the head, tail and body. • The head of the caudate nucleus is large and rounded and forms the lateral wall of the anterior horn of the lateral ventricle. • The head is continuous inferiorly with the putamen of the lentiform nucleus. • The caudate nucleus and the putamen are sometimes referred to as the neostriatum or striatum. Just superior to this point of union, strands of gray matter pass through the internal capsule, giving the region a striated appearance, hence the term corpus striatum. • The body of the caudate nucleus is long and narrow and is continuous with the head in the region of the interventricular foramen. • The body also forms part of the floor of the body of the lateral ventricle. • The tail of the caudate nucleus is long and slender and is continuous with the body in the region of the posterior end of the thalamus. • It follows the contour of the lateral ventricle and continues forward in the roof of the inferior horn of the lateral ventricle. • It terminates anteriorly in the amygdaloid nucleus. Lentiform Nucleus • The lentiform nucleus is a wedge-shaped mass of gray matter whose broad convex base is directly laterally and its blade medially. • It is buried deep in the white matter of the cerebral hemisphere and is related medially to the internal capsule, which separates it from the caudate nucleus and the thalamus. • The lentiform nucleus is related laterally to a thin sheet of white matter called the external capsule which separates it from a thin sheet of gray matter called the claustrum. • The claustrum in turn separates the external capsule from the subcortical white matter of the insula. • A vertical plate of white matter divides the nucleus into a larger, darker lateral portion, the putamen, and the inner lighter portion, the globus pallidus.

The paleness of the globus pallidus is due to the presence of a high concentration of myelinated nerve fibers. • Inferiorly at its anterior end, the putamen is continuous with the head of the caudate nucleus. Substantia Nigra and Subthalamic Nuclei • The substantia nigra of the midbrain and the diencephalon are functionally closely related to the activities of the basal nuclei. • The neurons of the substantia nigra are dopaminergic and inhibitory and have many connections to the corpus striatum. The neurons of the subthalamic nuclei are glutamatergic and excitatory and have many connections to the globus pallidus and substantia nigra. Claustrum • The claustrum is a thin sheet of gray matter that is separated from the lateral surface of the lentiform nucleus by the external capsule. • Lateral to the claustrum is the subcortical white matter of the insula. • The function of the claustrum is unknown. Connections of the Corpus Striatum and Globus Pallidus • The caudate nucleus and the putamen form the main sites for receiving input to the basal nuclei. • The globus pallidus forms the major site from which the output leaves the basal nuclei. • They receive no direct input from or output to the spinal cord. • Afferent Fibers: Corticostriate Fibers All parts of the cerebral cortex send axons to the caudate nucleus and the putamen. • Each part of the cerebral cortex projects to a specific part of the caudate putamen complex. • Most of the projections are from the cortex of the same side. • The largest input is from the sensory-motor cortex. Glutamate is the neurotransmitter of the corticostriate fibers. • Neurons in the substantia nigra send axons to the caudate nucleus and the putamen and use dopamine at their terminals. These fibers are INHIBITORY. • Ascending fibers from the brainstem end in the caudate nucleus and putamen and use serotonin which is INHIBITORY. • Striatopallidal fibers pass from the caudate nucleus and putamen to the globus pallidus. They use GABA as their transmitter. • Striatonigral fibers pass from the caudate nucleus and putamen to the substantia nigra. • Some of the fibers are GABAergic or use acetylcholine as the neurotransmitter whereas others use Substance P. Connections of the Globus Pallidus • Pallidofugal fibers can be divided into groups: • ansa lenticularis: which pass to the thalamic nuclei • fasciculus lenticularis: which pass to the subthalamus •

pallidotegmental fibers: which terminate in the caudal tegmentum of the midbrain • pallidosubthalamic fibers: which pass to the subthalamic nuclei. Summary of Neurotransmitters Utilized in the Basal Ganglia Substantia nigra Caudate and Putamen Dopamine Caudate and Putamen Globus Pallidus and SN GABA Cortex Caudate and Putamen Glutamate Functions of the Basal Nuclei • The corpus striatum receives afferent information from the: – cerebral cortex – thalamus – subthalamus – brainstem – substantia nigra • This information is integrated within the corpus striatum (caudate and putamen). Functions of the Basal Nuclei • The activity of the basal nuclei is limited by information from the premotor and supplemental areas of the motor cortex, the primary sensory cortex, the thalamus, and the brainstem. • The outflow from the basal nuclei is channeled through the globus pallidus, which then influences the activities of the motor areas of the cerebral cortex or other motor centers in the brainstem. • The basal nuclei control muscular movements by influencing the cerebral cortex and have NO direct control through descending pathways to the brainstem and spinal cord. • In this way the basal nuclei assist in the regulation of voluntary movement and the learning of motor skills. • Destruction of the primary motor cerebral cortex prevents the individual from performing fine discrete movements of the hands and feet on the opposite side of the body. • However, the individual is still capable of performing gross crude movements of the opposite limbs. • Destruction of the corpus striatum results in paralysis of the remaining movements of the opposite side of the body. CLINICAL NOTES • There are two basic disorders of the basal nuclei: – hyperkinetic disorders, those in which there are excessive and abnormal movements such as that seen with chorea, athetosis and ballism. – hypokinetic disorders which include those in which there is a lack or slowness of movement. • Parkinson’s disease includes both types of motor disturbances.

Chorea • In this syndrome the patient exhibits involuntary, quick, jerky, irregular movements that are nonrepetitive. • Swift grimaces and sudden movements of the head or limbs are good examples. Huntington’s Chorea • Huntington’s disease is an autosomal dominant inherited disease with the onset occurring most often in adult life. • Death occurs 15-20 years after onset. • The disease has been traced to a single gene defect on chromosome 4 which codes the protein huntingtin. • The codon (CAG) that encodes glutamine is repeated more times than normal. • The disease affects men and women with equal frequency. • Patients have the following signs and symptoms: • Choreiform movements: first appear as involuntary movements of the extremities and twitching of the face (facial grimacing). • Later, more muscle groups are involved so that the patient becomes immobile and unable to speak or swallow. • Progressive dementia occurs with loss of memory and intellectual capacity. • In this disease there is a degeneration of the GABA-secreting, substance-P secreting, and acetylcholine-secreting neurons of the striatonigral inhibiting pathway. • This results in dopamine-secreting neurons of the of the substantia nigra becoming OVERACTIVE so that the nigrostriatal pathway INHIBITS the caudate nucleus and putamen. • Sydenham’s chorea (St. Vitus’ dance) is a disease of childhood in which there is rapid, irregular, involuntary movements of the limbs, face, and trunk. • The condition is associated with rheumatic fever. • The antigens of the streptococcal bacteria are similar in structure to the proteins present in the membranes of striatal neurons. • The host’s antibodies not only combine with the bacterial antigens but also attack the membranes of the neurons of the basal ganglia. • This results in the production of choreiform movements, which are transient. Hemiballismus • This is a form of involuntary movement confined to one side of the body. – It usually involves the proximal extremity musculature. – The limb suddenly flies about out of control in all directions. • The lesion, which is usually a small stroke, occurs in the opposite subthalamic nucleus or its connections. • It is the subthalamic nucleus that smooth movements of different parts to he body are integrated. Parkinson’s Disease • Characteristic symptoms and signs of Parkinson’s Disease include: – Tremor: Result of alternating contraction of agonist and antagonist muscles. – The tremor is slow and occurs most obviously when the limbs are at rest.

It disappears during sleep. It should be distinguished from the intention tremor seen in cerebellar disease, which only occurs when purposeful active movement is attempted. • Rigidity: this differs from rigidity caused by lesions of the upper motor neurons in that it is present to an equal extent in opposing muscle groups. • If the tremor is absent, the rigidity is felt as resistance to passive movement and is sometimes referred to as plastic rigidity. • If the tremor is present, the muscle resistance is overcome as a series of jerks, called cogwheel rigidity. • Bradykinesis: There is difficulty in initiating (akinesia) and performing new movements. • The movements are slow, the face is expressionless, and the voice is slurred and unmodulated. • Swinging of the arms during walking is lost. • Postural disturbances: The patient stands with a stoop and his or her arms are flexed. • The patient walks by taking short steps and often is unable to stop. • He or she may even break into a shuffling run to maintain his balance. • Abnormal Gait and Posture: – The patient generally finds it difficult to get up from bed or an easy chair and tends to adopt a flexed posture on standing. • It is often difficult to start walking so that the patient may lean farther and farther forward while walking in place before being able to advance. • Abnormal Gait and Posture: The patient generally finds it difficult to get up from bed or an easy chair and tends to adopt a flexed posture on standing. • It is often difficult to start walking so that the patient may lean farther and farther forward while walking in place before being able to advance. • The gait itself is characterized by small, shuffling steps and absence of the arm swing that normally accompanies locomotion. • There is no loss of muscle power and no loss of sensibility. • Since the corticospinal tracts are normal, the superficial abdominal reflexes are normal and there is no Babinski response. • The deep tendon reflexes are normal. Known Causes of Parkinsonism • There are a few types of Parkinson’s Disease for which the cause is known: • Postencephalitic Parkinsonism developed following viral encephalitis in 19161917 in which damage occurred to the basal nuclei. • Iatrogenic Parkinsonism can be a side effect of antipsychotic drugs (eg. Phenothiazines). • Meperidine analogues (MPTP, used by drug addicts), poisoning from carbon monoxide, and manganese, can also produce Parkinsonism-like symptoms. • Atherosclerotic Parkinsonism can occur in elderly hypertensive patients. Treatments for Parkinson’s Disease • The primary treatment for Parkinson’s is achieved by elevating brain dopamine levels (dopamine pre-cursers such as L-Dopa).

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Unlike dopamine itself, L-Dopa can cross the BBB and is taken up by dopaminergic (DAergic) neurons in the basal nuclei and converted to dopamine. • Selegiline, a drug that inhibits MAO, which degrades dopamine, has also shown treatment efficacy. • There is evidence that selegiline can slow the process of degeneration of DAergic neurons in the substantia nigra. • Human embryonic stem cell transplantation of DAergic cells into the caudate nucleus and putamen. • Implantation of electrical probes into the subthalamic nucleus. • Gene Therapy: increase of GABA precursors in the sub-thalamic nucleus. • Pallidotomy: most of the symptoms of Parkinson’s disease are caused by an increased inhibitory output from the basal nuclei to the thalamus and the precentral motor cortex. • Surgical lesions in the globus pallidus (pallidotomy) have been shown to be temporarily effective (e.g. Michael J. Fox). Athetosis • This consists of slow, sinuous, writhing movements that most commonly involve the distal segments of the limbs. • Degeneration of the globus pallidus occurs with the breakdown of the circuitry involving the basal nuclei and the cerebral cortex. Basal Ganglia—Thalamocortical Circuitry • Two types of DA receptors (D1 and D2) are located on different sets of output neurons in the stratum that give rise to the direct and indirect pathways. • DA neurons degenerate upsetting the normal balance between DAergic inhibition and cholinergic (ACh) excitation of striatal output (GABA) neurons. • The net effect is to increase GABAergic output from the striatum. Treatment is directed toward restoring the dopaminergic:cholinergic balance in the striatum by blocking the effect of acetylcholine with anticholinergic drugs or by enhancing dopaminergic transmission. • The balance between DAergic and ACh influence on striatal output (GABA) neurons can be restored by • (1) blockade of cholinergic transmission with muscarinic antagonists drugs or • (2) enhancement of DAergic transmission with the DA precursor levadopa, DA agonists (e.g. bromocriptine) or amantadine (which stimulates the release of DA from existing DA terminals). Anti-Parkinsonian Agents • Selegiline (Eldepryl or deprenyl) is a MAO type B inhibitor and therefore inhibits the metabolic breakdown of DA. • It thus enhances the antiparkinsonian effect of levodopa and may reduce mild on-off fluctuations in responsiveness. • Some studies suggest that selegiline may also delay the progression of Parkinson Disease. Surgery: Thalamotomy or Pallidotomy

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Surgical treatment of parkinsonism by thalamotomy or pallidotomy is often helpful when patients become unresponsive to pharmacologic measures or develop intolerable adverse reactions to antiparkinsonian medication. Lesions of the internal segment of the globus pallidus (GPi), for example will attenuate its unbalance inhibitory output. Treatment by surgery is sometimes helpful in young patients with predominantly unilateral tremor and rigidity that have failed to respond to medication. Thalamotomy is more helpful for tremor and pallidotomy for hypokinesia.

LECTURE 39: Movement Disorders Movement disorders (some times called extrapyramidal disorders) impair the regulation of voluntary motor activity without directly affecting strength, sensation, or cerebellar function. • They include hyperkinetic disorders associated with abnormal, involuntary movements and hypokinetic disorders characterized by poverty of movement. • Movement disorders result from dysfunction of deep subcortical gray matter structures: the basal ganglia (or basal nucleus). • In clinical terms, the basal ganglia includes the caudate nucleus, putamen, globus pallidus, subthalamic nucleus, and substantia nigra. • The putamen and globus pallidus are collectively termed the lentiform nucleus. • The combination of lentiform nucleus and caudate nucleus is designated as the corpus striatum. • Abnormal movements can be classified as: • tremor • chorea • athetosis • dystonia • ballismus • myoclonus • tics • Such movements can arise for a variety of reasons. • In many disorders, abnormal movements are the sole clinical features. TREMOR • A tremor is a rhythmic oscillatory movement best characterized by its relationship to voluntary motor activity – i.e. according to whether it occurs at rest, during maintenance of a particular posture, or during movement. • Tremor is enhanced by emotional stress and disappears during sleep. • Tremor that occurs when the limb is at rest is generally referred to as static tremor or rest tremor. • If present during sustained posture, it is called a postural tremor; while this tremor may continue during movement, movement does not increase its severity. • When present during movement but not at rest, it is generally called an intention tremor. •

• Both postural and intention tremors are also called action tremors. CHOREA • The word chorea denotes rapid irregular muscle jerks that occur involuntarily and unpredictably in different parts of the body. • In certain cases, there is often forceful involuntary movements of the limbs and the head and the accompanying facial grimacing and tongue movements are unmistakable. • Voluntary movements may be distorted by the superimposed involuntary ones. • In mild cases, however, patients may exhibit no more than a persistent restlessness and clumsiness. • Power is generally full, but there may be difficulty in maintaining muscular contraction such that, for example, hand grip is relaxed intermittently (milkmaid grasp). • The gait becomes irregular and unsteady, with the patient suddenly dipping or lurching to one side or the other (dancing gait). • Speech often becomes irregular in volume and tempo and may be explosive in character. • In some patients, athetotic movements or dystonic posturing may also be prominent. • Chorea disappears during sleep. • Hemiballismus is unilateral chorea that is especially violent because the proximal muscles of the limbs are involved. • It is due most often to vascular disease in the contralateral subthalamic nucleus and commonly resolves spontaneously in the weeks following its onset. • It is sometimes due to other types of structural diseases (in the past was associated with a complication of thalamotomy). Dystonia and Athetosis • The term athetosis generally denotes abnormal movements that are slow, sinuous, and writhing in character. • When the movements are so sustained that they are better regarded as abnormal postures, the term dystonia is used, and many now use the terms interchangeably. Myoclonus • Myoclonic jerks are sudden, rapid, twitch-like muscle contractions. • They can be classified according to their distribution, relationship to precipitating stimuli, or etiology. • Generalized myoclonus has a wide-spread distribution, while focal or segmental myoclonus is restricted to a particular part of the body. • Myoclonus can be spontaneous, or it can be brought on by sensory stimulation, arousal, or the initiation of movement (action myoclonus). • Myoclonus may occur as a normal phenomenon (physiologic myoclonus) in healthy persons, as an isolated abnormality (essential myoclonus) or as a manifestation of epilepsy (epileptic myoclonus). • It can also occur as a feature of a variety of degenerative, infectious, and metabolic disorders (symptomatic myoclonus). Tics

Tics are sudden, recurrent, quick, coordinated abnormal movements that can usually be imitated without difficulty. • The same movement occurs again and again and can be suppressed voluntarily for short periods, although doing so may cause anxiety. • Tics tend to: – worsen with stress – diminish during voluntary activity or mental concentration – disappear during sleep Parkinsonism • Parkinsonism occurs in all ethnic groups. • In the US and western Europe it has a prevalence rate of 1-2/1000 population with an approximately equal sex distribution. • The disorder becomes increasingly common with advancing age. • It is characterized by: – tremor – hypokinesia – rigidity – abnormal gait and posture • Idiopathic: a very common variety of parkinsonism occurs without obvious cause; this idiopathic form is called Parkinson’s Disease or paralysis agitans. • Encephalitis Lethargica: In the first half of the twentieth century, parkinsonism often developed in patients with a history of von Economo’s encephalitis. – Since this type of infection is not now encountered, cases of postencephalitic parkinsonism are becoming increasingly rare. • Drug or Toxin-induced Parkinsonism • Therapeutic drugs: Many drugs, such as phenothiazines, butyrophenones metoclopramide, reserpine, and tetrabenazine, can cause a reversible parkinsonian syndrome. • Toxic substances: Toxins such as manganese dust or carbon disulfide can also lead to parkinsonism, and the disorder may appear as a sequela of severe carbon monoxide poisoning. • MPTP: a drug induced form of parkinsonism has been described in individuals who synthesized and self-administered a meperidine analogue. • This compound is metabolized to a toxin that selectively destroys dopaminergic neurons in the substantia nigra and adrenergic neurons in the locus ceruleus and induces a severe form of parkinsonism in humans and in subhuman primates. • The ability of this drug to reproduce neurochemical, pathologic, and clinical features of Parkinson’s disease suggests that an environmental toxin could be responsible for the idiopathic disorder. Idiopathic Parkinsonism • Pathological examination shows: – loss of pigmentation and cells in the substantia nigra and other brainstem centers – cell loss in the globus pallidus and putamen

presence of eosinophilic intraneural inclusion granules (Lewy Bodies) in the basal ganglia, brainstem, spinal cord, and sympathetic ganglia • These inclusion bodies are not seen in postencephalitic parkinsonism. • It is generally believed that the normal balance between various neurotransmitters (dopamine, acetylcholine and GABA) is disturbed because of DA depletion in the DAergic nigrostriatal system. • DA neurons exert a net inhibitory effect and acetylcholine (ACh) neurons a net excitatory effect on the GABAergic output from the striatum. Clinical Features of Parkinson’s Disease • Tremor: Tremor of parkinsonism is characteristically most conspicuous at rest. • It increases at times of emotional stress and often improves during voluntary activity. • It commonly begins in the hand or foot, where it takes the form of rhythmic flexion-extension of the fingers or of the hand or foot, or of rhythmic pronationsupination of the forearm. • It frequently involves the face in the area of the mouth as well. • Rigidity: Rigidity, or increased tone— i.e., increased resistance to passive movement, is a characteristic clinical feature of parkinsonism. • The disturbance in tone is responsible for the flexed posture of many patients with parkinsonism. • The resistance is typically uniform throughout the range of movement at a particular joint and affects agonist and antagonist muscles alike. • In some instances, the rigidity in parkinsonism is described as cogwheel rigidity because of ratchet-like interruptions of passive movement that may be due, in part, to the presence of tremor. • Hypokinesia: The most disabling feature of this disorder is hypokinesia (sometimes called bradykinesia or akinesia)—a slowness of voluntary movement and a reduction in automatic movements, such as swinging the arms while walking. • The patient’s face is relatively immobile (masklike) with widened palpebral fissures, infrequent blinking, a certain fixity of facial expression. Progressive Supranuclear Palsy • Progressive supranuclear palsy is an idiopathic degenerative disorder that primarily affects subcortical gray matter regions of the brain. • The principal neuropathologic finding is neuronal degeneration with the presence of neurofibrillary tangles in the midbrain, pons, basal ganglia, and dentate nuclei of the cerebellum. • Associated with neurochemical abnormalities include decreased concentrations of DA and its metabolite homovanillic acid in the caudate nucleus and putamen. • The classic clinical features are • supranuclear ophthalmoplegia • pseudobulbar palsy • axial dystonia with or without extrapyramidal rigidity of the limbs • dementia

Men are affected twice as often as women, and the disorder has its onset between ages 45 and 75 years. Huntington’s Disease • Huntington’s disease is characterized by the gradual onset and subsequent progression of chorea and dementia. • It is a hereditary disorder of the nervous system that has been traced to a single gene defect on the short arm of chromosome 4. • At this point there is an expanded and unstable CAG (codes for glutamine) repeat at 4p16.3. • The disorder is inherited in an autosomal dominant manner, so the offspring of an affected patient have a 50% chance of developing the disorder. • Huntington’s disease occurs throughout the world and in all ethnic groups. • Its prevalence rate is about 5 per 100,000 population. • Symptoms usually do not appear until adulthood (between 30 and 50 years of age). • By which time these patients have often started families of their own thus continuing the disease. • Postmortem examination of patients with the disease reveals cell loss, particularly in the cerebral cortex and corpus striatum. • In the corpus striatum, medium-sized spiny neurons that contain GABA and enkephalin and project to the external segment of the globus pallidus are affected earliest, but other classes of neurons are eventually involved as well. • Biochemical studies have shown that the concentration of GABA (and GAD) and ACh (and acetylcholinetransferase) are all reduced in the basal ganglia of patients with Huntington’s disease. • The concentration of DA is NORMAL or slightly INCREASED. • Changes in the concentrations of neuropeptides in the basal ganglia include decreases of: • substance P • enkephalin • dynorphin • cholecystokinin • increased somatostatin • neuropeptide Y • Symptoms usually begin in the 4th or 5th decade and the disease is progressive, with an average life span after onset of about 15 years. • Initial symptoms involve either abnormal movements or intellectual changes. • Dementia, the earliest mental changes often consist of irritability, moodiness, and antisocial behavior with more severe dementia subsequently develops. • Chorea: Movement disturbance may be characterized initially by no more than an apparent fidgetiness or restlessness, but grossly abnormal choreiform movements are eventually seen. Drug-Induced Movement Disorders • Drug-induced parkinsonism frequently complicates treatment with dopaminedepleting agents such as reserpine or antipsychotic DA receptor antagonists such as phenothiazines or butyrophenones.

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The risk is greatest when agents are used that are potent D2 receptor antagonists with little anticholinergic effect, such as piperazine phenothiazines, butyrophenones and thioxanthenes. Mechanisms and treatment of drug-induced parkinsonism. Symptoms result from pharmacological blockade of DA receptors by antipsychotic drugs (1), which mimics the degeneration of nigrostriatal DA neurons seen in idiopathic parkinsonism. Symptoms may be relieved by the administration of muscarinic anticholinergic drugs (2) or by substituting an antipsychotic drug with anticholinergic properties. These measures restore the normal balance between DAergic and Cholinergic transmission in the striatum.

Acute dystonia or dyskinesia (such as blepharospasm, torticollis, or facial grimacing) is an occasional complication of DA receptor antagonist treatment, generally occurring within 1 week after introduction of such medication and often within 48 hours. • Men and younger patients show increased susceptibility to this complication. • The pathophysiologic basis of the disturbance is unclear, but intravenous treatment with anticholinergic drugs ( benzatropine, diphenhydramine) alleviates it. Akathisia • Akathisia is a state of motor restlessness characterized by an inability to sit or stand still, which is relieved by moving about. • It is a very common movement disorder induced by chronic treatment with antipsychotic drugs and occurs more often in women than in men. Tardive Dyskinesia • Tardive dyskinesia may develop after long-term treatment with antipsychotic (DA-receptor antagonist) drugs. • It is commonly encountered in chronically institutionalized psychiatric patients. • The risk of developing tardive dyskinesia appears to increase with age. • The manner in which chronic drug treatment promotes this movement disorder is unknown. Gilles De La Tourette’s Syndrome • Gilles de la Tourette’s syndrome, characterized by chronic—typically lifelong — multiple motor and verbal tics, is of unknown cause. • Symptoms begin before 21 years of age, and the course is one of remission and relapse. • Most cases are sporadic, although there is occasionally a family history, and partial expression of the trait may occur in siblings or offspring of patients. • Inheritance has been attributed to an autosomal dominant gene with variable penetrance. • Males are affected more commonly than females. • The pathophysiology is obscure.

DAergic excess in the brains of patients has been postulated, mainly because of the beneficial effects of DA-blocking drugs can have on the tics associated with the disease. • The administration of DA receptor agonists often fails to produce the exacerbation of symptoms that might be anticipated from this hypothesis. • Symptoms usually commence between ages 2 and 21 years. • The first signs consist of motor tics in 80% of cases and vocal tics in 20%. • There may be a single tic or multiple tics. • All patients ultimately develop a number of different motor tics and involuntary vocal tics, the latter commonly consisting of grunts, barks, hisses, throat clearing or coughing. • Sometimes these tics take the form of verbal utterances including coprolalia (vulgar or obscene speech). • There may also be echolalia (parroting the speech of others), echopraxia (imitation of other’s movements) and palilalia (repetition of words or phrases). • The tics vary over time in severity, character, and the muscle groups involved. • In 40-50% of cases, some of the tics involve self-mutilation with such activities as severe nail-biting or hair-pulling, pulling at the nose, or biting the lips or tongue. • Behavioral disorders, including obsessive-compulsive disorder and attention deficit hyperactivity disorder, are common in patients with Tourette’s syndrome. • There is a higher than expected incidence of left-handedness or ambidexterity in this disorder. • Treatment: Clonidine (NE) and haloperidol have been shown to be effective in this disorder. Restless Legs Syndrome • Restless legs syndrome is characterized by an unpleasant creeping discomfort that is perceived as arising deep within the legs and occasionally in the arms as well. • Such symptoms tend to occur when the patient is relaxed, especially while lying down or sitting and lead to a need to move about. • They are often particularly troublesome at night and may delay the onset of sleep. • The cause is unknown, although the disorder seems especially common among pregnant women and diabetic patients with neuropathy. Symptoms sometimes resolve following correction of coexisting iron-deficiency anemia, and they may respond to treatment with drugs such as levodopa, bromocriptine, diazepam, clonazepam or opiates.

LECTURE 40: Limbic System The word limbic means ‘border’ or ‘margin’ and the term limbic system was loosely used to include a group of structures that lie in the border zone between the cerebral cortex and the hypothalamus. • Now however, it is known that the limbic system is involved with many other structures beyond the border zone in the control of emotion, behavior, drive and memory. • Thus, the limbic system (or lobe) is the anatomical substrate for drive-related and emotional behaviors. • The limbic system is considered to be an anatomical substrate underlying behavioral and emotional expression. • It plays a role in: • Feeling • Feeding • Fighting • Fleeing • And, Fu…..well…you know. • It expresses itself through the hypothalamus via the autonomic nervous system (ANS). • Anatomically, the limbic structures include: • cingulate • parahippocampal gyrus • hippocampal formation • amygdaloid nucleus • mammillary bodies • anterior thalamic nucleus Limbic System: Connecting Pathways • The alveus, fimbria, fornix, mammillothalamic tract and the stria terminalis constitute the connecting pathways of this system. Hippocampal Formation The hippocampal formation consists of the hippocampus the dentate gyrus and the parahippocampal gyrus. • The hippocampus is a curved elevation of gray matter that extends throughout the entire length of the floor of the inferior horn of the lateral ventricle. • It is named hippocampus because it resembles a sea horse in coronal section. • The convex ventricular surface is covered with ependyma, beneath lies a thin layer of white matter called the alveus. • The alveus consists of nerve fibers that have originated in the hippocampus and these converge medially to form a bundle called the fimbria. • The hippocampus itself is divided up into section called “CA” fields or sections. • The dentate gyrus and the hippocampus proper have the form of two interlocking Cs. • The hippocampus is also sometimes called “Ammon’s horn” (or cornu ammonis after an Egyptian deity with ram’s horns) because of the way the •

hippocampus curve downward and outward from the hippocampal rudiment into the temporal lobes. • The fimbria becomes continuous with the crus of the fornix. • The hippocampus terminates posteriorly beneath the splenium of the corpus callosum. • The anterior end is called the pes hippocampus. • The dentate gyrus is a narrow notched band of gray matter that lies between the fimbria of the hippocampus and the parahippocampal gyrus. • Posteriorly, the dentate gyrus accompanies the fimbria almost to the splenium of the corpus callosum and becomes continuous with the indusium griseum. • The indusium griseum is a thin, vestigial layer of gray matter that covers the superior surface of the corpus callosum. • The parahippocampal gyrus lies between the hippocampal fissure and the collateral sulcus and is continuous with the hippocampus along the medial edge of the temporal lobe. Afferents to the Hippocampus • The major afferent to the hippocampus (H) is the entorhinal cortex, which in turn collects inputs from the cingulate, temporal, and orbital cortices and from the amygdala (Am) and olfactory cortex. • Other inputs arrive from the septal nuclei and hypothalamus and from the contralateral hippocampus enter via the fornix.(A, anterior thalamic nucleus) Efferents from the Hippocampus • The major efferent pathway is the fornix, through which fibers reach an assortment of anteriorly situated forebrain structures. Many fibers pass directly from the subiculum to the entorhinal cortex, to the amygdala, or backward along the cingulum to the cingulate gyrus (A, anterior thalamic nucleus). The Amygdala • The amygdaloid nucleus is named because it resembles an almond. • It is situated partly anterior and partly superior to the tip of the inferior horn of the lateral ventricle. • It is fused with the tip of the tail of the caudate nucleus, which passes anteriorly in the roof of the inferior horn of the lateral ventricle. • The amygdala lies beneath the uncus of the limbic lobe at the anterior end of the hippocampus and inferior horn of the lateral ventricle. • It merges with the periamygdaloid cortex, which forms part of the surface of the uncus. • The amygdala is centrally involved in emotional responses thus receives a great deal of sensory input in a highly processed form. • It receives somatosensory, visual, auditory and all types of visceral inputs. Afferents to the Amygdala • Afferents to the amygdala arrive via four routes: from the hypothalamus (Hy), the septal nuclei (s) through the stria terminalis, from the thalamus (T) and hypothalamus (Hy) and from orbital and anterior cingulate cortex, olfactory bulb and olfactory cortex and directly from the hippocampus. Efferents from the Amygdala

Efferents from the amygdala take three routes: the stria terminalis which reaches the septal nuclei (S) and hypothalamus (Hy); the ventral amygdalofugal pathway to the hypothalamus, thalamus (T) frontal and insular cortex, olfactory structures and other sites; direct projections to the hippocampus (H), entorhinal cortex (E) and temporal and neocortical areas. Connecting Pathways of the Limbic System These pathways are the alveus, the fimbria, the fornix and the mammillothalamic tract and the stria terminalis. • The alveus consists of a thin layer of white matter that lies on the superior or ventricular surface of the hippocampus. • It is composed of nerve fibers that originate in the hippocampal cortex. • Fibers converge on the medial border of the hippocampus to form a bundle called the fimbria. • The fimbria now leaves the posterior end of the hippocampus as the crus of the fornix. • The crus from each side curves posteriorly and superiorly beneath the splenium of the corpus callosum and around the posterior surface of the thalamus. • The two crura converge to form the body of the fornix which is applied closely to the undersurface of the corpus callosum. • As the crura come together, they are connected by transverse fibers called the commissure of the fornix. • These fibers decussate and join the hippocampi of the two sides. • Anteriorly, the body of the fornix is connected to the undersurface of the corpus callosum by the septum pellucidum. • Inferiorly, the body of the fornix is related to the tela choroidea and the ependymal roof of the fourth ventricle. • The body of the fornix splits anteriorly into two anterior columns each of which curves anteriorly and inferiorly over the interventricular foramen (foramen of Monroe). • Then each column disappears into the lateral wall of the third ventricle to reach the mammillary body. • The mammillothalamic tract provides important connections between the mammillary body and the anterior nuclear group of the thalamus. • The stria terminalis emerges from the posterior aspect of the amygdaloid nucleus and runs as a bundle of nerve fibers posteriorly in the roof of the inferior horn of the lateral ventricle. • Mammillothalamic tract: Projection from the mammillary body to the anterior nucleus of the thalamus. • Part of the Papez circuit. • Stria terminalis: Efferent from the amygdala to the septal nuclei, basal forebrain and hypothalamus. Structure of the Hippocampus and the Dentate Gyrus • The cortical structure of the parahippocampal gyrus is six-layered. As the cortex is traced into the hippocampus there is a gradual transition from a six to a three-layered arrangement. • These three layers are the:

superficial molecular layer, consisting of many small neurons, pyramidal layer, consisting of many large pyramid-shaped neurons and the inner • polymorphic layer, which is similar in structure to the polymorphic layer of the cortex seen elsewhere. Functions of the Limbic System • The limbic system via the hypothalamus and its connections with the outflow of the ANS and its control of the endocrine system, influences many aspects of emotional behavior. • These include particularly the reactions of fear and anger and the emotions associated with sexual behavior. • Memory: the hippocampus is concerned with converting recent memory to long term memory. • Lesions of the hippocampus result in the individual not being able to store longterm memories. • Memory before the lesion are not affected (retrograde). • This is called anterograde amnesia. Papez Circuit • James Papez pointed out in 1937 that this loop provided for interactions among the neocortex, limbic structures, and the hypothalamus and proposed that it might be the anatomical substrate for emotional experience. • Beginning in the hippocampus, the pathway proceeds through the fornix to the mammillary body, from there in sequence to the anterior thalamic nucleus, the cingulate gyrus and part of the parahippocampal gyrus (entorhinal cortex) and finally back to the hippocampus. CLINICAL NOTES Schizophrenia • The symptoms of schizophrenia include chronically disordered thinking, blunted affect, and emotional withdrawal. • Paranoid delusions and auditory hallucinations may be present as well. • Present-day anti-psychotics block dopamine receptors (e.g. phenothiazine) in discrete areas of the limbic system, in turn, lessening the worst symptoms of the disease. • Unfortunately, these drugs have major motor side effects on dopaminergic receptors (primarily D2) within the extrapyramidal system, producing abnormal involuntary movements (tardive dyskinesia) • Research of late has focused on other receptors that may be involved in symptoms associated with schizophrenia (glutamatergic, AMPA,NMDA receptors). Destruction of the Amygdaloid Complex • Unilateral or bilateral destruction of the amygdala in patients suffering from aggressive behavior in many cases results in: – decrease in aggressiveness (docility), – emotional instability – restlessness – Hyperphagia (food)

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– Hypersexuality • Kluver-Bucy syndrome: results from bilateral ablation of the anterior temporal lobes, included the amygdaloid nuclei. • It causes psychic blindness (visual agnosia), hyperphagia, placidity, hypersexuality. Cingulate Gyrus • Lesions of the cingulate gyrus results in: – akinesia – mutism – apathy – indifference to pain Mamillary Bodies and Thalamus • Mamillary bodies and the mediodorsal nucleus of the thalamus are damaged by chronic alcoholism and thiamine (B1) deficiency which results in Korsakoff’s Syndrome (amnestic-confabulatory syndrome). • This syndrome is a late chronic stage of Wernicke encephalopathy. • Clinical signs include memory disturbances (amnesia), confabulation, and temporospatial disorientation. Temporal Lobe Epilepsy • The hippocampus is the most epileptogenic part of the cerebrum. • Temporal lobe epilepsy may be preceded by an aura of acoustic or olfactory experience. • The olfactory aura is usually an unpleasant odor. • The patient is often confused, anxious, and docile and may perform automatic and complicated movements, such as undressing in public or driving a car and then following the seizure may have no memory of what occurred. Lesions in Limbic Structures • Bilateral transection of the fornix may cause an acute amnestic syndrome—the inability to consolidate short-term memory into long-term memory. • Bilateral destruction or removal of the cingulate gyri causes loss of initiative and inhibition as well as dulling of emotions. – Memory is unaffected. • Lesions of the anterior cingulate gyrus cause placidity. • Cingulectomy is used to treat severe anxiety and depression. LECTURE 41: Limbic System: Drug Abuse I Basic Concepts • Substance abuse is a pattern of abnormal substance use that leads to impairment of occupational, physical, or social functioning. • Substance dependence is substance abuse plus withdrawal symptoms, tolerance, or a pattern of repetitive use. • Withdrawal: the development of physical or psychological symptoms after the reduction or cessation of intake of a substance. • Tolerance: the need for increased amounts of the substance to achieve the same positive psychological effect.

Cross-sensitization: the development of sensitization to one substance as a result of using another substance. • Cross-tolerance: the development of tolerance to one substance as the result of using another substance. • Caffeine, alcohol, nicotine, marijuana, cocaine, amphetamines and heroin are the most commonly used and abused substances in the United States. • The use of illegal substance is more common among young adults (age 18-25) and is three times more common in males. • Stimulants: caffeine, nicotine, amphetamines and cocaine. • Sedatives: alcohol, barbiturates, benzodiazepines. • Opioids: heroin, morphine, codeine, methadone etc. • Hallucinogens: lysergic acid diethylamide (LSD), phencyclidine (PCP, “angle dust”), cannabis, psilocybin and mescaline. Stimulants: Cocaine • Cocaine is an alkaloid found in the leaves of the shrub Erythroxylon coca which grows in the eastern highlands of the Andes mountains in Bolivia, Peru, Ecuador and Colombia. • The most famous cocaine user was Sigmund Freud who published Uber Coca which he extolled the drug’s virtues and recommended its use in the treatment of alcoholism, morphine addiction, depression and a variety of other ailments. • Freud also performed the first recorded psychopharmacological experiments on cocaine and published the results in an 1885 paper entitled “ A contribution to the knowledge of the effect of cocaine.” • In 1885, Parke Davis & Co. was manufacturing 15 different forms of cocaine and coca including cigarettes, cigars and inhalents. • One year later, a Georgia pharmacist named John Pemberton introduced a new beverage “Coca Cola” where he obtained cocaine from coca leaves and caffeine from cola nuts. • The cocaine in Coca Cola was eliminated in 1906. • “Crack” and “freebase” are smokable forms of cocaine; in pure form (powder) cocaine is sniffed into the nostrils or “snorted”. • Hyperactivity and growth retardation are seen in newborns of mothers who used cocaine during pregnancy. • Tactile hallucinations of bugs crawling on the skin (formication) is seen with the use of cocaine (“cocaine bugs”). Cocaine: Epidemiology • 3% of the US population have used cocaine in the last year. • 12% have used cocaine in their lifetime. • It is used primarily in lower socioeconomic groups in its inexpensive crack form. • It is used by people in higher socioeconomic groups in its expensive, pure form. • Use has declined after peaking in 1985. Acute Psychological Effects of Cocaine • Significant elevation of mood lasting about 1 hour. • Increased attention span.

• Aggressiveness, impaired judgment. • Psychotic symptoms such as formication (bugs crawling under skin). Acute Physical Effects of Cocaine • Loss of appetite and weight. • Agitation and insomnia. • Pupil dilation and increased energy. • Tachycardia and other cardiovascular effects which can be life-threatening. • Seizures and hypersexuality. Cocaine Withdrawal Symptoms • Significant depression of mood. • Strong psychological craving (peaking a few days after the last dose. • Irritability. • Hunger. • Pupil constriction. • Fatigue. Cocaine Action • Cocaine produces its effects, in part, by acting on the mesolimbic and mesocortical system. • Cocaine increases synaptic levels of catecholamines (DA, NE and 5-HT) by blocking their re-uptake. • The reinforcing effects of cocaine are mediated primarily through increasing levels of DA. • Increased availability of DA in the synapse is apparently involved in the euphoric effects of cocaine (and perhaps all drugs of abuse). • As in schizophrenia, increased DA availability may also result in psychotic symptoms. Cocaine Addiction: Treatment • Presently, there are no pharmacological treatments that are comparable to treatments like those for heroin addiction. • However, a variety of pharmacological agents, most of which are approved for other uses, have been and are being tested clinically for the treatment for cocaine dependence and relapse. • Some drugs used for the treatment of cocaine addiction include: • bupropion (Wellbutrin), • monoamine oxidase (MAO) inhibitors (selegiline [Eldepryl]); • SSRIs fluoxetine (Prozac), mazindol (Sanorex), pemoline (Cylert); • antipsychotics such as flupenthixol (Depixol), lithium; • several different calcium channel blockers, anticonvulsants (carbamazepine [Tegretol]), valproic acid (Depakene) and phenytoin (Dilantin). • Disulfiram (Antabuse). Stimulants: Amphetamine • Amphetamine is the common name for β -phenylisopropylamine. • Two stereoisomeric forms of amphetamine are: D-amphetamine (dextroamphetamine; trade name Dexedrine) and L-amphetamine (levoamphetamine.

D-amphetamine is more potent than the other isomer. D,L-amphetamine (trade name Benzedrine) refers to the racemic mixture. Methamphetamine (trade names Methedrine and Desoxyn) is a potent analog of amphetamine. • Amphetamine is structurally related to a plant compound called cathinone which is the principle active ingredient in khat; (Catha edulis; qat) an evergreen shrub native to East Africa and the Arabian peninsula. • Ephedrine (from Ephedra vulgaris) is also structurally related to amphetamine. • In 1932, the Benzedrine inhaler was introduced by the Smith, Kline & French pharmaceutical company as a nasal bronchial decongestant. • Amphetamine in tablet form was first marked in 1935 as a treatment for narcolepsy. • American military personnel were given amphetamines to maintain a heightened level of alertness. • At the same time, Japanese military were given methamphetamine for the same purpose. • Amphetamine is typically administered either orally or by intravenous or subcutaneous injection (“skin popping”). • Street names for amphetamines include: “uppers”, “bennies”, “dexies”, “black beauties” or “diet pills”. • To moderate the extreme stimulatory effect of IV amphetamine is to combine it with heroin (“speed ball”). • Methamphetamine is more potent than amphetamine and is favored by drug abusers when available. • Typical street names for Methamphetamine include: “speed”, “crystal”, “crank” and “go”. Amphetamine: Epidemiology • 1.3% of people in the US have used amphetamine in the last year. • 7% have used the drug in their lifetime. • Higher rate of use in professionals, people who work late at night and more prevalent in age groups 18-25 year olds. Amphetamine: Medical Uses • Amphetamines are medially indicated in the treatment of attention-deficit hyperactivity disorder (ADHD) and narcolepsy. • They are sometimes used to treat depression in the elderly and terminally ill, and depression and obesity in patients who do not respond to other treatments. • The most common clinically used amphetamines are dextroamphetamine (Dexedrine), methamphetamine (Desoxyn) and a related compound, methylphenidate (Ritalin). Acute Psychological Effects of Amphetamine • Significant elevation of mood. • Increased attention span. • Aggressiveness, impaired judgment. • Psychotic symptoms such as paranoid delusions. Acute Physical Effects of Amphetamine

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• Loss of appetite and weight. • Agitation and insomnia. • Pupil dilation and increased energy. • Tachycardia and other cardiovascular effects which can be life-threatening. • Seizures and hypersexuality. Amphetamine Withdrawal Symptoms • Significant depression of mood. • Strong psychological craving (peaking a few days after the last dose. • Irritability. • Hunger. • Pupil constriction. • Fatigue. Amphetamine: Neuropharmacolgy • Amphetamine is an indirect agonist of the catecholaminergic systems. • It has the combined ability to: – induce release of catecholamines from presynaptic endings – block catecholamine reuptake – and (at high doses) inhibit catecholamine metabolism by monoamine oxidase (MAO) Designer Amphetamines: Substituted Amphetamines • Substituted amphetamines have effects on the 5-HT and DAergic systems and have behavioral effects that reflect a combination of amphetamine-like and hallucinogen-like activities. • Examples of substituted amphetamines include: 3,4-mehylenedioxyamphetamine (MDMA), or “ecstasy”, “XTC” and “Adam”; n-ethyl-3,4methylenedioxyamphetame (MDEA) or “Eve”; MMDA and DOM or “STP”. Amphetamine Addiction: Treatment • Inpatient setting and the use of multiple therapeutic methods such as individual, family and group psychotherapy. • Amphetamine-induced psychotic disorder and amphetamine-induced anxiety disorder may be treated with antipsychotic and anxiolytics. • In the absence of psychosis, diazepam (Valium) is useful for agitation and hyperactivity. • Comorbid conditions (depression) may respond to antidepressant medication. • Bupropion (Wellbutrin) may be of use after patients have withdrawn from amphetamine. Stimulants: Caffeine • Caffeine is found in coffee beans, which are the seeds of the plant Coffea arabica. • Tea leaves contain significant amounts of both caffeine and another compound theophylline (which means “divine leaf”). • Caffeine is one of the most widely consumed drugs in the world. • The average adult caffeine intake in the US has been estimated to be approximately 400mg per day. • Children may ingest considerable amounts of caffeine through caffeinated soft drinks and chocolate.

Caffeine: Psychological and Physical Effects • Increased alertness & attention span. • Mild improvement in mood. • Agitation and insomnia. • Decreased appetite. • Increased blood pressure and heart rate (tachycardia). • Increased gastrointestinal activity. Withdrawal Effects of Caffeine • Lethargy. • Mild depression of mood. • Increased appetite with slight weight gain. • Fatigue. • Headache. • Mechanism of Action • Caffeine is thought to exert its effects by inhibiting phosphodiesterase, (the enzyme that degrades cAMP to AMP) and thus increases cAMP levels. • Caffeine also blocks adenosine receptors in the CNS. Caffeine Addiction: Treatment • Elimination from the diet and replacement with decaffeinated beverages. • Analgesics to control headache due to withdrawal. Stimulants: Nicotine • Nicotine was first isolated in 1828 by Posselt and Reimann and constitutes about 5% of the total weight of the dry plant leaves. • Nicotine (1-methyl-2-[3-pyridyl]pyrrolidine) is the active ingredient in tobacco leaves (Nicotiana tabacum; in honor of Jean Nicot [1530-1600]). • Without nicotine, the tobacco plant would likely be considered a useless weed. • Europeans learned about tobacco from the indigenous Americans who smoked tobacco leaves for ritual purposes. • The effects of tobacco were traced to nicotine and many cholinomimetics have since been developed such as: lobeline, arecoline, hyoscine, muscarine, physostigmine, pilocarpine. Smoking=Rat-Like Self-Administration (of Nicotine) • 30% of the population in the US have smoked within the last year. • 55% have smoked at least once in their lifetime. • Use has increased in women (female smokers outnumber male smokers), adolescents, and Black American adults. • In adolescents, use among Black Americans is lower than in Whites. • Cigarettes are nicotine delivery devices. Nicotine: Psychological and Physical Effects • Increased alertness & attention span. • Mild improvement in mood. • Agitation and insomnia. • Decreased appetite. • Increased blood pressure and heart rate (tachycardia).

• Increased gastrointestinal activity. Withdrawal Effects of Nicotine • Lethargy. • Mild depression of mood. • Increased appetite with slight weight gain. • Fatigue. • Headache. Nicotine Action • Cholinergic receptors are divided into 2 general classes: nicotinic and muscarinic. • The nicotinic receptor is an integral membrane protein with five subunits. • It is a directly gated ion channel which has 2 functions: – It recognizes and binds the neurotransmitter – Opens a channel in the membrane through which ions flow Nicotine Addiction: Treatment • Nicotine transdermal patch or chewing gum. • Antidepressants; in particular bupropion (Zyban). • Peer support groups. • 80% of abstainers relapse within 2 years and only 66% relapse when members of a peer support group also relapse. • 45% of all smokers that try eventually stop smoking. LECTURE 42: Limbic System: Drug Abuse II Sedative-Hypnotics • Sedatives are CNS depressants that include alcohol, barbiturates and benzodiazepines. • Sedative agents work primarily by increasing the activity of the inhibitory neurotransmitter γ -aminobutyric acid (GABA). • Hospitalization is required for those going through withdrawal syndrome associated with these substances. • Symptoms may include seizures and cardiovascular abnormalities which can be life-threatening. Alcohol • Mead, a fermentation product of honey, is the oldest alcoholic beverage, having existed in the Paleolithic age, about 8000 BC. • Beer and wine were made by fermentation dating back to 3700 BC in Egypt. • Distillation to obtain high alcohol concentrations was discovered in the Arab world about 800 AD. • The word “alcohol” is of Arabian origin, from the word that is transliterate as alkuhl or al-koh’l (“something subtle”). • Distillation of alcohol from fermented grain mixtures known as whisky became popular in the Middle Ages (whisky comes from the Gaelic word usquebaugh meaning “water of life”). Alcohol: Epidemiology • 50% of the population in the US have consumed alcohol within the last year.

85% have consumed alcohol in their lifetime. There is a 10-13% lifetime prevalence of abuse or dependence. The male:female ratio of abusers is at least 2:1. Higher rate of use occurs in Native Americans and Eskimos, the 21-34 year old age group and residents of the Northeastern states. • The lowest rate of use occurs in Utah because the Mormon religion prohibits alcohol use. Alcohol: Acute Problems • Traffic accidents, homicide, suicide and rape are correlated with the concurrent use of alcohol. • Child physical and sexual abuse, spouse abuse, and elder abuse are also associated with alcohol use. Alcohol: Chronic Problems • Thiamine deficiency resulting in Wernicke and Korsakoff syndromes is associated with long-term use of alcohol. • Liver dysfunction, gastrointestinal problems (e.g. ulcers), and reduced life expectancy are also seen in heavy users of alcohol. • Alcohol withdrawal delirium (delirium tremens or “the DTs”) may occur during the first week of withdrawal from alcohol. • It usually occurs in patients who have been drinking heavily for at least 5 years. • DTs is life threatening; mortality rate is about 20%. Fetal Alcohol Syndrome • Fetal alcohol syndrome is seen in the offspring of women who drink during pregnancy. • Characteristics include facial abnormalities, reduced height and weight and mental retardation. • A childhood history of problems such as attention-deficit hyperactivity disorder and conduct disorder correlate with alcoholism in the adult. Alcohol Intoxication • Legal intoxication is defined as 0.08%-0.15% blood alcohol concentration, depending on individual state laws. • Coma occurs at a blood alcohol concentrations 0.40%-0.50% in non-alcoholics. Alcohol: Neurochemistry • Unlike most other drugs of abuse, no single molecular target has been identified as the mediator for the effects of alcohol. • Data does support that alcohol produces its effects by increasing the fluidity of membranes with short-term use. • With long-term use however, membranes become rigid or stiff. • Recently studies have found that alcohol exerts effects on ion channels. • Specifically, nicotinic acetylcholine, serotonin 5-HT3 and GABAa receptors are enhanced by alcohol. • In contrast, ion channels associated with glutamate receptors or voltage-gated calcium channels are inhibited. Psychological and Physical Effects of Sedatives • Mild elevation of mood. • Decreased anxiety.

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• Somnolence. • Behavioral disinhibition. • Sedation. • Poor coordination. • Respiratory depression. Withdrawal Effects of Sedatives • Mild depression of mood. • Increased anxiety. • Insomnia. • Psychotic symptoms such as delusions and formication. • Disorientation. • Tremors, seizures and cardiovascular symptoms such as tachycardia and hypertension. Alcoholism: Treatment • Alcoholics Anonymous (AA) and other voluntary peer support groups (12step programs). • Disulfiram (Antabuse) to prevent use (causes a toxic reaction when alcohol is ingested. • Benzodiazepines for withdrawal symptoms. • Thiamine (B1) for immediate emergency room treatment. Sedatives: Barbiturates • Barbiturates are used medically as sleep aids, sedatives, antianxiety agents (tranquilizers), anticonvulsants, and anesthetics. • Frequently used and abused barbiturates include amobarbital, pentobarbital, and secobarbital. • Barbiturates cause respiratory depression and have a low safety margin; hence, they are drugs most commonly taken to commit suicide. Sedatives: Benzodiazepines • Benzodiazepines are used medially as tranquilizers, sedatives, muscle relaxants, anticonvulsants, and anesthetics, and to treat alcohol withdrawal (chlordiazepoxide and diazepam). • Benzodiazepines have a high safety margin unless taken with another sedative such as alcohol. Benzodiazepine and Barbiturate Addiction: Treatment • Hospitalization and gradual reduction in dosage of the abused drug by substituting long-acting barbiturates (such as phenobarbital) for the more commonly abused short acting types. • Replacement with non-addictive antianxiety agents (i.e. buspirone [Buspar]) or sleep agent (i.e. zolpidem [Ambien]). Opiates • Theophrastus in the third century B.C. mentioned the use of opiates. • In 1803, a German chemist isolated an active ingredient from opium which he called morphine after the god of dreams, Morpheus. • Opium is prepared by drying and powdering the milky juice taken from the seed capsules of the opium poppy, Papaver somniferum, just prior to ripening.

The majority of the world’s supply comes from Southeast Asia, India, China, Iran, Turkey, Russia and southeastern Europe. • In 1874, a minor chemical modification of the morphine molecule produced the compound diacetylmorphine, or heroin. • At the time, the new compound was promoted as a more potent, yet nonaddicting substitute for morphine. • We now know that heroin is converted to monoacetylmorphine and then to morphine in the brain. • Narcotics or opioid drugs include agents used medically as analgesics (e.g. morphine) as well as drugs of abuse (e.g. heroin). • Compared to morphine and methadone, abused opioids such as heroin are more potent, cross the blood brain barrier more quickly, have a faster onset of action and have more euphoric action. • In contrast to barbiturate withdrawal, which may be fatal, death from withdrawal of opioids is rare unless a serious physical illness is present. Heroin: Epidemiology • 0.2% of the population in the US have used heroin in the last year. • 1.3% have used the drug in their lifetime. • There is a higher use rate among people who live in large cities. • The male:female ratio of users is 3:1. Psychological and Physical Effects of Opioid Drugs • Elevation of mood. • Relaxation. • Somnolence. • Sedation. • Analgesia. • Respiratory depression (overdose may be fatal). • Constipation. • Pupil constriction. Psychological and Physical Effects of Withdrawal from Opioid Drugs • Depression of mood. • Anxiety. • Insomnia. • Sweating and fever. • Rhinorrhea (running nose). • Piloerection (goose bumps). • Yawning. • Stomach cramps and Diarrhea. • Pupil dilation. Opioid Peptides • Endorphins: are derived from pro-opiomelanocortin (POMC) the precursor of adrenocorticotropic hormone (ACTH). • Endorphins include β -endorphin (the major endorphin found in the brain). They play a major role in endocrine function. • Endorphinergic neurons are found almost exclusively in the hypothalamus (arcuate and premamillary nuclei).

These neurons project to the hypothalamus, amygdala, nucleus accumbens, septal area, thalamus, and locus ceruleus (midbrain and pons). • Enkephalins: are derived from proenkephalin and are the most widely distributed and abundant opioid peptides. • They are found in the highest concentrations in the globus pallidus. • Enkephalins are also synthesized in striatal neurons, which project to the globus pallidus. • Enkephalins are located mainly in local circuits of the limbic and striatal systems and play a role in pain suppression in the dorsal horn of the spinal cord. • Enkephalins are co-localized with dopamine, norepinephrine, ACh, and GABA. • Dynorphins are derived from prodynorphin and follow, in general, the distribution map for enkephalin. • Dynorphins have high concentrations in the hypothalamus and amygdala. Opioid Action • The reinforcing effects of opioids are mediated by the mesolimbic DA system through various opioid receptors (µ, delta and kappa). Opioid Action: Mesolimbic DA System • In the VTA, β -endorphin neurons (via µ-receptors) increase mesolimbic activity by inhibiting inhibitory GABA neurons. • The release of DA from mesolimbic nerve terminals is tonically inhibited by dynorphin activity (via kappa-receptors). • Basal DA release is determined by the balance between the two opioid systems. • D-1 receptors on cells in the nucleus accumbens that go to other brain areas, such as the ventral pallidum, may ultimately be responsible for “motivational” tonus (aversion, neutral state, positive reinforcement). Opioid Actions in the Locus Ceruleus • Opioids acutely inhibit LC neurons by increasing the conductance of K+ channels via coupling with subtypes of Gi and/or Go and by decreasing an Na+-dependent inward current via coupling with Gi/o and the consequent inhibition of adenylyl cyclase. • Reduced levels of cAMP decrease PKA and the phosphorylation of the responsible channel or pump. • Inhibition of the cAMP pathway also decreases phosphorylation of numerous other proteins and thereby affects many additional processes in the neuron. Opiate Addiction:Treatment • Methadone or LAMM maintenance program. • Narcotics anonymous (NA) or other 12-step program. • Naloxone (blocks opiate receptors) to precipitate withdrawal and to maintain abstinence. • Clonidine for withdrawal symptoms. • Methadone and 1-alpha-acetylmethodol acetate (LAMM) are synthetic opioids used to treat heroin addiction. • Both cause physical dependence and tolerance.

These legal opioids are used as substitutes for heroin and to prevent withdrawal symptoms. • Methadone and LAMM are dispensed by federal health authorities. • They can be taken orally. • The IV method of drug delivery employed by heroin users contributes to the spread of AIDS and Hepatitis B. • Methadone and LAMM have a longer duration of action. • They cause less euphoria and drowsiness, allowing people on maintenance regimens to keep their jobs and avoid the criminal activity that is necessary to maintain a costly heroin habit. • Hallucinogens include: • Cannabis (tetrahydrocannabinol, marijuana, hashish) • Lysergic acid diethylamide (LSD) • Psilocybin (from Psilocybin mushrooms) • Mescaline (from Peyote cactus, L. williamsii) • Phencyclidine (PCP, “angle dust”) Cannabis sativa: Epidemiology • 10% of the US population has used marijuana in the last year. • 33% have used it in their lifetime. • Marijuana is used more commonly than any other illegal psychoactive drug. • Use has increased recently in the 12-25 year old age group. • Linnaeus in 1753 gave a weed-like plant the name of Cannabis sativa. • Historically, hemp has served an important function in many cultures as a source of fiber for making rope, cloth, and paper. • The first president of the US, George Washington, was a hemp farmer. • There are over 60 compounds found in the plant which are collectively known as cannabinoids. • The word “marijuana” is from a Mexican word maraguanquo, meaning “an intoxicating plant”. • Tetrahydrocannabinol (THC) is the primary active compound found in marijuana. • In low doses, it increases appetite and relaxation and causes conjunctival reddening. • Chronic users experience lung problems associated with smoking and a decrease in motivation characterized by lack of desire to work and increased apathy. Cannabinoid Receptor • The cannabinoid receptor is a member of the G protein-linked family of receptors and is linked to inhibitory Gi which inhibits adenylyl cyclase. • The receptor is found in highest concentrations in the basal ganglia, hippocampus, and the cerebellum with lower concentrations in the cerebral cortex. • Animals do not self-administer cannabinoids like other drugs of abuse. • However, like other drugs of abuse, THC does indeed increase DA efflux in the nucleus accumbens.

Tolerance to cannabis does develop and psychological dependence has been documented. • Evidence for physiological dependence is not strong. Medical Use of Marijuana • Currently, cannabis is classified as a controlled substance with a high potential for abuse with NO medical use recognized by the Drug Enforcement Agency (DEA). • However, it is used to treat various disorders such as: – nausea secondary to chemotherapy – multiple sclerosis – chronic pain – AIDS – Glaucoma • Opposition to using cannabis medically is based on the illicit recreational use of the drug. • Some states now allow the use of medial marijuana. • However, physicians who prescribe the drug are subject to prosecution for a federal crime. Lysergic Acid Diethylamide (LSD) • Lysergic Acid Diethylamide (LSD) is a compound synthesized in 1938 by the Swiss chemist Albert Hoffmann while working at Sandoz in Basel. • Searching mainly for vasoconstrictor useful in controlling headaches and postpartum bleeding, LSD was shelved. • Five years later, Hoffmann accidentally ingested a small amount of LSD (possible absorbed it through his skin) and experienced the first LSD “trip”. • After experiencing a kaleidoscope of effects that he felt were “rather pleasant” he returned to his laboratory and intentionally ingested LSD (250ug). • However, the dose he chose was several times more than adequate doses (50100ug) and his “trip” much more powerful. • The first printed account of the phenomena associated with LSD intoxication was in 1947 after Hoffman’s colleague Stoll sampled the drug. • Stoll did studies on human subjects in a psychiatric clinic in Zurich. • Sandoz then began to synthesize the compound (Delysid), and made it available at no cost to medical researchers. • LSD is presently a Schedule I drug, the most restrictive class of substances with no medical value. LSD: Basic Pharmacology • LSD is the most potent psychoactive drug known and has an extremely high safety margin. • It can have effects at doses of 10-15ug; yet doses hundreds of times higher are unlikely to be fatal. • Animals will not self-administer LSD. Psychological and Physical Effects of LSD • Altered perceptual states (auditory and visual hallucinations, alterations of body image, distortions of time and space). • Elevation of mood.

“Bad Trips” (panic reactions that may include psychotic symptoms). “Flashbacks” Impairment of complex motor activity. Cardiovascular symptoms. Sweating and tremor. There are few, if any, psychological withdrawal symptoms. There are few, if any, physical withdrawal symptoms. Users of LSD report visual and auditory illusions and synesthesias, which are mixed sensations such as “seeing” smells or “hearing” colors after a small dose. • Senses are magnified and time is distorted. • A negative response to LSD (i.e. a “bad trip”) consists of acute panicky feelings in which one’s personality seems to be falling apart, with paranoia, depression and feelings of confusion and fragmentation. • Chronic adverse reactions include flashbacks, psychoses, depression, and chronic personality changes. • Flashbacks decrease over time whether they are treated or not. • LSD exerts its effects by acting on the serotonergic system; specifically, postsynaptic 5-HT receptors. • 5-HT receptor antagonists block the effects of LSD, the most potent of which (pirenperone and ritanserin) selectively block the 5-HT2a receptor subtype. Hallucination Intoxication: Treatment • Persons are treated for hallucinogen intoxication by psychological support for the remainder of the trip; so called, talking down. • Alternatively, or in conjunction, Diazepam (20mg/kg) is administered which calms the patient. Hallucinogen-Induced Psychosis • Treatment does not differ from conventional treatment for other psychoses. • Other drugs that have been used include: lithium carbonate, carbamazepine and ECT therapy have been helpful. • One hallmark of this disorder is that as opposed to schizophrenia (in which negative symptoms and poor interpersonal relatedness may be found) patients with hallucinogen-induced psychosis exhibit the positive symptoms of hallucinations and delusions while retaining the ability to relate to the psychiatrist. Phencyclidine (PCP) • Phencyclidine (PCP) also known as “angle dust” was developed and is classified as a dissociative anesthetic. • It was originally used as an anesthetic in humans. • However, it was associated with disorientation, agitation, delirium and unpleasant hallucinations on awakening. • PCP is potent by any route of administration and is highly reinforcing. • It carries a high risk of behavioral, physiological, and neurological toxicity. • A related compound, Ketamine (Ketalar) also referred to as “special K” is still used as a human anesthetic in the US. • PCP was first used illicitly in San Francisco in the late 1960s.

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Phencyclidine (PCP): Epidemiology • The highest PCP use in the US is in Washington, DC where PCP accounts for 18% of all substance-related deaths. • In Los Angeles, Chicago, and Baltimore, the comparable figure is 6%. • Most users of PCP also use other substances such as alcohol, but also opiates, marijuana, amphetamines and cocaine. • PCP is frequently added to marijuana with severe untoward effects on the user. • PCP is associated with 3% of substance abuse deaths and 32% of substancerelated emergency room visits nationally. PCP Neuropharmacology • PCP and Ketamine act as antagonists at the NMDA receptor subtype of glutamate receptors. • PCP binds to a site within the NMDA-associated Ca+ channel and prevents the influx of Ca+ ions. NMDA Glutamatergic Receptor • The NMDA receptor complex possesses a glutamate recognition site to which receptor agonists and competitive antagonists bind, as well as other binding sites for glycine, polyamines such as spermine and spermidine, phencyclidine (PCP) and related drugs, Mg2+, and Zn2+. • Channel opening permits an influx of Na+ and Ca2+ ions, and an efflux of K+ ions. PCP: Dopamine Interaction • PCP-like drugs stimulate firing of Ventral Tegmental Area dopaminergic neurons. • PCP also activates DAergic neurons of the VTA, which project to the cerebral cortex and the limbic system. • Activation of these neurons is mediates the reinforcing effects of the drug. Phencyclidine Intoxication Short-term PCP intoxication can have potentially severe complications and must be considered a psychiatric emergency. • Talking down, which may work for hallucinogen intoxication, is not useful for PCP intoxication. • Benzodiazepines and DA receptor antagonists are the drugs of choice for controlling behavior pharmacologically. • Physicians must monitor level of consciousness. • Muscle spasms are best treated with diazepam. Other Abused/Misused Substances • Inhalants • Anabolic Steroid Abuse • Gamma Hydroxybutyrate (GHB) • Nitrite Inhalants • Nitrous Oxide LECTURE 43: Anxiety • Everyone experiences anxiety: a diffuse, unpleasant, vague sense of apprehension, often accompanied by autonomic symptoms such as: – headache,

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– perspiration, – palpitation, – tightness in the chest, – mild stomach discomfort, – Restlessness (as indicated by an inability to sit or stand still for long). These constellation of symptoms vary among individuals. Anxiety is a normal alerting signal; it warns of impending danger and enables a person to take measures to deal with a threat. Fear is a similar alerting signal but should be differentiated from anxiety. Fear is a response to a known, external, definite, or non-conflictual threat. Anxiety is a response to a threat that is unknown, internal, vague, or conflictual. The anxiety disorders make up one of the most common groups of psychiatric disorders found in 10-30% of the general population. Anxiety disorders can be divided into several types based on clinical characteristics and response to psychopharmacologic agents. Major categories of anxiety disorders include:

– panic disorder – post-traumatic stress disorder (PTSD) – generalized anxiety disorder – social phobia – obsessive-compulsive disorder (OCD) – Three major schools of psychological theory have contributed theories explaining the causes of anxiety. – These include: – psychoanalytic – behavioral – existential Psychoanalytic Theories • Anxiety is viewed as the result of psychic conflict between unconscious sexual or aggressive wishes and corresponding threats from the superego or external reality. • In response to this signal, the ego mobilized defense mechanisms to prevent unacceptable thoughts and feelings from emerging into conscious awareness. • According to Psychoanalytic theory there are different types of anxiety that may arise in development: – Disintegration anxiety – Persecutory or paranoid anxiety – Castration anxiety (oedipal complex) – Superego anxiety Behavioral Theories • Behavioral or learning theories of anxiety have spawned some of the most effective treatments for anxiety disorders.

According to these theories, anxiety is a conditioned response to specific environmental stimuli (classical conditioning). • They may have learned the anxiety response from their parents (social learning theory). • Treatment is usually a form of desensitization by repeated exposure to the anxiogenic stimulus, coupled with cognitive therapy approaches. Existential Theories • Provide models for generalized anxiety disorder, in which there is no specifically identifiable stimulus for a chronically anxious feeling. • The central concept of existential theory is that people become aware of feelings of profound nothingness in their lives, feelings that may be even more discomforting than an acceptance of their inevitable death. • Anxiety is their response to the vast void in existence and meaning. Biological Theories • Biological theories of anxiety have developed from preclinical studies with animal models of anxiety, the study of patients in whom biological factors were ascertained, the growing knowledge about basic neuroscience, and the actions of psychotherapeutic drugs. • One faction of the biological theorists posits that measurable biological changes in patients with anxiety disorders reflect the results of psychological conflicts. • The other posits that the biological events precede the psychological conflicts. Autonomic Nervous System • Stimulation of the ANS causes: – cardiovascular (tachycardia) – muscular (headache) – gastrointestinal (diarrhea) – respiratory (tachypnea) • These peripheral manifestations of anxiety are neither specific to anxiety disorders nor necessarily correlated with the subjective experience of anxiety. • It is currently generally thought that the anxiety manifests itself through the CNS before peripheral manifestations; except when a specific cause is present (e.g. Pheochromocytoma). • However, the ANS of some patients with anxiety disorder, especially those with panic disorder, exhibit increased sympathetic tone, adapt slowly to repeated stimuli, and respond excessively to moderate stimuli. Neurotransmitters involved in Anxiety • Three major neurotransmitters associated with anxiety on the bases of animal studies and responses to drug treatment are norepinephrine (NE), serotonin (5HT), and γ -aminobutyric acid (GABA). • Animal models such as the conflict test and the Lick-suppression test (and others) have helped determine pharmacotherapies for anxiety. • In these models, anxiolytic drugs such as benzodiazepines facilitate adaptation of the animal whereas other drugs (e.g.amphetamines) disrupt behavior. Norepinephrine

The general theory about the role of norepinephrine in anxiety disorders is that affected patients may have a poorly regulated noradrenergic system with occasional bursts of activity. • The cell bodies of the noradrenergic system are primarily localized to the locus ceruleus in the rostral pons and they project their axons to the cerebral cortex, the limbic system, the brainstem and the spinal cord. • Experiments in primates have demonstrated that stimulation of the LC produces a fear response in the animals. • In contrast, ablation of the same area inhibits or completely blocks the ability of the animals to form a fear response. • In patients with panic disorder, β -adrenergic agonists (isoproterenol [Isuprel]) and α 2-adrenergic antagonists (yohimbine [Yocon]) can provoke frequent and severe panic attacks. • In contrast, clonidine (Catapres), an α 2-adrenergic agonist, reduces anxiety symptoms in some experimental and therapeutic situations. A less consistent finding is that patients with anxiety disorders, particularly panic disorder, have elevated CSF or urinary levels of the NE metabolite 3-methoxy-4hydroxyphenylglycol (MHPG). Serotonin • The identification of many serotonin receptor types has stimulated the search for the role of 5HT in the pathogenesis of anxiety disorders. • The effectiveness of buspirone (BuSpar), a 5HT1A agonist, in the treatment of anxiety disorders also suggests a connection between 5HT and anxiety. • Cell bodies of most 5HT neurons are located in the raphe nuclei in the rostral brainstem and project to the cerebral cortex, the limbic system (especially the amygdala and the hippocampus) and the hypothalamus. • Several reports indicated that m-chlorophenylpiperazine (mCPP), a drug with multiple serotonergic and non-serotonergic effects, and fenfluramine (Pondimin), which causes the release of serotonin, cause increased anxiety in patients with anxiety disorders. • Anecdotal reports indicated that 5HTergic hallucinogens and stimulants (e.g. LSD, MDMA) are associated with the development of both acute and chronic anxiety disorders in heavy users of these drugs. γ -aminobutyric acid (GABA) • A role for GABA in anxiety disorders is most strongly supported by the undisputed efficacy of benzodiazepines, which enhance the activity of GABA at the GABAa receptor, in the treatment of some types of anxiety disorders. • Although low-potency benzodiazepines are most effective for symptoms of generalized anxiety disorder, high-potency benzodiazepines, such as alprazolam (Xanax), are effective in the treatment of panic disorder. • Pre-clinical studies in primates have found that ANS symptoms of anxiety disorders are induced when a benzodiazepine inverse agonist, β -carboline-3carboxylic acid (BCCE), is administered, BCCE also causes anxiety in normal control volunteers. • A benzodiazepine antagonist, flumazenil, causes frequent severe panic attacks in patients with panic disorder.

These data have led to the conclusion that some patients with anxiety disorders have abnormal functioning of their GABAa receptors, although this connection has not been shown directly. Genetic Contribution • Studies have produced solid data showing that at least some genetic component contributes to the development of anxiety disorders. • Almost HALF of all patients with panic disorder have at least one affected relative. • The figures for other anxiety disorders, although not as high, also indicate a higher frequency of the illness in first-degree relatives of affected patients than occurs in the relatives of non-affected persons. • Data from twin studies support the hypothesis that anxiety disorders are at least partially genetically determined. Anxiety Disorders Due to a General Medical Condition • A wide range of medical conditions can cause symptoms similar to those of anxiety disorders. • Hyperthyroidism, hypothyroidism, hypoparathyroidism, and vitamin B12 deficiency are frequently associated with anxiety symptoms. • A pheochromocytoma produces epinephrine, which can cause paroxysmal episodes of anxiety symptoms. • Certain lesions of the brain and postencephalitic states reportedly produce symptoms identical to those seen in obsessive-compulsive disorder. • Other medical conditions, such as cardiac arrhythmia, can produce physiological symptoms of panic disorder. • Hypoglycemia can also mimic the symptoms of an anxiety disorder. • The diverse medical conditions that can cause symptoms of anxiety disorder may do so through a common mechanism: the noradrenergic system. Major Types of Anxiety • Panic Disorder • Post-traumatic Disorder (PTSD) • Generalized Anxiety Disorder • Social Phobia • Obsessive-Compulsive Disorder (OCD) Panic Disorder • Panic attacks are brief, recurrent, unexpected episodes of terror without a clearly identifiable cause. • The attacks are brief, lasting 15-30 minutes; rarely up to an hour. • An essential feature of these attacks is that they are unexpected. • They do not occur in situations that normally evoke fear or in which the patient is the focus of other people’s attention. • The attacks are characterized by: a sense of impending doom accompanied by an intense over-activity of the sympathetic nervous system (referred to as a sympathetic crisis): • the heart races • there is shortness of breath • dizziness

• trembling or shaking of the hands and legs • flushes or chills • chest pain • fear of dying or going crazy or of doing something uncontrolled • Shortness of breath is characteristic of panic attacks but not of the acute terror evident in battle, suggesting that panic attacks may represent a false alarm for suffocation. • In those patients that have panic disorder, a panic attack can be induced by the infusion of sodium lactate into the blood or the inhalation of carbon dioxide but not in normal subjects. • Antidepressants that are effective against spontaneous panic attacks also prevent the panic induced by the infusion. • Yohimbine, a drug that activates central noradrenergic neurons (by blocking α2adrenergic receptors that serve as inhibiting autoreceptors), precipitates panic attacks in patients but not in normal subjects. • This indicates that panic attacks involve an abnormality in the biogenic amine system of the brain. Post-Traumatic Stress Disorder (PTSD) • PTSD occurs in people after an extremely stressful event, such as lifethreatening combat or physical abuse. • It is manifested in recurrent episodes of fear, often triggered by reminders of the initial trauma. • Memory for the traumatic experience remains powerful for decades and is readily reactivated by a variety of stimuli and stressors. • This is due to the recruitment of the noradrenergic system by the reactivating stimuli. • Vietnam War veterans with PTSD show heightened noradrenergic functioning. • Excrete high levels of norepinephrine in their urine, presumably reflecting high circulating catecholamine levels. • Patients with PTSD are given yohimbine, they experience a type of panic attack: an intense memory accompanied by autonomic symptoms, frightening thoughts, emotional numbing and grief. • This evidence is consistent with the idea that uncontrollable stress produces substantial increases in noradrenergic functioning in the brain. • Propranolol and clonidine (noradrenergic antagonists) greatly ameliorate the symptoms of PTSD. • A large percentage (50%) of patients with PTSD also show concurrent panic disorder. Generalized Anxiety Disorder • Key feature of GAD is unrealistic or excessive worry, lasting for 6 months or longer. • The symptoms are: – motor tension (trembling, twitching, muscle aches, restlessness) – autonomic hyperactivity (palpitations, in creased heart rate, sweating, cold hands)

vigilance and scanning (feeling on edge, exaggerated startle response, difficulty in concentrating). • The disorder sometimes follows an episode of depression. • Patients with GAD respond well to the benzodiazepines such as chlordiazepoxide (Librium), and its derivative, diazepam (Valium) both bind to the GABAa receptor. Obsessive-Compulsive Disorder • OCDs are usually chronic disorders with recurrent obsessions and compulsions as the predominant features. • Obsessions are persistent and intrusive ideas, thoughts, images, or impulses that commonly fall into one of two categories: doubts or fears. • Obsessive doubting penetrates daily life, for example, leaving patients repeatedly unsure whether the apartment door was locked, whether the stove was turned off, or whether their hands are clean enough. • Obsessive fears focus on unrealistic and improbable dangers, such as the prospect of killing someone driving a car or lighting the stove. • To alleviate the anxiety and diminish the discomfort of the obsessive thoughts or urges, the patient often begins to carry out compulsive acts. • In contrast to obsessions (repetitive ideas), compulsions are repetitive acts. • To be defined as a compulsion a behavior must be repeated excessively and the repetition must not be realistically related to any environmental condition. • The most common compulsions are handwashing, counting, checking, touching, and pulling out of hair. • OCD is though to reflect a disturbance of the basal ganglia. • Some forms of OCD seem to be related to Tourette syndrome (hereditary chronic motor tic disorder with its locus in the basal ganglia). • Postencephalitic Parkinson disease • Sydenham chorea • Bilateral necrosis of the globus pallidus • Huntington Disease • These disorders are often associated with a component of obsessive-compulsive disorder. The head of the caudate nucleus and the pathway that connects the caudate with the prefrontal (orbitofrontal) cortex and cingulate gyrus is hyperactive in obsessivecompulsive disorder. OCD: Treatment • OCD is responsive to two types of treatments: specific behavioral therapies based on conditioning and specific serotonin reuptake inhibitors (SSRIs). • After effective treatment of the disease with either SSRIs or behavioral therapy, hyperactivity of the caudate nucleus and orbitofrontal cortex decreases significantly. LECTURE 44:Depression and Mania

• • •

Clinically, mood refers to a sustained emotional state lasting weeks or more, while the term affect (or affective response) refers to immediate or momentary emotional state of a person. Thus, affect is to mood as the weather (rainy or sunny) is to climate (tropical, moderate, cold). Major Mood Disorders can be either – Unipolar (Depressive Illness)

– – – – – •

– Bipolar (Manic Depressive Illness) Unipolar depression was described in the fifth century by Hippocrates. Freud, in his 1917 paper Mourning and Melancholia, pointed out that the definition of melancholia is uncertain…it takes on various clinical forms. Only in the past two decade have precise criteria for mood disorders been developed. Unipolar depression is characterized by an unpleasant (dysphoric) mood that is present most of the day, day in and day out. This mood is accompanied by intense mental anguish, the inability to experience pleasure (anhedonia), and a generalized loss of interest in the world. Other symptoms usually present include: disturbed sleep (usually insomnia with early morning awakening, but sometimes oversleeping or hypersomnia) – diminished appetite and loss of weight (sometimes the opposite), – loss of energy decreased sex drive – restlessness (psychomotoragitation) – slowing down of thoughts and actions, difficulty in concentrating – indecisiveness – feelings of worthlessness – Guilt, pessimistic thoughts – thoughts about dying or suicide Other common symptoms (not required for diagnosis) include: constipation, decreased salivation, diurnal variation in the severity of symptoms (worse in the morning). Exclusion criteria include schizophrenia or other neurological diseases, no recent death in the family or other traumatic events since some of the symptoms of unipolar depression are also NORMAL expressions of grief following trauma, personal loss, and mourning. Defined in this manner, about 5% of the world’s population have major unipolar depression. In the US 8 million people at any give time are affected. Severe depression can be profoundly debilitating; patients may stop eating or maintaining basic personal cleanliness. Average age of onset is 28 years though an episode can happen at any age. Women are affected about two to three times more often than men. –

– –

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Bipolar (Manic-Depressive) Disorder • About 25% of patients with major depression (two million in the US) will also experience a manic episode, if only a mild one. • Patients who experience both depressive and manic episodes have a distinct disorder called bipolar mood disorder. • The illness affects men and women equally, and the average age of onset of the first episode is a decade younger than that of unipolar depression (onset usually occurs at 20 rather than 30). • Episodes of depression in bipolar disorders are clinically similar to those of the unipolar type. • The manic episodes are characterized by an elevated, expansive, or irritable mood lasting at least one week, together with several other symptoms such as: • over-activity • over-talkativeness (pressure of speech) • social intrusiveness • increased energy and libido • flight of ideas • grandiosity • distractibility • decreased need for sleep • reckless spending • In very sever cases, patients are delusional and hallucinate. • Bipolar disorder is typically recurrent. • After an initial episode of euphoria, subsequent episodes of either depression or euphoria are likely to occur about twice as often in bipolar disorder as in unipolar disease. Subgenual Region of the Frontal Cortex and Depression • PET and fMRI studies have recently identified an anatomical abnormality in the prefrontal cortex ventral to the genu in the corpus callosum in familial cases of unipolar and bipolar depression. • During activity of the depressive phase of the illness, activity in this region is DECREASED in patients who have either unipolar or bipolar depression. • In contrast, in patients with bipolar disease this region shows an INCREASE in activity during the manic phase of the illness. Functional Abnormality in the Prefrontal Cortex in Depressive Illness • The two images show a decrease in metabolism in patient with depression relative to controls. • Both phases of the illness localize to the agranular region of the anterior cingulate gyrus ventral to the corpus collosum. (from Drevets et al. 1997). Depressive Illness: Brain Substrates • This region of the prefrontal cortex has extensive connection with other regions involved in emotional behavior: • amygdala • lateral hypothalamus • nucleus accumbens • noradrenergic

serotonergic dopaminergic systems People who have lesions in this area have difficulty experiencing emotion and have abnormal autonomic responses to emotionally arousing stimuli. • Lesions to the prefrontal cortex also severely compromise the ability to reason and make intelligent rational decisions. Treatments • There are four effective treatments for unipolar and bipolar illnesses: – electroconvulsive therapy (ECT) – antidepressant drugs – lithium – anticonvulsants ECT • Electroconvulsive therapy (ECT) is very effective for major depressive disorders. • It produces full remission or marked improvement in about 85% of patients with well-defined major depression. • The exact mechanism by which ECT acts is not known however it may be related to changes in aminergic receptor sensitivity. Pharmacotherapy • The most widely used antidepressant drugs fall into three major classes: • Monoamine oxidase inhibitors, such as phenelzine. The first effective antidepressants, which is used infrequently today. • Tricyclic compounds or general re-uptake inhibitors of biogenic amines, such as imipramine, are so named for their three-ring molecular structure. – The most effective for the severely depressed. • Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (Prozac), paroxetine (Paxil), and sertraline (Zoloft). • These are the most commonly used antidepressants, and they work by selectively inhibiting the uptake of serotonin. • They are most commonly used for patients who are only moderately depressed but are commonly used in severely ill patients as well. • MAO and the tricyclic antidepressants produce remission or marked improvement in about 70% of patients with major depressions. • With optimal dosages, the success rate with tricyclic drugs and the specific SSRIs may reach 85%, almost as effective as ECT. • Patients with bipolar depression occasionally become manic during treatment with either class of antidepressant drugs. • Although a few patients with bipolar disease begin to improve immediately, there usually is a lag of 1-3 weeks before the symptoms of depression begin to improve and 4-6 weeks for a full response. Lithium Salts • Lithium salts, first reported in the psychiatric treatment of manic-depressive illness in 1949 by John Cade, are effective in terminating manic episodes and are used as mood stabilizers.

• • •

Maintenance therapy with lithium is of significant prophylactic value in preventing or attenuating recurrent manic and, to a lesser extent, depressive episodes. • It is frequently used in conjunction with MAO inhibitors, tricyclic compounds, or SSRIs to augment the response of these conventional antidepressants. Lithium Action • The exact therapeutic action of lithium is unknown however, lithium has been shown to affect the phosphoinositide second-messenger system. • Many synaptic receptors act through a G-protein to mediate the conversion of phosphoinositol diphosphate (PIP2) into DAG and IP3. • IP3 is further broken down to inositol phosphate (IP), which is then converted to free inositol by the enzyme inositol-1-phosphatase. • Lithium blocks this enzyme and therefore reduces the responsiveness of these neurons by causing IP3 to accumulate in the cytoplasm, dampening excessive neural activity in mania. Anticonvulsants • Drugs effective as anticonvulsants (such as sodium valproate and carbamazepine) are also used as mood stabilizers and are quite effective in reducing psychotic symptoms in acute mania or severe depression. • Antipsychotic drugs are also used frequently in combination with tricyclic drugs, and even with ECT when depression is accompanied by delusions and hallucinations. Drugs Effective in Depression Act on 5HT and NE Pathways • Drugs that act on the 5HT system are particularly impressive in treating depression—all SSRIs tested have produced some benefits. • The action of these drugs, therefore, provides the first clues to a neurochemical basis of depressive disorders. • The major 5HT pathways have their origin in the raphe nuclei in the brain stem. • Cells from the rostral parts of these nuclei project to the forebrain; single serotonergic neurons project to hundreds of target cells in a large diffuse distribution. • Serotonergic receptors are classified into at least seven major types. • Some types decrease adenylyl cyclase, some increase it, other are coupled to phosphatidylinositide turnover and others are ligand-gated ion channels. • Certain components of the NE system appear to be involved with arousal and fear, while others are thought to be involved, together with the mesolimbic components of the DAergic system, in positive motivation and pleasure. • The pervasive anxiety and loss of pleasure characteristic of melancholia and atypical depression might therefore be related to dysregulation of these two components of the NE system. • The NE pathway originates in the locus ceruleus. • The axons of some LC neurons ascend to innervate the hypothalamus and all regions of the cerebral cortex, including the hippocampus. • Other neurons have descending axons that reach the dorsal and ventral horns of the spinal cord.

Like 5HT cells, NE neurons innervate broad areas and act on a number of receptor types. Biogenic Amine Transmission in Depression • Until recently, the general view concerning what caused depression at the receptor level was that depression represented a decreased availability of either NE or 5HT or both. • Mania was believed to result from the over-activity of NE systems. • This hypothesis was derived from studies of the effects of various drugs on the 5HT and NE systems in the brain. • The idea originally came from the observation in the 1950s that reserpine, a Rauwolfia alkaloid then used extensively in the treatment of hypertension, precipitated depressive syndromes in about 15% of treated patients. • Reserpine produces depression-like symptoms in animals. Bernard Brodie and his colleagues found that reserpine depletes the brain of 5HT and NE (and DA) by inhibiting the reuptake of the transmitter into synaptic vesicles, keeping the transmitter in the cytoplasm, where it undergoes degradation by monoamine oxidase. • Isoniazid, originally developed as a drug for tuberculosis in the 1950s, was found to have antidepressant properties acting by blocking MAO. • Next, was the tricyclics that block the active reuptake of 5HT and NE by presynaptic neurons thereby prolonging the action of the transmitters in the synaptic cleft. • The third group of compounds found to be effective were the SSRIs, drugs that acted ONLY on 5HT, by inhibiting its reuptake or degradation. Unanswered Questions • The biogenic amine hypothesis fails to explain why the clinical response to all antidepressant drugs is so slow after administration of the drugs. • If the clinical response is a result of an increase in 5HT transmission, what accounts for the delay in response? • Tricyclic drugs vary widely in their relative abilities to block 5HT or NE reuptake yet their clinical efficacy is about the same. • ECT increases serotonergic transmission. • It does this by increasing the sensitivity of 5HT1A receptors in the hippocampus and increasing the number of 5HT2A receptors. • In some patients with depression the onset of the illness is associated not with a decrease but with an INCREASE in the level of NE in spinal fluid and plasma and treatment leads to reduction to normal levels. 5HTergic Drugs Produce Sensitivity • It is now clear that antidepressant agents affect processes other than the reuptake and accumulation of 5HT. • Both MAO inhibitors and tricyclic antidepressants produce a delayed but long-term increase in the sensitivity of serotonin receptors. • Conversely, the SSRIs produce a delayed decrease in the sensitivity of 5HT1A and 5HT1B inhibitory autoreceptors present on many 5HT cells, leading to increased release of 5HT.

Both of these actions lead to a slow increase in the effectiveness of 5HT synaptic transmission. Disturbances in Neuroendocrine Function • Edward Sachar pointed out that depression is associated with clinical signs of hypothalamic disturbance. • The best-understood hypothalamic disturbance in severe depression is neuroendocrine and is reflected in excessive secretion of adrenocorticotropic hormone (ACTH) by the pituitary, leading to excessive secretion of cortisol from the adrenal cortex. • The hypersecretion of ACTH is so great that enlargement of the adrenal gland can be detected on CAT scans of some patients. Disturbances in Neuroendocrine Function • The circadian cycle for the secretion of cortisol is disturbed in about 50% of depressed patients. • The disturbance is not dependent on stress and is not found in other psychiatric disorders. • Cortisol secretion returns to normal with recovery. • Studies have shown that the increased secretion of cortisol results from hypersecretion of corticotropin-releasing hormone (CTRH) from the hypothalamus, and that the level of CTRH correlates positively with depression. • Release of CTRH is stimulated by norepinephrine and acetylcholine, and release of CTRH induces anxiety in experimental animals. • CTRH and NE systems may reinforce one another. Dexamethasone Test • Hypersecretion of cortisol is sometimes resistant to feedback suppression by the potent synthetic corticosteroid dexamethasone, which depresses secretions of adrenocorticotropin. • The dexamethasone suppression test has been used to diagnose depression because in at least 40% of rigorously diagnosed patients with depression hypersecretion of cortisol is resistant to feedback suppression by dexamethasone. • However, the test is not specific; dexamethasone suppression is ALSO abnormal in patients who have dementia, anorexia nervosa, bulimia, alcohol withdrawal, or weight loss. LECTURE 45: Schizophrenia • • In medicine the term disease refers to a cluster of symptoms and signs that results from a specific cause and leads through a defined course to a specific outcome. Ideally a diagnosis is based on two additional factors: – (1) a clear and evident causative agent (whether the illness results from a genetic abnormality, a viral or bacterial infection, toxins, tumors, or stress) and

(2) a plausible pathogenesis (a clear idea of the mechanism by which the causative agent produces the disease). • Unfortunately, unlike most other medial illnesses the causes and pathogenesis of most mental illness have not, as of yet, been determined. • This is especially the case in regards to schizophrenia. • Schizophrenia is perhaps the most devastating mental disorder of humankind. • It strikes about 1% of the population worldwide and affects men slightly more frequently than women. • In addition to the 1% with schizophrenia, an additional 2-3% of the general population have schizotypal personality disorder, a milder form of schizophrenia proper. • Bleuler called a certain group of illnesses schizophrenia, a splitting of the mind. • This condition is NOT to be confused with multiple or split personalities an uncommon disease in which a person alternately assumes two or more identities. • People with schizophrenia may show evidence of this splitting by having inappropriate affect. • For example, they may laugh while recounting a tragic event or may show no emotion (flat affect) while describing a joyous occasion. Schizophrenia: Symptoms • Psychotic Episodes Mental states in which some of the patient’s thought processes are not able to test reality correctly. • The patient is unable to examine their beliefs and perceptions realistically and to compare them to what is actually happening in the world. • This is called loss of reality testing. • Other symptoms include: • disturbances of higher mental functioning, • delusions (aberrant beliefs that fly in the face of facts and are not changed by evidence that the beliefs are unreasonable) • hallucinations (mostly auditory) • incoherent thinking • disordered memory • confusion One example, people with schizophrenia often hear internal voices that tell them things that are not true, for example that their parents are trying to poison them. Neuroanatomy of Hallucinations in Schizophrenia • Studies have shown that the inferotemporal cortex is critically involved in the recognition and discrimination of visual objects and is the area disturbed in prosopagnosia, a disorder concerned with the recognition of faces. • The output nuclei of the basal ganglia—the substantia nigra pars reticulata— project via the thalamus to the inferotemporal cortex. • The inferotemporal cortex is not only a source of input to the basal ganglia but also a target of basal ganglia output. • The basal ganglia can influence higher-order visual processing. •

In essence, abnormalities in the basal ganglia (DAergic) loop (substantial nigra —thalamus—infratemporal cortex) may lead to alterations in visual perception, including visual hallucinations characteristic in schizophrenia. • In fact, visual hallucinations are a major side effect of L-DOPA and other DAergic agents used in the treatment of Parkinson disease. • Approximately 30% of patients with Parkinson disease treated in this manner experience this side effect. Thus, hallucinations in these patients may be due to excessive stimulation of DA receptors in the visual striatum, which leads to a net INCREASE in activity in the nucleus pars reticulata and thus abnormal increases in thalamic input to the inferotemporal cortex. • Brain imaging studies of schizophrenic patients experiencing hallucinations support this hypothesis. • Subjects display significant changes in blood flow at several brain sites that are part of the inferotemporal system. Prodromal Signs • The first psychotic episode of schizophrenia is often preceded by prodromal signs. • These include: – social isolation and withdrawal – impairment in the normal fulfillment of expected roles – odd behavior and ideas – neglect of personal hygiene – blunted affect • The prodromal period is followed by one or more psychotic episodes that may include loss of reality testing, memory disturbances, delusions, and hallucinations. • These periods are sometimes separated by long periods when the patient is not overtly psychotic but behaves: – eccentrically – is socially isolated – has a low level of emotional arousal (flat affect) – impoverished social drive – poverty of speech – poor attention span – lack of motivation Positive and Negative Symptoms • Symptoms of the nonpsychotic period are called negative symptoms because they reflect the absence of certain normal social and interpersonal behaviors. • In contrast, the striking abnormalities of psychotic episodes are called positive symptoms because they reflect the presence of distinctively abnormal behaviors. • Negative symptoms are chronic features of the illness and are the most difficult to manage. Diagnosis

Criteria for diagnosing schizophrenia require that a patient be continuously ill for at least six months and that there be at least one psychotic phase followed by a residual phase. • During the psychotic episode one or more of the following three groups of positive symptoms must be present: • (1) Delusions (for example, the belief that one is being persecuted or that one’s feelings, thoughts, and actions are controlled by an outside force) • (2) Prominent hallucinations, usually auditory (for example, hearing voices commenting on one’s actions) • (3) Disordered thoughts, incoherence, loss of the normal association between ideas, or marked poverty of speech accompanied by a loss of emotional expression (flattening of affect). Subtypes of Schizophrenia • During psychotic episodes patients with schizophrenia may also exhibit unusual postures, mannerisms, or rigidity. • On the basis of these criteria and other differences, schizophrenia is often divided into three subtypes: – paranoid schizophrenia – disorganized schizophrenia (hebephrenia) – catatonic schizophrenia • Paranoid schizophrenia is found more often in men in which systematic delusions of persecutions predominate. • Disorganized schizophrenia (hebephrenia) is a form characterized by early age of onset, a wide range of symptoms, and a profound deterioration of personality. • Posturing, grimacing and mirror gazing are symptomatic of this subtype. • Catatonic schizophrenia, a rare form in which mutism and abnormal postures dominate. • The patient is usually immobile, demonstrating waxing flexibility. • Appendages are often in an uncomfortably position and facial expression is characterized by a Schnauzkrampf or frozen snout. Genetic Predisposition • Franz Kallmann discovered that the incidence of schizophrenia throughout the world is uniformly about 1%, even though social and environmental factors vary dramatically. • He found however, that the incidence of schizophrenia among parents, children, and siblings of patients with the disease is about 15%, strong evidence the disease runs in families. • Early this century, it was found that comparing the rates of illness in monozygotic (identical) and dizygotic (fraternal) twins was found to be the best way to analyze the contribution of genetics in schizophrenia. • Monozygotic twins essentially have identical genomes; they share almost 100% of each other’s genes. • In contrast, dizygotic twins share only 50% of their genes are genetically equivalent to siblings. • If schizophrenia were caused entirely by genetic factors, monozygotic twins would have an identical tendency to have the disease to develop.

The tendency for twins to have the same illness is called concordance. Studies of twins have established that the concordance for schizophrenia in monozygotic twins is about 45%, but in dizygotic twins only about 15%, about the same as for other siblings. • Studies of adoptees show that some of the blood relatives of adoptees with schizophrenia show odd behavior even if they do not manifest signs of schizophrenia. • They are socially isolated, have poor rapport with people, ramble in their speech, tend to be suspicious, have eccentric beliefs, and engage in magical thinking. • This group of symptoms is called schizotypal personality disorder, and is thought to be a mild form of the disease, a nonpsychotic condition related to schizophrenia. • If schizophrenia were caused entirely by genetic abnormalities, then the concordance rate for monozygotic twins, who share almost 100% of each other’s genes, would be nearly 100%. • The finding that the concordance rate in monozygotic twins is only about 45% indicates that the genetic transmission is unusual and that genetic factors are not the only cause. Anatomical Abnormalities • CT and MRI and cerebral blood flow studies have revealed that SOME patients with schizophrenia have one or more of four major anatomical abnormalities. • First, early in the disease there is a reduction in blood flow to the left globus pallidus suggestive of a disturbance in the system that connects the basal ganglia to the frontal lobes. • Second, there appears to be a disturbance in the frontal lobes themselves since blood flow does not increase during tests of frontal lobe function involving working memory as it does in normal subjects. • Third, the cortex of the medial temporal lobe is thinner and the anterior portion of the hippocampus is smaller than in normal people, especially on the left side, consistent with a defect in memory. • Finally, the lateral and third ventricles are enlarged and there is widening of the sulci, especially in the thinner temporal lobe and in the frontal lobe, reflecting a reduction in the volume of this lobe as well. • Anatomical abnormalities have also been studied in monozygotic twin pairs of where only one twin had schizophrenia. • In 12 of 15 cases examined, the twin with schizophrenia had larger ventricle compared to the normal twin. • The twin also had a smaller anterior hippocampus on the left side, and this reduction in hippocampal mass correlated highly with the reduction in blood flow in the left prefrontal cortex. Neural Substrate • The smaller the hippocampal volume of the affected twin, the less the left prefrontal cortex was activated during a cognitive task.

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These and several other findings suggest that the hippocampus, prefrontal cortex, globus pallidus, are part of a cognitive system that is impaired in schizophrenia. Antipsychotic Drugs • In the 1950s the French Neurosurgeon Henri Laborit, by trial and error, discovered that chlorpromazine had a calming action in patients. • He thought this drug may have a wider use in psychiatric patients. • In 1951, John Delay and Pierre Deniker, discovered that chlorpromazine calmed highly agitated and aggressive patients who had either schizophrenic or manic depressive symptoms. By the mid 1960s it was found that chlorpromazine (and drugs of the phenothiazine class) mitigated or abolished delusions, hallucinations, and some types of disordered thinking in schizophrenic patients. These findings led to the delineation of a group of drugs, now called typical antipsychotics, which include the phenothiazines (chlorpromazine), butyrophenones (haloperidol) and the thioxanthenes. • More recently a second group of drugs, the atypical antipsychotics (clozapine, risperidone, olanzapine) have also proved useful in the treatment of schizophrenia. • Atypical antipsychotics are better than typical antipsychotics in treating negative symptoms (cognitive effects) in schizophrenia, and they produce fewer side effects on the extrapyramidal system. How Do Antipychotics Work? • The first clue in determining how these drugs worked was the side effects. • The drugs often produce a syndrome resembling Parkinsonism. • Arvid Carlsson first suggested that these drugs may block DA receptors and that DA transmission could be an important part of the pathogenesis of schizophrenia. • Above: Having a similar structure to DA, chlorpromazine sits on the DA receptor blocking it without triggering a response. • Typical antipsychotic drugs have a high affinity for D2 receptors, which are therefore thought to be one of the major sites of therapeutic actions of these drugs. • Indeed, clinical potency of the typical antipsychotic agents in patients with schizophrenia is closely correlated with the affinity of these drugs for the D2 receptor. Dopamine D2-like Receptors • The D2 receptor is part of a family of related receptors (D2 group or D2-like receptors) which include the D3, and D4 receptors. • All three inhibit adenylyl cyclase and are expressed at particularly high levels in neurons of the caudate nucleus, the putamen, and the nucleus accumbens. • D2 receptors are also present in the amygdala, hippocampus, and parts of the cerebral cortex. • Since D2-like receptors are expressed in the caudate and putamen, these receptors presumably contribute to the side effects of the antipsychotic drugs on the extrapyramidal systems.

The amygdala, hippocampus, and neocortex, however, are possible sites of therapeutic action. D3 Receptors: Atypical Antipsychotics • The atypical antipsychotic agents, such as clozapine, bind to D3 and even more effectively to D4 receptors. • These two subtypes of the D2 group are expressed primarily in the limbic system and cortex and are weakly expressed in the basal ganglia. • This selective distribution may explain why the atypical antipsychotic agents do not give rise to side effects in the extrapyramidal systems. • Both the D2 and D3 receptors are of further interest because they are present on DAergic neurons themselves, on both the cell body and the terminals. • Here they act as inhibitory auto-receptors to control both the rate of firing of the neuron and the release of DA by the action potential at the terminals. Abnormalities in DAergic Transmission in Schizophrenia • Excessive release of DA in the mesolimbic DA system may contribute to the expression of schizophrenia. • Drugs that increase the level of DA, such as L-dihydroxyphenylalanine (LDOPA), cocaine, and amphetamine, can induce psychotic episodes resembling paranoid schizophrenia. • Some of these drugs, such as amphetamine, also cause bizarre, repetitive stereotyped behavior in monkeys. • Antipsychotic drugs reverse not only amphetamine psychosis in humans but also the bizarre behavioral syndrome in monkeys. Neurobiological Substrate for Schizophrenia • The DAergic mesolimbic system has its origin in the cell bodies of the VTA (ventral tegmental area) which is medial and superior to the substantia nigra. • These cells project to the components of the limbic system: • nucleus accumbens • ventral striatum • nuclei of the stria terminalis • amygdala • hippocampus • lateral septal nuclei • entorhinal cortex • mesial frontal cortex • anterior cingulate cortex • The idea that the mesolimbic DA system is affected in schizophrenia is supported by the finding that the earliest sign of brain disturbances in schizophrenia, detectable with PET imaging, is a decrease in blood flow in a region of the basal ganglia (globus pallidus). • This disturbance is before the prominent frontal lobe deficit becomes evident. • Among the projections of the mesolimbic system, those to the nucleus accumbens are thought to be particularly important because of the extensive connection of this nucleus to the limbic system.

The nucleus accumbens receives and integrates inputs from the amygdala, hippocampus, entorhinal area, anterior cingulate area, and parts of the temporal lobe. • After loss the dorsal prefrontal cortex, patients are poorly motivated, plan poorly and have flattened affect. • Patients with Parkinson’s disease who have lost DA neurons not only have a motor disorder but also lack motivation and have flat affect and reduced spontaneity, defects that can be reversed with DA agonists. • Lesions that destroy the VTA cause demential and psychotic symptoms. • Overactive modulation of the integration of the inputs to the nucleus accumbens and of the output from it could contribute to positive symptoms of schizophrenia. • The mesocortical DA system originates in the VTA and projects to the neocortex, in particular the prefrontal cortex. • The prefrontal cortex is involved in the temporal organization of behavior, in motivation, planning, attention, and social behavior. • This system may be important in the negative symptoms of schizophrenia, symptoms that bear some resemblance to the defects seen after surgical disconnection of the frontal lobes, especially the dorsal prefrontal cortex. Neurobiological Substrate for Schizophrenia: Pulling It All Together • An INCREASE in activity in the mesolimbic pathway (perhaps through the D2 and D3 receptors and particularly through D4 receptors) would account for the positive symptoms. • DECREASED activity of the mesocortical connections in the prefrontal cortex would account for the negative symptoms. Imbalance Between the Mesolimbic and Mesocortical Pathways • According to this model, the imbalance between the cortical and subcortical DA transmission underlies the development of schizophrenia. • It has been proposed that activity in the mesocortical pathway to the prefrontal cortex normally INHIBITS the mesolimbic pathway by FEEDBACK INHIBITION and that the primary defect in schizophrenia is a REDUCTION in this activity, which leads to disinhibition and overactivity in the mesolimbic pathway. Dopamine Doesn’t Explain It All • Primary treatments for schizophrenia act on DAergic systems yet we do not know for sure if these systems cause the disease. • Pharmacological manipulation may produce changes that compensate for the disease without directly affecting the disordered mechanism itself. • For example, the primary defect in Parkinson’s Disease is a decrease in DA levels but some symptoms can be alleviated by drugs that block cholinergic transmission. • In addition, although antipsychotic drugs occupy DA receptors very quickly after administration the maximal therapeutic (antipsychotic) effects are often delayed several weeks. • Activity in certain neural circuits may need to adjust to a new level of modulation.

The drugs or the resulting alterations in neuronal activity might produce changes in gene expression, the consequences of which may not become manifest for one or more weeks. • These alterations may reflect changes in other neurotransmitter systems that interact with DA such as 5HT. • Indeed, most typical antipsychotics act on 5HT2 receptors at which lysergic acid diethylamide (LSD) and other psychedelic hallucinogens also act. • Long-term administration of antipsychotic agents leads to a downregulation of 5HT2 receptors that parallels in time course the therapeutic action of the antipsychotic drugs. Other Receptors Other Systems • 20% of patients do not respond to DAergic drugs that block D2 receptors. • These patients often respond to the atypical antipsychotic agents such as clozapine, which is only a weak blocker of D2 receptors. • Clozapine produces few, if any, Parkinson-like side effects, which characteristically occur with blockade of D2 receptors. • Clozapine and risperidone bind to D3 and D4 receptors. • D3 and D4 receptors are limited to the limbic system in their distribution. • Clozapine also blocks 5HT2a and α1 norepinephrine and H1 histamine receptors. • Phencyclidine (PCP) produces a psychosis that resembles the psychosis in schizophrenia and exacerbates psychosis in patients with schizophrenia. • Normal subjects given IV PCP experience depersonalization and feel disconnected from their environment. • They also have delusion of being controlled by external agents and have auditory and visual hallucinations. • PCP binds to two identified molecular targets in the brain: • (1) the dopaminergic terminals in the nucleus accumbens • (2) the N-methyl-D-aspartate (NMDA) class of glutamate receptors • NMDA receptors are present on DAergic axon terminals in the prefrontal cortex and enhance DA release from the terminals. • PCP, when it binds to the NMDA receptors, inhibits release of DA. • In contrast, at the DAergic terminals in the nucleus accumbens PCP increases DA release and inhibits reuptake, much like amphetamine. • Specific drugs developed to block NMDA receptors selectively (used for the treatment of NMDA induced neurotoxicity after stroke or prolonged seizure activity) have the undesirable side effect of producing psychosis, perhaps by reducing the release of DA in the mesocortical pathway to the frontal lobe. This evidence points towards other possible therapeutic targets besides DA (e.g. NMDA receptors) for the treatment of schizophrenia. LECTURE 46: Headache and Facial Pain • Headache can be caused by traction, displacement, inflammation, vascular spasm, or distention of the pain sensitive structures in the head or neck.

Isolated involvement of the bony skull, most of the dura, or most regions of brain parenchyma does NOT produce pain. Pain-Sensitive Structures Within the Cranial Vault Pain-sensitive structures within the cranial vault include the venous sinuses (e.g. sagittal sinus), the anterior and middle meningeal arteries and the dura at the base of the skull. • In addition, the trigeminal (V), glossopharyngeal (IX), and vagus (X) nerves, the proximal portions of the internal carotid artery and its branches near the circle of Willis, the brain stem periaqueductal gray matter, and the sensory nuclei of the thalamus are pain sensitive structures. Extracranial Pain-Sensitive Structures • These include the periosteum of the skull, the skin, the subcutaneous tissues, muscles, and arteries, neck muscles and third cervical nerves. • In addition, the eyes, ears, teeth, sinuses, and oropharynx, mucous membranes of the nasal cavity are pain-sensitive structures. Radiation or Projection of Pain • The trigeminal (V) nerve carries sensation from intracranial structures in the anterior and middle fossa of the skull, above the cerebellar tentorium. • Discrete intracranial lesions in these locations produce pain that radiates in the trigeminal nerve distribution. • The glossopharyngeal (IX) and vagus (X) nerves supply part of the posterior fossa, pain originating in this area may also be referred to the ear or throat (e.g. glossopharyngeal neuralgia). • The upper cervical nerves transmit stimuli arising from infratentorial and cervical structures. • Therefore, pain from posterior fossa lesions projects to the second and third cervical dermatomes. Differential Diagnosis • Acute headaches and facial pain: Headaches that are new in onset and clearly different from any the patient has experienced previously are commonly a symptom of serious illness and therefore demand prompt evaluation. • The sudden onset of “the worst headache I’ve ever had in my life” (classic subarachnoid hemorrhage), diffuse headache with neck stiffness and fever (meningitis) and head pain centered about one eye (acute glaucoma) are examples. • Acute headaches may also accompany more benign processes such as viral syndromes or other febrile illnesses. Subacute Headaches and Facial Pain • Subacute headaches occur over a period of weeks to months. • Such headaches may also signify serious medical disorders, especially when the pain is progressive or when it develops in elderly patients. • Inquiries should be made about: – recent head trauma (subdural hematoma or post-concussive syndrome) – a history of malaise, fever, or neck stiffness (subacute meningitis)

other neurologic abnormalities or weight loss (primary or metastatic brain tumor) Precipitating Factors • Precipitating factors may include: – Recent eye or dental surgery – Acute exacerbation of chronic sinusitis or hay fever – Systemic viral infection – Tension, emotional stress or fatigue – Menses – Hunger, ice cream food containing nitrite – Phenylethylamine – Tyramine – Bright lights • Precipitation of headache by alcohol is especially typical of cluster headache. • Chewing and eating commonly trigger – glossopharyngeal neuralgia – tic douloureux – jaw claudication of giant cell arteritis – these activities also trigger pain in patients with temporomandibular joint dysfunction • The use of oral contraceptive agents or other drugs such as nitrates may precipitate or exacerbate migraine and even lead to stroke. Prodromal Symptoms • Intense headache can occur in response to coughing in patients with structural lesions in the posterior fossa. • Prodromal symptoms or auras, such as scintillating scotomas or other visual changes, often occur with migraine. • They may also occur in patients with seizure disorder who present with postictal headaches. Characteristics of Pain • Pulsating, throbbing pain is frequently ascribed to migraine and tension headaches. • A steady sensation of tightness or pressure is also commonly seen with tension headache. • Intracranial mass lesions tend to produce dull and steady pain. • Sharp, lancinating pain suggests a neuritic cause such as trigeminal neuralgia. • Ice pick-like pain may be described by migraine, cluster headache, or giant cell arteritis patients. Temporal Pattern of Headache • Headaches from mass lesions increase in severity over time. • Cluster headaches frequently awaken patients from sleep and recur the same time each day or night. • Tension headaches can develop whenever stressful situations occur and are often maximal at the end of a workday. • Migraine headaches are episodic and may be worse during menses. Conditions Relieving Headaches

Migraine headaches are frequently relieved by darkness, sleep, vomiting, or pressing on the ipsilateral temporal artery. • Postlumbar-puncture headaches are typically relieved by recumbency, while headaches caused by intracranial mass lesions may be less severe with the patient standing. • Discomfort exacerbated by rapid changes in head position or by events that transiently raise intracranial pressure, such as coughing and sneezing, is often associated with an intracranial mass but can occur in migraine. • Anger, excitement, or irritation can precipitate or worsen both migraine and tension headaches. • Stooping, bending forward, sneezing, or blowing the nose characteristically worsens the pain of sinusitis. • Postural headache (maximal when upright nearly absent when laying down) occurs with low CSF pressure caused by lumbar puncture, head injury, or spinal fluid leak. Brudzinski’s Sign • With the patient supine and the examiner’s hand on the patient’s chest, passive neck flexion results in flexion at the hips (which is often asymmetric). • The sign is present with meningeal irritation from disorders such as infectious meningitis or subarachnoid hemorrhage. Subarachnoid Hemorrhage • Spontaneous (nontraumatic) subarachnoid hemorrhage (bleeding into the subarachnoid space) is usually the result of a ruptured cerebral arterial aneurysm. • Rupture of a “berry” aneurysm accounts for about 75% of cases and occurs most often during the fifth and sixth decades, with an approximately equal sex distribution. Headaches of Acute Onset • Cerebral artery aneurysms are most commonly congenital “berry” aneurysms, which result from developmental weakness of the vessel wall, especially at sites of branching. • These aneurysmal dilatations arise from intracranial arteries about the circle of Willis at the base of the brain and are multiple in about 20% of cases. • Rupture of an intracranial artery elevates intracranial pressure and distorts pain-sensitive structures, producing headache. • Intracranial pressure may acutely decrease cerebral blood flow. • Together with the concussive effect of the rupture, this is thought to cause the loss of consciousness (50%). • Rapid elevation of intracranial pressure can also produce subhyaloid retinal hemorrhages. • The classic presentation of subarachnoid hemorrhage is the sudden onset of an unusually severe generalized headache “the worst headache I ever had in my life”. • Loss of consciousness, vomiting and neck stiffness are common. • The most significant feature of the headache is that it is NEW. • Blood pressure frequently rises precipitously as a result of the hemorrhage.

Because bleeding occurs mainly in the subarachnoid space, prominent focal signs are UNCOMMON on neurological examination. Aneurysmal Subarachnoid Hemorrhage • Nonenhanced CT scan from a patient with an acute aneurysmal subarachnoid hemorrhage. • Areas of high density (arrows) represent blood in the subarachnoid space at the base of the brain (most aneurysms occur in this region about the Circle of Willis). • Arrows in B point toward interpeduncular cistern: suprasellar cistern, small arrow. Surgical Treatment • Definitive surgical therapy consists of clipping the neck of the aneurysm or the endovascular placement of a coil to induce clotting. • The neurologic examination is used to grade the patients clinical state relative to surgical candidacy. • The mortality rate from aneurysmal subarachnoid hemorrhage is high. • About 20% of patients die before reaching a hospital, 25% die subsequently from the initial hemorrhage or its complications, and 20% die from rebleeding if the aneurysm is not surgically corrected. • Most deaths occur in the first few days after the hemorrhage. Meningitis or Encephalitis • Headache is a prominent feature of inflammation of the brain (encephalitis) or its meningeal coverings (meningitis) caused by bacterial, viral, or other infections; granulomatous processes, neoplasms, or chemical irritants. • The pain is caused by inflammation of intracranial pain-sensitive structures, including blood vessels at the base of the brain. • The headache is throbbing in character, bilateral and occipital or nuchal in location. • It is increased by sitting upright, moving the head, compressing the jugular vein, or performing other movements (coughing, sneezing) that increase intracranial pressure. • The headache commonly develops over hours to days, especially with subacute infections (tuberculous meningitis). • Diagnosis is by CSF showing increased white blood cell count and other immunological tests. Other Causes of Headache • Seizures: Postictal headache that follows generalized tonic-clonic seizures. • Lumbar Puncture: Pain is typically occipital. Headache is caused by persistent spinal subarachnoid leak with resultant traction on pain-sensitive structures at the base of the brain. • Hypertensive Encephalopathy: Headache due to a sudden elevation in blood pressure such as is caused by pheochromocytoma, sexual intercourse, the combination of MAO inhibitors and tyramine-containing foods and malignant hypertension. • Giant Cell Arteritis

Also known as temporal arteritis, is characterized by a subacute granulomatous inflammation (consisting of lymphocytes, neutrophils, and giant cells) that affects the external carotid arterial system, particularly the superficial temporal artery, and the vertebral artery. • Inflammation of the pain sensitive arterial wall produces the headache. • Thrombosis may occur in the most severely affected arteries. • Affects women twice as frequently as men, common after 50 and is associated with nonspecific signs and symptoms, such as malaise, myalgia, weight loss, arthralgia, and fever. • Pain is localized to the scalp, especially over the temporal arteries. • Involvement of the ophthalmic artery leads to permanent blindness in 50% of untreated patients, in half of these, blindness will be become bilateral. • Diagnosis is made by biopsy of affected temporal arteries. Intracranial Mass • The new onset of headache in middle or later life should always raise concern about a mass lesion. • A mass lesion, such as a brain tumor, subdural hematoma, or abscess, MAY or MAY NOT produce headache depending upon whether or not it compresses or distorts pain-sensitive intracranial structures. • Only 30% of patients with intracranial tumor present with headache as the first symptom, although 80% have such a complaint at the time of diagnosis. • Subdural hematoma frequently presents with conspicuous headache, since its large size increases the likelihood of impinging upon pain-sensitive areas. • Headache associated with brain tumors are most often: • nonspecific in character, • mild to moderate in severity, • dull and steady in nature, and • intermittent. Trigeminal Neuralgia • Trigeminal neuralgia (tic douloureux) is a facial-pain syndrome of unknown cause that develops in middle to late life. • In many instances, the trigeminal nerve roots are close to some vascular structure, and microvascular compression of the nerve is believed to cause the disorder. • Pain is confined mainly to the area supplied by the second and third divisions of the trigeminal nerve. • Characteristically, lightning like momentary jabs of excruciating pain occur and spontaneously stop. • Sensory stimulation of trigger zones about the cheek, nose, or mouth by touch, cold, wind, talking, or chewing can precipitate pain. • Treatment includes carbamazepine, phenytoin (Dilantin), lamotrigine or baclofen. Glossopharyngeal Neuralgia • Patients with glossopharyngeal neuralgia, an uncommon pain syndrome, present with either a paroxysmal pain that is identical in quality to that of trigeminal neuralgia, or a continuous burning or aching discomfort.

The pain is localized to the oropharynx, the tonsillar pillars, the base of the tongue, or the auditory meatus. • The trigger areas are usually around the tonsillar pillars, so that symptoms are initiated by swallowing or by talking. • Carbamazepine or phenytoin therapy usually produces dramatic relief. Postherpetic Neuralgia • Herpes zoster—a vesicular skin eruption in dermatomal distribution, accompanied and followed by local pain and tenderness is due to reactivation of varicella-zoster virus in patients with a history of varicella infection. • It becomes increasingly common with advancing age (70% in those over 70 years) in immunocompromised patients with certain malignant diseases (e.g. leukemia, lymphoma). • Characterized by constant, severe, stabbing or burning, dysesthetic pain that may persist for months or years in a minority of patients, especially older ones. • It occurs in the same dermatomic distribution as a previous bout of herpes zoster, conforming to the distribution of the involved nerve root, where residual scars may be present. • The most effective treatment is with tricyclic antidepressants such as amitriptyline. • Topicals: lidocaine-prilocaine cream, lidocaine gel, capsaicin cream (Zostrix). Chronic Headaches • Migraine is manifested by headache that is usually unilateral and frequently pulsatile in quality. • It is often associated with nausea, vomiting, photophobia and lassitude. • Visual or other neurologic auras occur in about 10% or patients. • Two-thirds to ¾ of cases of migraine occur in women. • Onset is early in life: 25% beginning during the first decade, 55% by 20 years of age, and more than 90% before age 40. • A family history of migraine is present in most cases. • The aggregation of migraine within families has long been recognized, although consistent mendelian patterns of inheritance have not been found. • Concordance rates in monozygotic twins of only 28-52 attest to the genetic component, but also predict a significant environmental contribution. Migraine: Pathogenesis • Intracranial vasoconstriction and extracranial vasodilatation have long been held to be respective causes of the aura and headache phases of migraine. • This theory received support from the efficacy of vasoconstrictive ergot alkaloids (e.g. ergotamine) in aborting the acute migraine attack and vasodilators such as amyl nitrite in abolishing the migraine aura. • More recent studies of regional cerebral blood flow during migraine attacks show a reduction in regional flow, which begins in the occipital region during he aura phase. • The “spreading depression” in cerebral blood flow, however, proceeds according to cytoarchitectural patterns in the cerebral cortex and does not reflect the distribution of major vascular territories.

In addition, the areas of decreased blood flow do not correspond to the cortical areas responsible for the particular aura, and regional cerebral blood flow may remain depressed after focal neurologic symptoms have resolved and headache has begun. • Later in the headache phase, blood flow increases to parts of the cortex (cingulate, auditory, and visual association areas) and the brainstem (serotonin dorsal raphe nucleus and locus ceruleus). • Treatment with effective agents (sumatriptan, ergotamine) attenuates the cortical but not the brainstem changes. • These data imply that vascular abnormalities in migraine may be secondary to a primary disturbance in neuronal function in the brainstem. • Indeed, many effective antimigraine drugs act as antagonists or partial agonists at 5HT receptors. • Platelet 5HT decreases and urinary 5HT increases during the acute phase of a migraine attack. • Depletion of 5HT with reserpine precipitates migraine. • Classic migraine headache is preceded by transient neurologic symptoms such as the aura. • The most common auras are visual alterations, particularly hemianopic field defects and scotomas and scintillations that enlarge and spread peripherally. • A throbbing unilateral headache ensues. • The frequency of headache varies, but more than 50% of patients experience no more than one attack per week. • The duration of episodes is greater than 2 hours and less than 1 day in most patients. • During the headache, symptoms include, nausea vomiting, photophobia, phonophobia, irritability, osmophobia, and lassitude. • Vasomotor and autonomic symptoms are frequent such as light-headedness, vertigo and ataxia. Common Migraine • Migraine without Aura The common migraine headache lacks the classic aura, is usually bilateral and periorbital, and is seen more frequently in clinical practice. • The pain may be described as throbbing. • As the pain persists, associated cervical muscle contractions can compound the symptoms. • Scalp tenderness is often present during the episode. • Vomiting may occasionally terminate the headache. Bedside Test • A useful bedside test for both common and classic migraine is reducing headache severity by compressing the ipsilateral carotid or superficial temporal artery. Precipitating Factors • Migraine attacks can be precipitated by certain foods (tyramine-containing cheeses, meat, nitrite preservatives, chocolate containing phenylethylamine •

but not chocolate alone) and by food additive such as monosodium glutamate. • Fasting, emotion, menses, drugs (especially oral contraceptive agents and vasodilators such as nitroglycerin) and bright lights may also trigger attacks. Treatment • Acute migraine attacks may respond to simple analgesics (aspirin, acetaminophen, naproxyn). • If not, they usually respond to ergot preparations or to the 5HT agonist sumatriptan. • Ergot alkaloids and 5HT agonists are potent vasoconstrictors and are contraindicated in patients with significant hypertension or cardiac disease. • Drugs used as prophylactics include propranolol, amitriptyline and valproic acid. • In addition, calcium channel antagonists such as verapamil or nicardepine are also effective. • SSRIs are NOT an effective therapy for migraine. Cluster Headache • Cluster headache is a common headache syndrome seen much more frequently in men and women. • Cluster headaches characteristically begin later in age compared to migraine (25years). • There is rarely a family history. • The syndrome presents as clusters of brief, very severe, unilateral, constant non-throbbing headaches that last from 10 min to less than 2 hours. • Always unilateral and usually recur on the same side in a given patient. • Commonly occur at night, awakening the patient from sleep, and recur daily, often at nearly the same time of day for a cluster period of weeks to months. • The headache may begin as a burning sensation over the lateral aspect of the nose or as a pressure behind the eye. • Ipsilateral conjunctival injection, lacrimation, nasal stuffiness, and Horner’s syndrome are commonly associated with the attack. • Episodes are often precipitated by alcohol or vasodilating drugs. • Treatment is with sumatriptan, 100% oxygen and dihydroergotamine. Tension-Type Headache • Tension headache is the term used to describe chronic headaches of inapparent cause that lack features characteristic of migraine or cluster headache. • The underlying pathophysiologic mechanism is unknown, and tension is unlikely to be primarily responsible. • It its classic form, tension headache is a chronic disorder that begins after age 20. • It is characterized by frequent (often daily) attacks of non-throbbing, bilateral occipital head pain that is not associated with nausea, vomiting, or prodromal visual disturbance. • The pain is sometimes likened to a tight band around the head.

LECTURE 47: The Neurological Exam Class Handout

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