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BASAL GANGLIA
INPUT Primary input from: Cerebral Cortex (frontal cortex mediates motor functions of BG) Other input from: Thalamus ¯ Input nuclei: Caudate nucleus Putamen
OUTPUT Output nuclei: Globus Pallidus Substantia Nigra Subthalalmic nucleus ¯ Output goes to: Thalamus ¯ Prefrontal cortex Premotor cortex Motor cortex
Motor Disturbances characteristic of Basal Ganglia Diseases 1. Tremor or involuntary movement 2. Changes in posture or muscle tone 3. Poverty and slowness of movement without paralysis
Pyramidal tract syndrome vs. Extrapyramidal tract syndrome - Spasticity - Involuntary movements - Paralysis - Muscle rigidity - Immobility without paralysis
Basal Ganglia: the details
Caudate and Putamen - INPUT nuclei - Striatum or neostriatum - Develop from Telencephalon - Composed of identical cell types - Fused anteriorly: Nucleus Accumbens - Caudate: eyes and cognitive - Putamen: motor
Globus Pallidus - OUTPUT - Paleostriatum - Develops from the diencephalon - Internal and external segments
Substantia Nigra - OUTPUT - pars reticulata (pale) - pars compacta (dark)
Corpus Striatum = Caudate, Putamen, and Globus pallidus Lenticular/Lentiform nucleus = Putamen and Globus pallidus Neostriatum or striatum = Caudate and Putamen (input) Paleostriatum = Globus Pallidus (output) INPUT from Cortex
Motor ® Corticostriate ® dorsal part of Putamen Pre-motor dorsal striatum
Limbic ® Corticostriate ® ventral part of Putamen ventral striatum
Association ® Corticostriate ® Caudate areas
INPUT from Thalamus
Circuits
Motor circuit Cortex ® Putamen ® Globus Pallidus/Substantia Nigra ® Cortex
Ocular Motor circuit (saccadic eye movements) Frontal eye field ® Caudate ® Superior Colliculus ® Frontal eye field
Dorsolateral Prefrontal Circuit (memory concerned with orientation in space) D-L prefrontal cortex ® Caudate ® Thalamus ® D-L prefrontal cortex
Lateral Orbitofrontal Circuit (ability to change behavior set) Lateral orbitofrontal cortex ® Caudate ® Lateral orbitofrontal cortex
PARKINSON’S DISEASE
1. Rhythmic tremor at rest 2. Unique increase in muscle tone or rigidity 3. Akinesia or Bradykinesia 4. Posture
Tremor, Rigidity, Akinesia, Posture
Deficiency in transmitter: Dopamine Reduction in dopamine projections from the substantia nigra pars compacta Lewy body – inclusion body within neuron
Loss of dopamine = activity of INDIRECT pathway - striatum inhibits the external globus pallidus from inhibiting the subthalamic nucleus - \ subthalamic nucleus fires onto internal globus pallidus and substantia nigra pars reticulata more - \ internal globus pallidus & substantia nigra pars reticulata inhibit thalamus from exciting cortex - \decreased activity
Exogenous L-Dopa can cross the blood/brain barrier and reduce symptoms. The course of the disease is not altered –neurons will continue to die.
HUNTINGTON’S DISEASE
1. Inherited (autosomal dominant) 2. Chorea 3. Dementia 4. Death 15-20 years after symptoms
Due to expanded unstable trinucleotide repeat. Glutamine repeats form a zipper that interacts with HAP-1 protein to form insoluble toxic inclusion bodies Huntington protein is normally found in cytoplasm of dendrites.
Symptoms 1. absentmindedness, irritability, depression 2. fidgeting, clumsiness, sudden falls 3. speech becomes slurred, then distored, then stops altogether 4. cognitive functions deteriorate and facial expressions become grotesque and distorted 5. ability to reason is lost
Medium spiny neurons in the striatum that release GABA/enkephalon are particularly vulnerable
Huntington’s = ¯¯ activity of Indirect pathway - striatum stops inhibiting the external globus pallidus - \globus pallidus inhibits the subthalamic nucleus more - \subthalamic nucleus fires onto internal globus pallidus and substantia nigra pars reticulata less - \ internal globus pallidus and substantia nigra pars reticulata inhibit the thalamus less - \thalamus excites the cortex more - \increased activity
CEREBELLUM
Anatomy
Vermis –medial stripe Lateral lobes Nodulofloccular lobe – oldest part phylogenetically, Achecerebellum Anterior lobe – primitive part, Paleocerebellum (receives inputs from spinal cord for control of walking) Posterior lobe – Neocerebellum (receives from cerebral cortex through pons to coordinate planning of mvt)
Always has an underlying trunk of white matter Convolutions Two Functional Divisions: Intermediate and Lateral
4 Deep Nuclei 1. Fastigial 2. Globose 3. Emboliform 4. Dentate
3 Brainstem Connections 1. Superior Cerebellar Peduncle - Brachium Conjuctivum - Efferent pathways leaving the cerebellum from globus, emboliform & dentate - Afferent fibers from various tracts - Connects to Midbrain, enters decussation
2. Middle Cerebellar Peduncle - Brachium Pontis - Connects to Pons - Afferent fibers from the Pons
3. Inferior Cerebellar Peduncle - Restiform Body - Connects to Medulla - Afferent & Efferent from Vestibular Nuclei
Cellular Organization
5 Types of Neurons 1. Granule - Axons extend into molecular layer and bifurcate into parallel fibers - Receive inputs from Mossy fibers - Excitatory connection with Purkinje cells, Glutamate
2. Purkinje - Receive inputs from Parallel fibers of granule cells (indirect from Mossy fibers) & Climbing fibers - Sole output cells of cerebellar cortex - Inhibitory –GABA
3. Golgi 4. Basket 5. Stellate
3 Layers of Cortex (1mm thick) 1. Molecular Layer - axons of Granular cells that bifurcate into Parallel fibers - scattered Stellate and Basket cells - dendrites of Purkinje cells (in a single plane)
2. Purkinje Layer - Purkinje cells (very large cells that form a single layer)
3. Granular Layer - Granule cells - One of most dense areas of cells in the body - Golgi cells - Glomerulus Mossy fiber Granule cell dendrite Golgi cell axon
Afferent Input into Cbl
- Excitatory, Glutamate (tonic circuit through collateral pathways to deep Cbl nuclei) - Major afferent input into Cbl - Originate: brainstem nuclei in Pons, Spinocerebellar tract of Spinal Cord - Synapse with Granular cells (influence Purkinje cells indirectly) - Activate clusters of granular cells - Fire spontaneously at High rates - Simple Spike
- Excitatory, Glutamate (tonic circuit through collateral pathways to deep Cbl nuclei) - Thought to modulate the input from Mossy fibers - Originate: ONLY from the Inferior Olive (gets input from spinal olivary tract and cortex) - Enter through Inferior Cerebellar Peduncle - Synapse with 1 – 10 Purkinje cell soma and dendrites (very powerful connection) - Fire spontaneously at Low rates - Complex Spikes
Pathways
Output - Purkinje cell is only output from Cbl cortex - All information leaving the Cbl acts first on the Deep Nuclei - Deep Nuclei and Vestibular nuclei transmit all output from the Cbl
Primary Cerebellar Circuit - Mossy and climbing fiber collateral pathways activate neurons in the Deep Nuclei; Modulated by inhibitory action of Purkinje cells
Glomerulus Mossy fibers ® + Granular cells - ¬ Golgi cells
Granule cell ® Parallel fibers ® + Purkinje cells ® - output + Golgi cells ® - granule + Basket cells ® - purkinje + Stellate cells ® - purkinje
Functional Subdivisions
1. Vestibulocerebellum
Flocullonodular lobe
· Input: Vestibular nuclei (from semicircular canals and otolith organs) Superior cerebellar peduncle
· Deep nucleus: Lateral Vestibular (inferior cerebellar peduncle)
· Output: Medial systems: Axial motor neurons
· Function: Axial control (control of balance) Vestibular reflexes (coordinate eye movements with head movements)
· Diseases: Ataxic gait, wide based standing position, & nystagmus
Semicircular canals & otolith organs ® flocculonodular lobe ® vestibular nuclei ® medial vestibulospinal tracts (through vestibular nuclei) lateral vestibulospinal tract
2. Spinocerebellum
Vermis
· Input: Spinocerebellar tracts: somatosensory information from the spinal cord Receives: proximal body, facial, auditory, visual, & vestibular information somatotopically organized
· Deep nucleus: Fastigial
· Output: Medial systems: Vestibular nucleus Reticular formation Motor cortex
· Function: Axial and proximal motor control Ongoing execution of movement and muscle tone
Intermediate Part (extends rostrally – caudally)
· Input: Spinal afferents from distal body - Dorsal and Ventral Spinocerebellar tracts from trunk and legs - Cuneo and Rostral Spinocerebellar tracts from arms and neck
· Deep nucleus: Globose and Emboliform nuclei (interposed)
· Output: Lateral systems: Red nucleus (magnocellular part) Distal regions of motor cortex
· Function: Distal motor control Ongoing execution of movement
Lesions involving spinocerebellum affect limbs IPSILATERALLY because fibers cross 2 times
Dorsospinocerebellar tract Nucleus Dorsalis of Clarke ® Dorsal lateral funiculus ® Inferior Cbl peduncle ® terminate as mossy fibers ¯ Vermis or Intermediate zone Ventrospinocerebellar tract Dorsal Horns, crosses midline ® ventral lateral funiculus ®Superior Cbl peduncle ® terminate as mossy fibers
Superior Cbl peduncle ® Thalamus ® 10 motor cortex
Vermis Purkinje cells ® Fastigial nuclei Brainstem reticular formation ® reticulospinal tract
Lateral Vestibular nuclei ® vestibulospinal tracts
Thalamus ® Cortex ® Corticospinal tract
Intermediate Zone ® Globose ® Superior Cbl ® Red nucleus Purkinje cells Emboliform Peduncle Nuclei Rubrospinal tract
3. Cerebrocerebellum
Lateral part of Cbl hemispheres
· Input: Exclusively from cells in the Pons (relay info from cerebral cortex) cortical afferents Middle Cerebellar Peduncle
· Deep nucleus: Dentate (superior cerebellar peduncle)
· Output: Integration areas: Red nucleus (parvocellular part) VL nucleus of Thalamus Premotor cortex (area 6)
· Function: planning, initiation, & timing of movement precision and control of rapid movement (fine dexterity)
Cortex ® Pontine ® middle ® cerebrocerebellum ® Dentate ® VL of Thalamus ® pre-motor / Nuclei cerebellar (lateral hemisphere) nuclei motor peduncle cortex
Motor Learning Climbing fibers modulate the input from the parallel fibers (granule cells
–original input from mossy fibers)
Four Types of Disturbances 1. Delay in the initiation and termination of movements 2. Terminal tremor (intention tremor, tremor at end of movement) 3. Disorders in temporal coordination of certain movements involving multiple joints 4. Disorders of spatial coordination of hand and fingers
Cerebellar Diseases Signs & Symptoms 1. Hypotonia – diminished resistance to passive limb displacement 2. Ataxia – abnormality in the execution of movement Delay in initiating Error in range or force of movement Abnormality in rate and regularity of movement 3. Action tremor (intention tremor) –tremor due to moving; most pronounced at end of movement
More on Cerebellar Lesions · Disorders in the limb ipsilateral to the lesion Two decussations: Superior cerebellar peduncle Corticospinal or rubrospinal tract
· Lesions of Vermis or Fastigial nuclei ® disturbances in axial and truncal control Tremors in trunk when standing and sitting / patient has tendency to fall backwards / wide gait / sway
· Lesions of Intermediate cerebellum or Interposed nuclei ® disturbances in limb movements & action tremors
· Lesions of lateral hemisphere (cerebrocerebellum) ® delays in initiating movement loss of fine dexterity / Trouble with multi-joint movement
· Most severe disturbances occur due to lesion of Superior Cerebellar Peduncle (most of output goes through it)
· Unable to make small adjustments to fine tune movement (errors in planning and execution)
· Sometimes accompanied by: motor distrubances in extra-ocular eye movements / problems with speech
· Symptoms of cerebellar disease can improve with time (if underlying disease doesn’t make things worse)
Clues - relapsing and remitting –demyelination associated diseases like MS - sudden onset –vascular - slowly progressive –neoplastic or neurodegenerative
Basal Ganglia Cerebellum INPUT: entire cerebral cortex cortex related to sensory motor functions
OUTPUT: premotor cortex / prefrontal association cortex premotor and motor cortex
Connections: Brainstem very few yes Spinal cord no yes
Function: higher cognitive aspects of motor control regulates execution of movement planning & execution of complex motor strategies CLINICAL CORRELATION: BASAL GANGLIA AND CEREBELLUM
Basal Ganglia vs. Cerebellum Basal Ganglia ® rhythmic tremor (like Parkinson’s) Cerebellum ® dis-rhythmic tremor (like Huntington’s)
Parkinson’s - loss of dopamine pathway - D1 and D2 involve motor pathway / D3, D4, & D5 involve psychic phemonema
Anti-psychotic Drugs can cause Parkinson’s symptoms - anti-psychotic drugs cause bilateral deficits - Parkinson’s is usually unilateral - Anti-psychotic drugs can precipitate Parkinson’s by bringing 70% loss of substantia nigra over edge to 80%
Other diseases vs. Parkinson’s Benign Essential Tremor (familial tremor) - tremor at rest & with movement; both at same frequency - NO rigidity, NO akinesia, NO postural instability
Peripheral Neuropathy - postural instability with eyes closed (+ Romberg sign) due to loss of proprioceptive input - NO retropulsion (Parkinson’s patients stumble backwards when tapped on the shoulders with eyes open)
Shy- Dregor (multiple systems atrophy) - stand up ® pass out - progressive autonomic disease - degeneration of downstream circuitry of dopamine pathways
Olivopontocerebellar Atrophy - postural instability –stagger - atrophied cerebellum - cerebellum and pontine input lost
Progressive Supranuclear Palsy - lose superior input - substantial visual loss - loss of vertical and horizontal eye movements in that order
Cortical Basilar Ganglionic Degeneration - unilateral atrophy of cortex - prominent sensory loss (only minor sensory loss in Parkinson’s)
Normal Pressure Hydrocephaly - unilateral deficit in leg (Parkinson’s is usually in arm) - Bilateral Babinski / Hyperreflexia - TRIAD Urinary incontinence Parkinson’s gait Dementia
Carbon Monoxide poisoning can mimic Parkinson’s
Treatments for Parkinson’s - Levodopa – precursor for dopamine - Dopamine agonist – stimulate dopamine receptor EEG
General - Most bioelectrical recordings are of alternating currents - Frequency Ranges Delta – 1-3 Hz Theta – 4-7 Hz Alpha – 8-13 Hz (detected at back of brain when person is relaxed) Beta - >13 Hz - Scalp EEG only detects cortical neurons close to the skull (does not detect the activity of deeper structures) - Signal is amplified by a million fold - Medical states effect EEG recordings Before dialysis – slow waves; wave activity more dynamic after dialysis Hyponatremia – low Na+ affects electrical transmission - EEG not specific to etiology
Uses - Define start of Sleep Amplitude smaller Frequency faster K complexes and sleep spindles - Look at comatose state - Indicate if patient is brain dead - Categorize Seizures
Evoked Potential EEG - Stimulus and a time locked response - Visual, auditory, or somatosensory evoked responses
Magnetic Encephalogram ( MEG) - Images clear -magnetic fields are not attenuated through fat or bone - Cannot localize well - No clinical application yet
Depth EEG - Electrodes placed in brainE - Use Depth EEG to localize region of brain that is causing seizures - CT scan used to help place EEG electrode in brain - Placements: Occipital cortex ® Uncus (hot bed for start of epileptic seizures) Temporal lobe Orbitofrontal area - Look for epileptic spikes
Epileptic Seizure on EEG - 3 stages Beginning (excitatory event –excitatory neurotransmitters) Evolution (fast activity running on top of slow activity) End (seizure is stopped by endogenous mechanisms of the brain –GABA used) - Seizures do not stop due to neuronal exhaustion - People who die from static seizures (seizures for days) die from complications not neuronal exhaustion DEMYELINATION AND LIPID STORAGE DISEASES
Oligodendroglia - Found in CNS - Syntheses and maintenance of myelin - Can produce 3x its weight in myelin for up to 40 different axonal segments
Myelin - High resistance, low capacitance insulator - Reduces conduction time (increases conduction efficiency) - Nodes of Ranvier areas of low resistance location of Na+ channels allow for saltatory conduction - Internodal regions have fast K+ channels - High lipid : protein ratio 75% lipid galactolipids – 30% (galactocerebrosides & sulfatides) 25% protein proteolipid protein basic protein
Classification of Myelin Disorders · Class I: Acquired Allergic/Inflammatory & Infectious Diseases - Multiple Sclerosis - Progressive Multifocal Leucoencephalopathy
· Class II: Hereditary Metabolic Diseases - Metachromatic Leucodystrophy - Krabbe’s Disease (globoid cell leucodystrophy) - Pelizaeus-Merzbacher
· Class III: Acquired Toxic-Metabolic Diseases
· Class IV: Nutritional Diseases - Vitamin B12 deficiency
· Class V: Traumatic Diseases - edema/compression
Multiple Sclerosis
Description: Class I Demyelinating
Prevelance: 30/100,000 Higher: young adults & northeast
Clinical: Multiphasic course of exacerbation & remission
Pathology: Plaques (areas of focal demyelination -loss of oligodendroglia & gliosis ) Sparing of axons Perivascular Infiltration : lesions around blood vessels invaded by T cells, B cells & macrophages Synthesis of oligoclonal IgG by plasma cells Loss of supressor/inducer T cells Progressive Multifocal Leuconencephalopathy
Description: Class I Demyelinating
Prevalence: Rare Re-emerging because of HIV
Clinical: Dementia ® Coma ® Death (3–12 months)
Pathology: Multiple foci of demyelination that progressively increase in size and number NONinflammatory Oligodendroglia and myelin are absent from lesions Oligodendroglia contain PAPOVA VIRUS (JC VIRUS) INCLUSIONS
Metachromatic Leucodystrophy
Description: Class II –autosomal recessive Dysmyelinating
Prevalence: Rare, 1/40,000
Clinical: Peripheral and central white matter disorder Age of onset ® 12-18 months Baby starts to developmentally regress
Pathology: abnormal metachromatic staining myelin degradation products Extensive involvement of entire white matter Inclusions of accumulated sulfatides Mutant ARYLSULFATASE A present but no activity (normally catabolizes sulfatides) Newly formed myelin unstable due to sulfatides
Krabbe’s Disease
Description: Class II –autosomal recessive Dysmyelinating
Prevalence: Rare
Clinical: degenerative white matter disease Presents between 3-6 months of age Irritability, spasticity, hypersensitivity to stimuli, tonic spasms
Pathology: Marked reduction in white matter Myelin, oligodendroglia, & axon - lost Extensive gliosis Globoid cells with inclusions present Accumulation of Galactocerebrosides Deficiency in GALACTOSYL-BETA GALACTOSIDASE
Pelizaeus-Merzbacher
Description: Class II –X-linked recessive Dysmyelinating
Prevalence: Males only, rare
Clinical: slow and progressive, can last 30 years Nystagmus, head tremor, cerebellar ataxia, and intention tremor
Pathology: failure to form myelin Loss of oligodendroglia Almost total depletion of nyelin Sparing of axons Mutation in gene encoding PROTEOLIPID PROTEIN
Tay-Sachs Disease
Description: Class II –autosomal recessive Dysmyelinating
Prevalence: Non-Jewish 1/360K Jewish 1/3600
Clinical: 6 months old ® infant listless, hypotonic, & quiet Lag in pyschomotor development Later, infant cannot stand or walk
Pathology: lipid storage disease Initial gray matter degeneration White matter degeneration Progressive macular degeneration (cherry red macula) Loss of neurons Universal distention of neurons by storage inclusions (gangliosides GM2) Enzyme defiency: HEXOSAMINIDASE A (catobolizes GM2) Reactive gliosis Reduction of white matter
Prefrontal cortex: important in behavorial choices & inhibiting inappropriate behavior Cingulate cortex: involved with intense emotional response Hippocampus: important in learning, (long-term) memory, and spatial location Nucleus Accumbens: activated by movement and stressors
Damage to Limbic System
Korsakoffs Syndrome: seen in chronic alcoholism / due to Vitamin B1 deficiency / destruction of MD nucleus of thalamus & mamillary bodies / memory loss
Kluver-Bucy Syndrome: damage to temporal lobe (esp. amygdala) / oral fixation & hypersexuality / taming of wild animals
Septal Rage: lesion to Septum / violent behavior / increased blood pressure & heart rate / sympathetic stimulation / dis-inhibition of hypothalamic structures
Sham Rage: decorticate transection (rostral to hypothalamus) –decerebrate is caudal to hypothalamus and does not produce rage Role of Hypothalamus
Pituitary gland · Adenohypophysis - neurons in arcuate nucleus (infundibulum) of hypothalamus produce hypothalamic releasing factors - hypothalamic releasing factors ® portal vein system to act on trophic cells in adenohypophysis - trophic cells release their hormone into the portal vessels - Indirect release of hormones · Neurohypophysis - projections from paraventricular & supraoptic nuclei send axons down to neurohypophysis - these projections produce Vasopressin (ADH) reabsorb water in collecting duct of kidney stimulates thirst - these projections produce Oxytocin neuronal-hormonal reflex – suckling ® milk ejection - these projections discharge their peptide directly into circulation of neurohypophysis
Other Functions · Anterior Hypothalmus - Heat Sensitive Neurons - Damage causes Hyperthermia –uncontrollable rise in body temperature - Cannot activate compensatory mechanisms like sweating - Cannot sleep –continuously active - Excites parasympathetic nervous system
· Posterior Hypothalamus - Histamine Neurons - Damage causes body temperature to drop - Cannot activate compensatory mechanisms like shivering - Comatose - Excites sympathetic nervous system
· Ventromedial Hypothalamus - stimulation inhibits urge to eat (satiety center) - lesions causes weight gain - raises set point - interrupts fibers of medial forebrain bundle (convey carrying qualities of food) - hypersensitive to sweet tastes
· Lateral Hypothalamus - stimulation induces urge to eat - lesions cause weight loss - reduces set point - interrupts fibers of medial forebrain bundle (convey carrying qualities of food) - become very finicky
Stimuli that Hypothalamic neurons respond to in order to regulate weight - fatty acids - glucose - body temp (hot:eat more) - orexigenic peptides –stimulate eating neuropeptide y (most potent) orexin - peptides that inhibit eating CCK –paraventricular nucleus & arcuate nucleus Leptin –produced by adipose cells, bind in arcuate & ventromedial hypothalamus
Thirst Regulation Blood osmolality – hypothalamic mechanisms in paraventricular nucleus release ADH/vasopressin ® thirst ¯ Blood volume ® renin (kidney) ® angiotensin ® medial preoptic region of hypothalamus ® thirst
Hypothalamic Neurons Participate in Four Classes of Reflexes 1. neural – neural
2. neural – humoral milk –ejection reflex
3. humoral – neural steroids released from adrenal gland have direct affects on areas of brain
4. humoral – humoral blood loss ® renin ® angiotensin ® activates neurons in medial preoptic area ® release of ADH, thirst LEARNING AND MEMORY
Non-Associative Learning Habituation - decrease in response to a repeated stimuli
Sensitization - increased response to adverse stimulus - pathway receptors bound to GTP proteins adenylyl cyclase ® increased cAMP ® phosphorylates kinases phosphorylate K+ channels ® K+ channels stays open ® prolong action potential more Ca++ is allowed through ® more neurotransmitter is released - long term memory by sensitization is thought to be due to synaptic strength
Long Term Memory - changes in synaptic strength - enhanced transmitter release - cAMP ®phoshorylate transcriptional proteins (CREB proteins) ® increased growth & activation
Short Term Memory - involves covalent modification of proteins
Associative Learning Classical Conditioning - association of 2 paired stimuli - conditioned response Ca++ channel is open
Reflexive Learning – memory learned through repetition Declarative Learning – uses past memory
Four Generalizations about Neural basis of Memory 1. Memory has stages & is constantly changing 2. Long term memory is represented by physical changes in synaptic connections in the brain 3. Memory is stored thoughout the brain and physical changes are represented thoughout the brain 4. Declarative and reflexive memory involve different circuits, memory from different parts of the brain
Long Term Potentiation (LTP) - located in hippocampus and cortes - important for spatial memory - results from a brief high frequency train of stimuli
AGING AND DEMENTIA
Natural changes with Aging - motor coordination - sleep patterns - balance difficulties - muscle weakness - loss of neurons ® decrease in brain weight - reduction in neurotransmitter enzymes - reduction in receptor density
Decline in mental function is not a consequence of aging
Dementia - progressive decline of mental function - diffuse; affects all areas of the brain - at least one of the following symptoms impairment of judgement impairment of abstract thinking other disturbances of higher cortical functioning personality change
Alzheimers
Senile plaques Neurofibrillary tangles – twisted filaments in cells Cortical atrophy Loss of neurons Granulovacular degeneration Nucleus Basalis Meynert Diagonal band of Broca Locus Coereleus Beta –amyloid peptide (core of plaques)
Parameters for Alzheimer’s Disease 1. documented progressive memory loss via mental status tests over 6 months to a year 2. Cat scan or MRI showing cortical atrophy (no tumors or strokes) 3. Blood work to make sure everything else is normal (thyroid and vit. B12)
SLEEP
NREM sleep - non rapid eye movement - idling brain in moveable body - 4 stages Stage 1: transition from wakefulness to sleep – when consciousness is lost Stage 2: deeper stage of sleep (most NREM sleep occurs here Stage3 & 4 : high amplitude Delta waves difficult to arouse someone from these stages –confused arousal only occur in first 1/3 of night sleep walking night terrors bed wetting - very homeostatic - body temp, heart rate, & response to pCO2 all respond as if person is awake
REM sleep - active brain in paralyzed body - EEG shows low voltage, fast activity pattern - nocturnal myoclonus –twitching in sleep - occurs about every 90 minutes of sleep - longer episodes at end of sleep - NOT homeostatic Body temperature is not regulated (poikilothermic) Response to pCO2 is depressed O2 consumption is high - Children & babies have REM sleep (premature babies have even more) / decreases to adult pattern at » age 5 - REM sleep is necessary for nervous system development Altricial (immature born) – more REM sleep as babies ® declines as reaches adulthood Precocial (mature born) – less REM ® amount stays constant throughout life - When someone is deprived of sleep, when they finally sleep, they fall into REM sleep immediately
Sleep Distribution NREM – 75% Stage 1: 5% Stage 2: 45% (largest amount of time spent in stage 2) Stage 3: 12% Stage 4: 13% REM – 25%
Outcome of Sleep Deprivation - death - skin lesions - increased food & water intake - increased energy expenditure - decreased weight - decreased body temperature
Sleep Better - stick to a regular schedule - be consistent with naps - exercise regularly in morning or early afternoon - no caffeine after 4pm - avoid alcohol after dinner - do not take sleeping pills more than four weeks - room temperature - relax before bed - do not eat heavily before bed - even if you can’t sleep, preserve your usual 24 hour cycles of activity
Narcolepsy 1. excessive sleepiness 2. cataplexy – episodes of muscle weakness 3. hallucinations 4. sleep paralysis
sleep apnea most common cause of hypersomnolence narcolepsy #2
narcoleptic goes right into REM bypassing NREM when narcoleptic gets sleeping goes into full blown REM attack (threshold for REM sleep is lower) NEUROPHYSIOLOGY and NEUROPHARMACOLOGY of SLEEP
Transections
Cerveau Isole Transection (CI) - transection between superior colliculus and inferior colliculus - disrupts histamine neurons in the mammillary area - results in constant slow wave sleep - separates the red nucleus from the vestibular nuclei - exhibit decerebrate rigidity (extensor rigidity) - can also see Sham rage due to loss of inhibition (disinhibition) of hypothalamic mechanisms - \ mechanism posterior to transection must be the driving force for arousal system
Mid-pontine Transection (MP) - results in permanent insomnia (animal stays awake until it dies) - \ arousal system must be between the CI transection and the MP transection - this area must have potent arousal system responsible for the fast low voltage activity of aroused states & REM
Mid-medullary Transection (MM) - produces constant slow wave sleep like CI
Encephale isole Transection (EI) - transection between caudal medulla and spinal cord - results in normal sleep cycles - \ spinal cord is not responsible for arousal system
posterior hypothalamic lesion: permanent slow wave sleep anterior hypothalamic lesion: permanent insomnia
summary of transections - CNS anterior to spinal cord contains all structures necessary for normal sleep cycling - Forebrain and Midbrain alone cannot produce “activated” states (waking & REM sleep) - Structures that produce activated states reside in Rostral Pons (Raphe, locus coeruleus, lateral dorsal tegmental nucleus) - a secondary SWS inducing structure resides in the anterior medulla (probably solitary nucleus inhibiting arousal system in rostral pons)
Specific Nuclei involved in Sleep State Regulation
Nuclei of the Reticular Activating System - Dorsal & Median Raphe (synthesize 5-HT) - Locus Coeruleus (synthesizes NE) - Lateral Dorsal Tegmental (LDT) nucleus & Parabrachial neurons (synthesize ACh) (LDT is a major generator of arousal states) - Medial Pontine Gigantocellular (FTG) neurons (cholinoceptive: transmitter unknown)
Hypothalamic Nuclei - tuberomammillary neurons (synthesize Histamine) - ventrolateral preoptic (VLPO) neurons –SWS producer found in anterior hypothalamus (synthesize GABA) - Suprachiasmatic (SCN) neurons (synthesize GABA)
Medullary Region - solitary nucleus (transmitter unknown)
Models of Arousal State Generation Hobson-McCarley
VLPO Model
Pharmacological alteration of Sleep & Arousal
Enchancement of SWS Work at GABA receptor sites /drawbacks: daytime sleepiness & REM sleep suppression) - alcohol - barbiturates - benzodiazepines Others - Antihistamines (H3 agonists / H1 antagonists) - Adenosine A1 agonists - Alpha-1 NE antagonists, Alpha-2 NE agonists
Enhancement of Waking state - Caffeine & A1 blockade - H3 histamine antagonist - Alpha 1- NE agonists, alpha-2 antagonists, NE uptake blockers, NE releasers (ex. amphetamine) - Nicotine
New Approaches in Drug Therapy - highly selective receptor subtype ligands (GABA, 5-HT, ACh) - small molecule mimicry of peptides (somatostatin, VIP) - biological clock – selective agents (modafanil – arousal generating drug)
Electrophysiological Signatures of Sleep Related Neurons
Brains: highest activity during wake state and REM sleep
Most Aminergic Neurons (5-HT, NE, Histamine): steady decline in firing rate from Wake ® SWS ® REM sleep
Dopamine Neurons: steady firing rate across arousal states
Cholinergic Neurons (LDT & Parabrachial area): most active in REM sleep
VLPO neurons (hypothalamus): most active in SWS Conclusions
- small set of neurons generate arousal states
- waking state is generated by specific cell groups of the reticular activating system which project to forebrain areas such as the thalamus and cortex. Those neurons include raphe (5-HT) & locus coeruleus (NE). Histamine neurons of the hypothalamus contribute to behavioral arousal.
- REM sleep and REM sleep signs (desynchronized EEG, PGO waves, hippocampal theta) are specifically generated by pontine cholinergic neurons, with some involvement of cholinoceptive neurons of the pons (FTG). Certain peptides (VIP, somatostatin) are colocalized with ACh in cholinergic neurons and probably contribute to generation of REM sleep.
- Small group of hypothalamic GABA neurons (VLPO) may be critical to the generation of SWS. SWS may refelct the engagement of wide areas of GABAergic neuropil in the forebrain or the ubiquitous release of adenosine in forebrain areas. HIGHER ORDER COGNITIVE and AFFECTIVE FUNCTIONS
Association Cortices - responsible for coordinating events in regions of the brain endowed with motor & sensory function 1. Prefrontal association cortex –complex motor functions 2. Parietal-temporal-occipital cortex –integration of sensory function and language 3. Limbic cortex –important for motivation, memory, and emotion
Prefrontal Association Area - located anterior to the premotor area (which is anterior to the primary motor area of frontal lobe) 1. Dorsolateral cortex –prefrontal association cortex proper 2. Orbitofrontal cortex
Limbic Association Cortex 1. Orbitofrontal cortex -emotional 2. Cingulate gyrus -emotional 3. Some of Temporal lobe –memory
Left/Right - majority of right-handed people are left parietal lobe dominant - if a patient’s dominant parietal lobe is damaged, symptoms include: aphasia (language disorder) agnosia (inability to perceive sensations through functioning sensory channels) astereoagnosia (inability to recognize the form of a held object with somatosensory function still intact) - Gertmannis Syndrome –insult to inferior left parietal cortex Left-right confusion Finger Agnosia (naming the finger that is touched is difficult) Dysgraphia (difficulty writing despite intact motor and sensory systems Dyscalculia (inability to perform mathematical operations) - What percentage of right handed subjects have left hemisphere speech? 96%
Wernicke’s Aphasia - Wernicke’s area = Brodmann’s area 22 - difficulty understanding speech and writing - can’t comprehend what they are saying or what they are being told - seem to speak fluently BUT may use wrong words, make up words, and add extra syllables (gibberish)
Broca’s Aphasia - Broca’s area = Brodmann’s 44 & 45 - Patients can comprehend normally but cannot create language - Slow labored speech ® muteness - Aware of errors that they make b/c can comprehend spoken and written language - Found near motor cortex, so hemiparesis and homonymous hemianopsia almost always present too
Aprosodia = disturbances in affective components of language associated with damage to the right hemisphere
Alexia = cessation of patient’s ability to read Agraphia = cessation of the patient’s ability to write
Alexia with agraphia results from lesion in the angular or supramarginal gyrus of the parietal-temporal-occipital association cortex. Patients cannot connect letters with sounds indicated by the letters.
Alexia without agraphia: cannot read but can derive meaning from words spelled aloud and can copy words About half of these patients have color agnosia (can match colors but not name them) or achromotopsia (don’t perceive color / see entirely in grayish hues) DISORDERS OF THOUGHT
Grouped by Affected Mental Faculty - mood - intelligence - development - thinking
Kraeplin’s Approach - signs of the disease - course of the disease - outcome of the disease
Diagnostic Criteria for Classifying Mental Illness - identifiable group of signs symptoms - clustering of signs and symptoms to form a SYNDROME - validation of the proposed syndromeby one of three commonly used independent measures natural history: course and outcome (clinical course & outcome) response to specific treatment causality (etiology and pathogen / anatomical or molecular defect)
Schizophrenia - 1% incidence worldwide - Kraeplin: Dementia Praecox –early deterioration of intellect, progressive course without remission - Eugene Bleuler observed adult onset patients as well as remissions - Splitting of the cognitive and emotional sides of the personality - Characteristics: Hallucinations Delusions Incoherent thinking Disordered memory - psychotic episodes – not specific for schizophrenia preceded by prodromal signs isolation and withdrawal odd behavior poor hygiene blunted affect positive symptoms – presence of distinctive behaviors during psychotic episodes hallucinations delusions bizarre behavior followed by residual symptoms (negative symptoms –absence of normal interpersonal & social functions) absence of normal social/interpersonal function poverty of speech isolation poor attention flat affect eccentric behavior these negative symptoms are the most unmanageable part of the illness
DSM-III-R - diagnostic and statistical manual of the American Psychiatric association - objective vigorous criteria - inclusive & exclusive criteria
Modern Diagnostic Criteria - continuously ill for at least 6 months - at least 1 psychotic episode, followed by a residual phase - catatonic (mutism and abnormal posturing) and paranoid subtypes based on psychotic phase - diagnosis must exclude a mood disorder or drug induced pychosis - prognosis –poor / after each relapse, social function deteriorates & patient is more withdrawn
Genetics - 1 % population - 30-50% in monozygotic twins - 15% in dizygotic / siblings
Anatomical Changes to Brain - enlarged lateral & third venticles due to loss of brain tissue - widening in sulci, atrophy of prefrontal cortical tissue
Anti-psychotic Drugs - Reserpine: depletes endogenous monoamines (Dopamine, Serotonin, & NE) - Typical anti-psychotic: related to anti-histamine agents from 1950’s / improved thought disorder, blunted affect, withdrawal, & hallucinations / not as good for negative symptoms - Atypical anti-psychotic: slightly better at treating negative symptoms - Maintenance therapy reduces rate of relapse
Anti-psychotic Drugs Block Dopamine receptors - also block serotinin, alpha, & muscarinic receptors - cause Parkinsonism via caudate D2 receptors - cortical & limibic D2, D3, & D4 –therapeutic affects
Excess of Dopamine Neurotransmitters - hypothesis: dopamine neurotransmission underlies schizophrenia - binding affinity of DA receptors correlate well with therapeutic potency - L-DOPA, cocaine (blocks re-uptake), amphetamines – produce psychosis resembling paranoid schizophrenia
Dopamine System - nigrostriatal - mesolimbic – modulates flow to disturbed corticolimbic areas –increased activity ® positive symptoms - mesocortical – decreased activity implicated in negative symptoms
Non–dopamine Abnormalities - delayed response to DA blockers due to secondary consequences gene induction decreased DA cell activity several other transmitter/receptor systems may be involved SCHIZOPHRENIA
Anatomical Studies · Basal Ganglia - Pallidal volume is reduced in catatonic schizophrenia - Striatal microneurons are reduced in diameter - Bilateral increase in striatal volumes seen with chronic use of anti-psychotic drugs (left>right) - Anti-psychotic drugs block D2 receptor ® can lead to Parkinsonian symptoms
· Thalamus - significant reduction of neurons in mediodorsal nucleus of thalamus - reduction of periventicular gray matter around 3rd ventricle (reason for enlargement of 3rd ventricle) - thalamus dysfunction is associated with negative symptoms of schizophrenia
· Cortex - abnormalities seen in cingulate, frontal, and hippocampal gyrus - asymmetry seen in temporal lobe (left temporal lobe enlargement) - asymmetry seen in Sylvian fissure (fissure is elongated) - Cortical atrophy in thickness and paucity of neurons - Correlates with negative symptoms and cognitive deficits
· Limbic Structures - reduced cell number and size in hippocampus, parahippocampus, and entorhinal cortex - reduced volume in the hippocampus, parahippocampus, and amygdala - reduced volume of white matter in hippocampus and parahippocampal gyrus - hippocampal, entorhinal, and cingulate cortex have disorganized cell arrangement (more vertical axons in cingulate gyrus) - left temporal horn enlargement - increased incidence of cavum septi pellucidi - limbic system dsyfunctions are correlated with abnormal integrative and associative brain functions (drives, cognition, and emotion)
· Brain Size and Weight - inconsistent studies show that brain weight can decrease by 5-8% and length by 4%
· Glial cells - no association between gliosis and anatomical abnormalities associated with schizophrenia
· Ventricular Enlargement - lateral and 3rd ventricular enlargement - associated with negative symptoms
Neurochemical Studies · Dopamine (DA) - cause of schizophrenia unknown - dopamine hypothesis: over-activity of the mesolimbic, mesocorical, and nigrostriatal systems involving DA neurons - Receptors involved: D2 receptors: in nigrostriatal pathway (basal ganglia) and limbic systems (nucleus accumbens) D2, D3, D4, receptors are inhibitory D1 & D5 are stimulatory - increased number of D2 receptors in basal ganglia & nucleus accumbens –may be result of medication - low CSF HVA (homovanilic acid) correlates with negative symptoms - increased [DA] in nucleus accumbens & caudate nucleus (maybe DA turnover) · Norepinephrine (NE) - increased level of NE - associated with hyperarousal & paranoid symptoms
· Serotonin (5-HT) - anti-psychotic drugs block the 5-HT2 receptor - levels of serotonin involved in schizophrenia differ from one brain region to another - correlates with mannerism an posture deficits
· Metabolic Enzymes - decreased MAO enzymes - decreased Dopamine-b-Hydroxylase in paranoid schizophrenics
· Other Neurotransmitter / Neuroreceptor systems - vasopressin: 40% decrease - naloxone: opiate antagonist (decreases schizophrenic symptoms) - CCK decrease in hippocampus - Somatostatin decrease
Neuroimaging CT & MRI - 3rd & lateral ventricular enlargement - cortical atrophy (although no direct evidence seen of active degeneration) - degenerated areas seen in the earliest stages of illness - most severe degeneration in patients with negative symptoms Functional Studies: AT REST - blood flow decreased in frontal lobe - increased in posterior lobe SPATIAL COGNITIVE TASK - left hemispheric blood flow (normal flow to the right) - anti-psychotic drugs increase right hemisphere blood flow PET, CT - low metabolic rates seen in basal ganglia - attention deficit schizophrenics show low metabolism in right superior frontal gyrus - reduced activity most marked in frontal lobes, basal ganglia, and temporolimbic systems
Proposed Etiologies Genetic vs. Environmental - stress-diathesis model: person can’t handle stress and develops schizophrenia - vulnerability model: genetic system not capable of handling stress - oligogenic hypothesis: few genes involved in schizophrenia development - family and twin studies: 1% in general population 5% relatives 15% sibs 37% if both parents 50% identical twins Fetal Neural Development - type A2 influenza infection in 2nd trimester may contribute to neuronal development patterns going wrong - disruptions of neuronal generation, migration, and organization - destruction of pre-existing neurons
DEPRESSION
Nonfunctional Depression - depression that has an identifiable physiologic cause - dysphoric symptoms are secondary to a diagnosable medical condition
Functional depression - has no identifiable organic disease - types of functional depression Dystimia - low grade, chronic dysphoria - patient cannot remember when they became depressed - patent never returns to baseline Major Depression - relapsing - patient returns to normal baseline
MAJOR DEPRESSION
Symptoms and Diagnosing - persistent and unchanged by encouragement - weight loss or gain - insomnia (90%) or hypersomnia (10%) - fatigue - feelings of guilt - inability to concentrate - suicidal thoughts - feeling down or isolated - generalized pessimistic view - symptoms must last for 2 weeks before diagnosis can be made
**major depression cannot be diagnosed if it is secondary to another medical condition
Complications - disability - drug abuse and dependence - suicide - occupational and marital problems
Epidemiology - 6% of population will have one episode in their lifetime - women 2X more likely - untreated symptoms last 6-9 months - incidence increases with age
80% respond to treatment 50% relapse 15% commit suicide
Neurotransmitters - decrease in the amounts of NE & 5-HT - \ treatments either 1. stimulate release 2. decrease re-uptake 3. inhibit MAO or COMT (these break down neurotransmitters so we want to stop them) (schizophrenia patients show decreased MAO & \increased neurotransmitters ® opposite problem) Neuroendocrine Abnormalities - Hyperactivity of hypothalamic pituitary axis seen in 50% of patients Blunting of TSH response to TRH Blunting of Gh response to alpha-2 receptor agonists
Sleep Disturbances 3 types of insomnia - Initial Insomnia: takes hours to get to sleep - Middle Insomnia: waking in the middle of the night - Early Morning Awakening: correlates with hypothalamic pituitary axis hyperactivation (cortisol peaks at 4am)
Decreased sleep latency REM latency Increased REM density and frequency of awakenings Anti-depressants suppress REM REM rebound is a consequence of anti-depressant discontinuation sleep deprivation may treat patient next day they relapse
Imaging Studies - resting studies decreased activity in the left frontal lobe (Brodmann’s areas 9, 10, 11) - active studies normal: left frontal cortex, cingulate gyrus, amygdala depressed: left prefrontal cortex, blunting in cingulate, blunting in amygdala
Example of Non-functional Depression Post-stroke depression Depends on location of lesion Closer lesion is to the left prefrontal lobe the more likely the patient is to show symptoms of depression
Bipolar Disorder - effects women and men equally - prevalence 1% - depression phase is similar to Major Depression - Manic phase: everything is accelerated (unable to sleep, grandiose delusions) - Treatment different than for major depression Lithium carbonate for acute and prophylactic treatments
Post-partem Depression - Treated the same as Major Depression
Anxiety Disorders - adaptive anxiety - Pathological anxiety - Panic disorders: bilateral abnormality in the parahippocampal area - Generalized anxiety disorder: GABA-A receptor complex
NEURAL MECHANISMS of DRUG REINFORCEMENT and ADDICTION
Society - $100 billion –alcohol abuse - $65 billion –tobacco use - > 500,000 deaths annually attributed to alcohol and tobacco use
Drug Reinforcement: behavior changes occur in response to acute exposure to a reinforcing drug Drug Reinforcers: drugs that increase the probability of drug seeking behavior upon drug exposure
Rapid and Powerful association: directly modulate preexisting brain reinforcement systems
Drug Addiction: a biological process - effects of repeated exposure to a biological agent (drug) on a biological substrate (brain) over time - long term alteration of neuronal circuits lead to the complex behaviors of craving, dependence, tolerance, etc.
Mesolimbic Dopamine System: a major neural substrate of the reinforcement produced by opiates, nicotine, etc.
Receptor Subtypes: D1 & D2
SEXUAL DIFFERENTIATION
Embryology - basic phenotype is female - XO (Turner’s) –female phenotype - Differentiated sex in mammals is male - process of differentiation requires formation of a testis regression of Mullereian Ducts (MIH) preservation of Wolffian ducts (testosterone)
Genetic Basis - SRY: Sex Determining Region on the Y chomosome ® single gene that codes for the gonad to become a testis - TDF: Testis Determining Factor on the SRY –early switch known for differentiation into a male - Estrogen & Testosterone largely responsible for anatomical, phyiosolgical, and behavioral differentiation - genetic sex (XX or XY) - gonadal Sex (ovary or testis) - Phenotype sex (external genetalia) - exceptions: SRY crosses over during meiosis
Steroid Hormones differentiation - Peripheral Tissues & Brainstem: reduction of *testosterone ® 5a-DHT (dihydrotestosterone) by 5a-reductase - Hypothalamic neurons: by aromatization of *testosterone ® estradiol by aromatase - Estradiol is involved in differentiating the male CNS Protecting the Female Brain from masculinization - a-fetoprotein: binds estrogens (not testosterone) in male and female fetuses females: estrogen is inhibited from entering the CNS males: testosterone gets into CNS and then is converted to estradiol Key to differentiation: Steroid Hormones Steroid ® nuclear ® hormone/receptor ® hormone response ® stimulate/inhibit hormone receptor complex element transcription
*Steroid Hormone Effects
1. Organizational - permanent - sexual phenotype of the CNS is determined by exposure to certain sex hormones
2. Activational - transitory - actions of sex steroids on the mature CNS stimulate certain behaviors and psychological processes
Sexual Dimorphisms Anatomy - CNS anatomical differences relatively minor - Microscopic level: near median eminence (lot of remodeling hear during female cycle - sexual dimorphic nucleus (in rats) located in the preoptic hypothalamus (involved in sexual behavior) - bigger in women splenium of the corpus callosum anterior commissure massa intermedia (more likely present) - bigger in men preoptic area 3rd interstitial nucleus of the anterior hypothalamus
Physiology - liver metabolism –lipoproteins that carry cholesterol - adrenal steroids –diurnal release of cortisol is amplified by the presence of estrogen - autoimmune disease –80% occur in women - reproductive hormones –cyclic vs. tonic (normally male brains can’t release LH in cyclic fashion) - female brains can be masculinized with either testosterone or estrogen - many differences disappear after menopause
Brains of male primates not as differentiated as non-primates - transplanted ovary ovulated regularly - secreted LH in response to estrogen
Gender Identity – what you think you are Gender Role – how you behave (culture) Gender orientation – hetero vs. homosexual
Blah, Blah, Blah - males have greater strength / females have better fine motor skills - boys are more aggressive than girls - girls show childhood play of adult female roles - girls whose mothers were treated with androgenizing progestins during pregnancy show more male behaviors - males segregate paths in their brains more than females do - females tend not to lateralize functions as much as males - female brains are less functionally asymmetrical than male brains (cognitive function) - females better at verbal fluency and interpreting facial expressions than males - males are better at mathematical reasoning and understanding spatial relationships
Disorders of Sexual Differentiation Genetic - aneuploidy – number of chromosomes (up to 7 or 8 sex chromosomes) - mosaicism – two or more cell lines - chimerism – two or more cell lines from different genetic origin: 46, XX / 46, XY - structural errors – short or long chromosomes Enzymatic (steriodogenic) Receptor Abnormalities
Assignment of Sex - baby with ambiguous genitalia - reassignment after 18-24 months can result in serious psychiatric and social consequences
5a- reductase Deficiency - XY individuals are raised as girls until puberty - At puberty, they become phenotypic males
Androgen Insensitivity Syndrome – Testicular Feminization - absence of androgen receptors lack of androgen receptors in XY phenotype phenotypic females (estrogen from testes/adrenal) have testes (MIH, Testosterone) no Mullerian derivative (uterus or oviducts) because of MIH no Wolffian derivatives (vas deferens, seminal vesicles) can’t see testosterone
Congentital Adrenal Hyperplasia - cannot convert androstenedione ® cortisol - elevated androgens (no cortisol to inhibit ACTH) - females with this genetic condition are masculinized, and there may be problems with gender identity
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