Lecture 18 - Language PDF

Lecture 18 - Language Speech comprehension : Brain Laterization : the specialization of certain functions to one side of the brain more than the other. left hemisphere & right hemisphere each have dominant roles in specific tasks - verbal behavior is lateralized in the brain (it happens in one spec...

Lecture 18 - Language Speech comprehension : Brain Laterization : the specialization of certain functions to one side of the brain more than the other. left hemisphere & right hemisphere each have dominant roles in specific tasks - verbal behavior is lateralized in the brain (it happens in one specific side) - most language disturbances (like comprehension & expression) that occur after brain damage, occur after damage to the left side of the brain ( left cerebral hemisphere ) * not true for everyone tho * - when do FMRI's (to locate where brain damage causes problems with language) it shows that : the left hemisphere is dominant for language abilities (speech) in 90% of the population (94% of right handed are left hemisphere dominant vs 70% for left handed) functions related to language handled by the non dominant hemisphere (mainly right) : Prosody : Rhythm, tone & emphasis (human speech has a regular rhythm & cadence) - emphasize certain word, change the pitch of words, etc. : the rhythm, emphasis & tone of speech is prosody ( people communicate a lot of info about their emotional state through prosody (by changing the prosody of how we talk) Prosody is typically a function of the right hemisphere ( ppl with left hemisphere damage struggling with language comprehension, can still extract information from prosody) = they can tell the emotional state, if its a question, etc. Recognition of people's voices - ppl recognize familiar voices (even infants can recognize parents voices) - voice recognition is independent of understanding the actual words (ppl with left hemisphere damage that cannot understand language, can still recognize the voices) Phonagnosia : disorder where ppl have difficulty recognizing voices (comes from damage to right cerebral cortex - temporal lobe) Unfamiliar metaphors - unfamiliar metaphors strongly activates right hemisphere - left hemisphere often needed to understand literal meaning of words VS right hemisphere which involves the not literal definition of words (metaphorical language) Damage to the language dominant hemisphere (left) : Aphasia : language deficits following brain damage a disturbance in understanding, repeating or producing meaningful speech - to classify an aphasia : the language problems cant be caused by simple sensory or motor deficits, nor lack of motivation - deficit must be relatively isolated ( patient has to be capable of recognizing when others attempting to communicate, has to be aware of what is happening around them ) Brain Damage in the left cerebral hemisphere (for most ppl) ; Middle Cerebral Artery : (one of the artery's giving blood to the left side of our brain) - Many Aphasia's relate to damage to this artery (clogged, ruptured) - symptoms vary massively according to where exactly cell death occurred middle cerebral artery is largest as it goes around the lateral fissure, between the temporal, frontal & parietal lobes We classify aphasia's into 2 groups ; 1 : FRONT HALF : damage concentrated on front half of the brain, frontal lobe : where were planning our actions, controlling our mouth, hands, its what we use to express ourselves Damage to the frontal lobe causes deficits in speaking & writing Synonyms for this type of aphasia ; - anterior aphasia (front half of the brain) - motor aphasia (problems with movement) - expressive aphasia (problem with expressing yourself) - Broca's aphasia (doctor first described it) - non-fluent aphasia (speech is non-fluent) 2 : BACK HALF : damage concentrated in back half of the brain, temporal & parietal lobes : damage to sensory association cortex, where we process sensory information & try to make sense of it - causes deficits in understanding language Synonyms for this type of aphasia : - posterior aphasia (back half of the brain aphasia) - sensory aphasia (trouble with sensory processing) - receptive aphasia (trouble with receiving the information) - Wernicke's aphasia (after doctor first described it) - fluent aphasia (can speak fluently but words dont make sense) Types of Aphasia : - generally 3 main questions when classifying aphasia's 1 : Does the frontal lobe work? Can they speak fluently? 2 : Do they understand language when you talk to them? Do the words make sense when they speak? Can you comprehend the spoken messages? 3 : Can they repeat after you? Word Comprehension - Understanding Language - we can hear, speak, read or write words (like dog), but what does it mean to understand what the word means? Memories/Knowledge = a web of associations we have with something when we see/hear/smell/etc. a dog, it brings up all the associations we have in our head = this is what it means to understand what a dog is All the associations/information, processed in the association cortices around the brain Association Cortex As soon as you process that information, try to characterize & make sense of it, it happens in the association cortices Somatosensory cortex : What does a dog feel like? Visual association cortex : What does a dog look like? Auditory association cortex : What does a dog sound like? Premotor cortex : What does petting a dog entail? all association cortex distinct regions, but they’re interconnected : see a dog = neurons responsible for perceiving that unit of visual stimuli are interconnected through direct transcortical connections to all other neurons related to the concept of dog Think of dog = All the associations come up as soon as you think of a dog Language Areas parallel network related to language processing right next to primary sensory regions (what we see, hear, feel), theres the neurons responsible for recognizing you’re seeing, hearing, feeling a dog, NEXT to those, theres a language area = see the word dog = goes to an area called the Visual Word Form Area = very different neurons related to processing language than processing the actual information the language is referring to Language Areas = ALL INTERCONNECTED : theres also motor areas right next to it, areas that help us plan out the movement of our fingers & hands to write the words, areas that plan out how to move our mouth to actually speak & communicate verbally There seem to be parallel circuits - think theres an area that is the interface between the concept of smt, & the language representation of it - this interface seems to be surrounding the temporal & parietal lobes (posterior language area) Posterior Language Area : Critical for language comprehension (we can probably see or read the word dog without it, but we wont actually know what the word dog means) This area : the interface where all language information has to come in, then it looks up what it represents & then activates the parallel nodes that correspond to the concept represented The neurons here interconnect throughout the entire brain (through the sensory association cortices that store the representations (meanings) of specific words) = activating dog neurons = activity throughout all sensory association cortices associated with the word dog Damage to Language Comprehension Area (usually unbothered, dont notice it, will talk a lot but its gibberish, a word salad) = Transcortical Sensory Aphasia Transcortical Sensory Aphasia : failure to comprehend the meaning of words and an inability to express thoughts with meaningful speech - they can repeat after people - they can read (even if words have no meaning) - they can write (without understanding words) Located at the posterior part of lateral fissure near the junction of the temporal, occipital & parietal lobes Receptive Fluent Aphasia If you lose posterior Language Area : Normally when we read, we see a pattern of light, interpret that pattern of light as a written word & look up what it means, or we hear sounds, recognize the sounds as a spoken word & look up what it means Language Comprehension area : we pass information through this lookup table to give meaning to things Conduction Aphasia you speak fluently & understand, but you have the inability to repeat the exact words you hear (language comprehension & expression is generally fine tho) Ex. : repeat the word house, the person will say home - these ppl cant repeat nonsense words, will say they didn’t hear its damage between the connections in the front half & back half, it disrupts your ability to use working memory The damage is breaking the connection (a working memory connection between what you hear & what you speak) = without the connection The arcuate fasciculus : the bundle of axons that interconnect the Wernicke's area & the Broca's area - the back & front half of the brain related to language damage = we can still hear words, but there has to be an association with them in our head for us to be able to hold on to them (they cant repeat words that have no meaning) Wernicke's Area Wernicke's area = where sounds are recognized as spoken words Its part of auditory association cortex in the left temporal lobe - being able to hear is one thing (from primary auditory cortex) - recognizing sounds as words is another thing (from Wernicke's area) - then understanding the meaning of a word (word comprehension) is also another thing (from posterior language area) - which overlaps with Wernicke's area Pathway : primary auditory cortex Wernicke's area Posterior language area Pure Word Deafness - (damage in or around Wernicke's area - can hear, just not words) A disorder of auditory word recognition (inability to comprehend or repeat spoken words) Person can hear me, but cannot recognize the words im saying nor repeat them - they cant even hear themselves talk (no longer getting auditory feedback) its just noise - the can hear just fine - interpret non speech sounds fine (know the difference between the doorbell, microwave, dog barking) - can read & write - can read lips - can speak intelligently, but cant recognize words they say solely by listening to themselves, speech starts to resemble a deaf person over time Damage around Wernicke's area & Posterior language area. = a combination of transcortical sensory aphasia & pure word deafness Wernicke's Aphasia both Wernicke's & transcortical sensory aphasia = poor language comprehension - speak fluently, but meaningless speech & use of function words (the, a, about) instead of nouns & verbs = word salad - speech seems natural, filled with intonation & emphasis (prosody), words seem to come easy, yet they are meaningless, typically not fully aware of problem = unbothered by it - Wernicke's aphasia & transcortical sensory aphasia = receptive aphasias (inability to understand words that are heard, read or signed) + fluent aphasias ( ability to speak fluently without conveying much meaning) DIFFERENCES Wernicke's Aphasia vs Trascortical Sensory Aphasia - cannot repeat what is said to them - repeat what is said to them - cannot recognize spoken words - can process + recognize spoken - both word recognition & word words comprehension are impaired - word recognition yes, but no word - damage = Wernicke's area + posterior comprehension language area - damage to posterior language area Disorders of reading Reading = seeing light on a page, recognize it as a written word, and either speak it or look up what it means Visual Word Form Area (VWFA) = the visual association cortex that helps interpret lights coming in your eye as written words (written word perception) Damage to VWFA = you cant read Pure Alexia - a vision problem where you’re not making sense of the visual information damage to VWFA in visual association cortex = disrupts ability to perceive written words - VWFA is in left fusiform gyrus of left hemisphere - damage = dont recognize words - damage to VWFA = pure alexia/pure word blindness, they cannot recognize written words - they can write just fine, but then cannot read what they write (damage to ventral visual stream) Language usually localized in left hemisphere, which includes VWFA : recognizing written words Wernicke's area : understanding word meaning Broca's area : producing speech Primary Visual Cortex : - if damage occurs in left primary visual cortex (V1) = patient cant see right visual field, but he can still see words in his left visual field & process them with his right primary visual cortex (who will then say its not a face), so it travels back through corpus callosum to the left VWFA - damage to both left primary visual cortex + corpus callosum = pure alexia Reading : involves 2 diff processes ; 1: directly recognizing whole words (Whole Word Reading ) - familiar words sight reading = recognition of whole words 2: sounding out words letter by letter (Phonetic Reading) - unfamiliar words sound reading = recognizing words by sounding out strings of letters Sight Reading : - we immediately recognize words (like car & ear) because we have pattern recognition detectors in our visual system designed to see the patterns - its instantaneous recognition - once we get familiar with a word, we dont sound it out, we see it & recognize it as a whole Disorders of Reading : Dyslexia "faulty reading", these people have difficulty reading - problem is largely hereditary - neural basis not well known Developmental Dyslexia reading difficulties that emerge when children are learning to read - mostly a type of phonological dyslexia - ppl have trouble sounding out the words - they have a big difficulty learning to read - really struggle with reading (difficulty sounding out words reduces ability to learn to read) - some never become fluent readers - have trouble with grammar and spelling - trouble distinguishing the order of sound sequences Surface Dyslexia - sight reading damaged the inability to recognize whole words (whole-word reading is damaged), but phonetic reading still intact - weirdly spelled words are difficult for them to read (since sounding them out hard) Phonological Dyslexia - phonetic reading damaged person can read familiar words but problems with reading unfamiliar words, (deficits in phonetic reading) /sounding out words - people can read using the whole word method (can use sight reading), so only have problems reading unfamiliar words or nonwords, but not familiar words These disorders are both damage to VWFA - making sense of what you’re seeing Selective Disorders of Reading very small strokes create very specific deficits Direct Dyslexia - damage to pathway connecting VWFA to posterior language area deficits in ability to extract meaning from written words - but can read out loud ppl can see words, read and speak them out loud, but not understand what it means Reading we have no clue when language evolved... but we know the history of reading & writing ( the birth of modern history ), when ppl started to write things down - questions surrounding if parts of the brain evolved to allow us to read and write : no we just developed a system that took advantage of the abilities we have when we try & recognize things by sight, we pay attention to what’s constant, when we view an object from diff angles - the most reliable cues to identify visual information is to look at the lines & look at where they meet up (where they meet vertices), so where are the intersections, or the junctions of the lines taking out the corners makes it really hard to make sense of things = visual information becomes very ambiguous - but if you put all the corners & take out middle = our brain easily fills it in processing visual information = grabbing the edges, grabbing the corners to say what this represents so when we write, we have letters that have clear junctions Speech Production Broca's area is a part of motor cortex involved in speech damage to this = disruption in ability to speak Broca's Aphasia disruption in ability to speak - show, laborious, non-fluent speech ppl can understand language, but are not speaking well (damage to front half of the brain) ppl have difficulty expressing themselves verbally ; when they have something to say, they can try to; - move their mouth or express themselves with language but will have trouble saying what they want to = ppl are aware and get frustrated Encompasses 3 semi-distinct issues : (often come together) - articulation problems - agrammatism (use of grammar) - anomia (use of finding the words you want to say) Articulation how you organize the muscles (tongue, lips, jaw, other speech organs controlling breathing) to articulate the word for people to make sense of it, to make speech sounds - cant articulate the words together, dont have great control over the muscles (mumbling), makes it hard for ppl to hear the words you’re saying - can be a sequencing problem (lipstick becomes lickstip), its putting the sounds in the right order, its done in motor planning Agrammatism difficulty in comprehending or using grammatical devices like verb endings or word order (man bit dog) - they just say the essential nouns & verbs, they dont conjugate them - they dont care about word order, they dont extract information from it - if you give them 2 sentences ; (the cow kicked the horse vs the cow got kicked by the horse), they will struggle identifying which is which, putting them in order - they struggle understanding sentences where word order or grammar rules are important - they almost exclusively use content words, but not function words these ppl comprehend speech better than they produce it, theres still some comprehension deficits Anomic Aphasia Anomia difficulty finding the right words to describe object/action/attribute - words are on the tip of their tongue - common symptom of all aphasia's, specifically Broca's Aphasia Anomic Aphasia - relatively mild aphasia : ppl have hard time thinking of the words they want to say they understand words, speak just fine, but describe things in roundabout ways (circumlocution) circumlocution : ppl find alternative ways to say something when they cant think of the most appropriate word Emotions : - exist in the abstract - we can cognitively think about emotions & make our face artificially express specific emotions (when someone tells you to smile & look happy) - this aspect of emotions is processed in the neocortex emotions also exist as a raw reflexive feeling - this aspect is processed in the limbic system (fear typically requires a functional amygdala) sensory inputs diverge into multiple pathways - cerebral cortex : streams of thought - limbic system : streams of feeling Expression of Emotion - facial expressions of emotion are innate, natural, unlearned responses involving complex muscle movements - babies as young as 36 hours display them - we dont just broadcast emotions by facial expressions, we use our body posture, nonverbal sounds (sighs, moans), in complex ways - ppl often show their emotions less when alone 6 classic core emotions 6 emotions that have distinct facial expressions, which ppl can reliably label by a photograph - fear - anger - surprise - disgusted - sad - happiness - we recognize emotions & facial expressions in an automatic manner (automatic, rapid, fairly accurate) recognizing these is a skill Ability vs Motivation - in social situations, some ppl can identify others emotions in a automatic, easy & straightforward way, BUT , this skill does not naturally come to many ppl, which can create a source of frustration for them - expression of emotion transcends cultural & linguistic barriers, its smt we all have and that is innate Sexual Behaviour Circuitry Medial Amygdala: if stimulated, animals can have sex or fight - contains glutamate & GABA GABA neurons stimulated a little : animals try to have sex GABA neurons stimulated 2x more : animals have sex with any animals nearby GABA neurons stimulated 15-20x more : rage overpowered sexual behavior Common Sense Theory perceive emotional event/stimulus -> emotion occurs -> physiological response James Lange Theory perceive emotional event/stimulus -> physiological response -> emotion occurs The Limbic System - cingulate cortex is a large area overlying the corpus callosum - cingulate = encircling - it interconnects many limbic areas of the brain Amygdala : critical for feeling & recognizing emotions - particularly fear Central Nucleus of the Amygdala - regulates emotional responses, fear - lesions of central nucleus reduce/eliminate innate & learned fear responses = they have no fear but, fear of suffocation is normal (even heightened) in ppl with bilateral amygdala damage stimulation of central nucleus : causes fear, anxiety, agitation Recognition of Emotion - Beyond the Amygdala - many brain areas activated when we view emotional faces, including ; - somatosensory cortex - insular cortex - premotor cortex - cingulate cortex but seems to be mostly in the right cerebral hemisphere, that seems involved in recognizing emotions in others Prefrontal Control of Emotions Ventromedial Prefrontal Cortex (vmPFC) involved in regulating expressions of emotions, usually inhibitory influence damage to vmPFC : - weakens behavioral control - impairs decision making ?consequence of emotional dysregulation? Risky Behavior & Impulse control - small correlation between risky behaviour, impulsive. aggression & low serotonin levels monkeys with low serotonin metabolite 5-HIAA (serotonin signaling) - more risk takers, typically died earlier Neurological Problems Stroke - 2nd most frequent cause of death - they’re associated with ischemic heart disease 1 in 4 adults experience a stroke, its related to age after 45, chances increase each decade, reach 1-2% Main Cause ; Atherosclerosis hardening of the arteries, linings of the arteries develop a layer of plaque : deposits of cholesterol, fats, calcium, cellular waste products precursor to heart attacks (myocardial infarction) & strokes - atherosclerosis plaques form in the internal carotid artery, which supplies blood to the cerebral hemispheres the narrowing can be seen with an angiogram, produced by injecting a radiopaque dye into the blood & examining the artery #1 : Ischemic Stroke blockage of a cerebral blood vessel Thrombus : blood clot that forms within a blood vessel, which reduces blood flow to affected area. can directly cause a stroke or pieces break off & form embolus Embolus : piece of tissue dislodges from its site of origin & occludes an artery, can cause a stroke - 87% of strokes are ischemic #2 : Hemorrhagic stroke rupture of a cerebral blood vessel #1 : "clot busting" drugs = thrombolytics - tPA = tissue plasminogen activator #2 : give clot inducing drugs Risk Reduction & Treatment to secure and/or remove occlusions, devices are thread through the vascular system to the site of an occlusion ; 1: Coils (coil retriever) 2: Aspiration Devices 3: Stents (Stent retriever) After Strokes... treatments include ; - drugs that reduce brain swelling & inflammation - physical, speech, and/or occupational therapy - exercise & sensory stimulation (constraint -induced movement therapy) Tumors starts off as 1 cell that starts to divide uncontrollably, if 1 cell goes rogue it can cause problems for the whole body tumor = a mass of cells whose growth is uncontrolled & serves no useful function Non-malignant tumor : noncancerous "benign" tumor. has a distinct border around it and cannot metastasize Malignant tumor : Cancerous "harm-producing" tumor. Lacks distinct border & may metastasize "benign" tumors is false - they can still produce neurological symptoms & threaten life - they damage brain tissue by 2 means : compression & infiltration compression can directly destroy brain tissue, or indirectly by blocking flow of cerebrospinal fluid & intense pressure, cause hydrocephalus (water brain) Types of Brain Tumors Gliomas Glial Cells Tumors : glial cells start to divide uncontrollably - Astrocytoma (astrocytes), Ependymoma (ependymal cells that line ventricles), Medulloblastoma (cells in roof of fourth ventricle), Oligodendrocytoma Meningioma (cells of the meninges) Pituitary Adenoma (hormone secreting cells of the pituitary gland) Neurinoma (Schwann cells or cells of connective tissue covering cranial nerves) Metastatic Carcinoma (depends on the nature of the primary tumor) Angioma (cells of blood vessels) Pinealoma (cells of pineal gland) Infectious Brain Diseases Encephalitis : inflammation of the brain - caused by infection (bacterial or viral), toxic chemicals, allergic reaction Meningitis : inflammation of the meninges - caused by viruses or bacteria - first symptoms are headache & stiff neck Well Known Viruses Polio (acute anterior poliomyelitis) - viral disease that destroys motor neurons of brain & spinal cord, causes paralysis Rabies - viral disease that causes brain damage & death (usually transmitted through bite of an infected animal) Herpes Simplex Virus - virus that normally causes cold sores near the lips or genitals - can enter the brain in rare cases, causing encephalitis & brain damage Traumatic Brain Injury’s Closed-Head Injury (Concussion) - brain comes into violent contact with the inside of the skull (coup) - brain recoils in opposite direction & smashes against skull again (contrecoup) Open-Head Injury - caused by penetrating brain injuries - damaged blood vessels exacerbate the injury - increased pressure in brain due to blood loss & inflammation = more damage In TBI survivors, theres scar tissue, a kind of hard plaque in the area where the neurons died, which increase risk of developing seizures (imbalance of excitatory & inhibitory neurons around the scar tissue) undiagnosed cases of TBI (mTBI) increase risk of developing neurodegenerative diseases Seizure Disorders (seizures have many causes) most common is scarring, which often relates to an injury, stroke, growing tumor, developmental brain abnormality other causes : high fevers (especially in young children), withdrawal from GABA antagonists, like alcohol & barbiturates - most seizures do not involve convulsions of the body - the ones that do : activate neurons in the motor system Convulsion : violent sequence of uncontrollable muscle movements caused by a seizure Partial (focal) Seizure Begins at a focus & remains localized, not generalizing rest of the brain Simple Partial Seizure : does not produce loss of consciousness Complex Partial Seizure : produces loss of consciousness when ppl repeatedly have seizures, seizures tend to recruit more neural tissue & grow, spread around the brain, spreads further & further Generalized Seizure Involves most of the brain (non-localized seizure) - going on everywhere - includes ; tonic-clonic seizures atonic seizures absence seizures Grand Mal Seizures seizures that are generalized, that cause loss of consciousness, affect the whole brain Aura : the sensation that precedes a seizure, exact nature depends on the location of the seizure focus, depends on where the seizure is starting Tonic-Clonic Seizure : generalized, grand mal seizure typically starts with an aura, followed by a tonic phase and then a clonic phase - this type of seizure involves convulsions Tonic Phase : 1st phase of tonic-clonic seizure, all muscles contract, ppl stop breathing, they clench up - loss of consciousness Clonic Phase : 2nd phase of tonic-clonic seizure, ppl have wild convulsions, rhythmic jerking of the body - Children are especially susceptible to seizure disorders... usually have brief seizures (spells of absence) instead of tonic-clonic episodes absence seizures (petite mal seizures) generalized complex seizures - involving the whole brain & loss of consciousness, but they dont involve convulsions ( typically 15secs, eyes blink repeatedly ) The Classification of Seizure Disorders I : Generalized Seizures (whole brain + loss of consciousness) A : Tonic-Clonic (grand mal seizures) B : Absence (petite mal seizures) C : Atonic (loss of muscle tone, temporary paralysis) II : Partial Seizures (starts from focus point) A : Simple (no loss of consciousness) 1 : Localized motor seizure 2 : Motor seizure with progression of movements as seizure spreads along primary motor cortex 3 : Sensory cortex (somatosensory, visual, auditory, olfactory, vestibular) 4 : Psychic - cognitive region (forced thinking, fear, anger, etc.) 5 : Autonomic region (sweating, salivating, etc.) B : Complex (loss of consciousness) includes all 1-5 symptoms above III : Partial seizures (simple or complex) evolving to generalized cortical seizures, starts as either simple or complex, then becomes grand mal seizure - Seizures are treated with anticonvulsant drugs, like benzodiazepines : they increase effectiveness of inhibitory synapses, boost GABA receptor activity - most seizure disorders respond to medication, ppl can lead a normal life - if drugs dont help, or can only barely help, need to go in & remove the neural tissue, brain surgery is required Disorders of Development things that happen in utero, in pregnancy, that can disrupt developmental process of the baby - exposure to certain toxins, viruses & drugs during pregnancy can impair fetal brain development & cause intellectual disability Dangerous Toxins : Organophosphates (from insecticides) Heavy Metals (lead & mercury) Famous Viruses : (alter brain development) Rubella Virus (German measles) Zika Virus (spread fast in Brazil) Alcohol : one of the most dangerous drugs during pregnancy babies typically smaller than average (premature) & develop more slowly Fetal Alcohol Syndrome condition associated with alcohol consumption during 3rd & 4th week (2 day window) - associated with certain facial anomalies & severe intellectual disabilities Inherited Metabolic Disorders gene mutations that make it so that some proteins need to develop the brain normally aren’t made "errors of metabolism" are genetic abnormalities, where specific instructions for a particular protein are in error - an enzyme is not made on account of mutations in both copies of the gene Phenylketonuria (PKU) : hereditary disorder caused by absence of enzyme that converts the amino acid phenylalanine to tyrosine accumulation of phenylalanine causes brain damage unless a special diet implemented soon after birth Tay-Sachs Disease : heritable, fatal, metabolic storage disorder lack of an enzyme in lysosomes causes accumulation of waste - produces swelling of cells within the brain, neurons start to die Down Syndrome result of having an extra 21st chromosome it is congenital (there from birth) but not necessarily hereditary - moderate to severe intellectual disability & physical abnormalities Autoimmune Disorders Multiple Sclerosis (MS) autoimmune demyelinating disease that starts in late 20's, the immune cells fight myelin certain genes increase risk of getting MS, but generally a sporadic disease (one not obviously caused by an inherited gene mutation or an infectious agent) at diff locations in CNS, myelin sheaths are attacked by immune system, leaving behind hard patches of debris called sclerotic plaques = action potentials cant successfully propagate down demyelinated axons damage occurs in white matter (axon paths) throughout the brain & spinal cord = wide variety of neurological disorders - symptoms often go trough cycles (flare ups) & then recede for varying periods of time in most cases : remitting-relapsing MS, followed by progressive MS : a slow, continuous increase in symptoms no effective treatment for MS yet, but some drugs help a bit ; - Interferon - we give a protein that modulates the immune system activity, gets it to focus on other things besides the myelin - Glatiramer Acetate - flood the blood with peptides that mimic myelin (decoy approach) ppl who grew up far from equator : more likely to develop MS Neurodegenerative Disorders theres many kinds of neurodegenerative diseases (like Alzheimer's, Parkinson's, Huntington’s, FTD-ALS, Prion diseases, etc.) some of these conditions associated with the degeneration of a particular cell type, while others cause more widespread degeneration similarity across them : neural degeneration driven by apoptosis, which is triggered when clumps (aggregates) of misfolded proteins disrupt normal cellular function ( at high enough concentrations, all proteins have likelihood of clumping tgt) - evolution has favored proteins that are resistant to clumping cells have numerous ways to ensure that proteins fold up into their correct 3-D shape, bcus misfolded proteins have high probability of clumping tgt cells also have a lot of ways of destroying misfolded proteins, but clearly have a hard time getting rid of (clumps) aggregates of misfolded proteins Prion Protein Disease aka Transmissible Spongiform Encephalopathy the only neurodegenerative disease that is transmissible (a contagious disease )that causes widespread neurodegeneration, making the brain look like a sponge, holes all over the brain ( includes mad cow and Creutzfeldt-Jacob disease ) Accumulation of misfolded prion proteins Prion : misfolded proteins that can cause other copies of the same protein to misfold, which spreads the problem throughout the brain, propagates really quickly - transmissible because : when a misfolded prion protein meets a healthy correctly folded prion protein, it causes that one to misfold too (animals can get it from eating brain of other animal...) the only infectious agent that is just a protein, all other infectious agents (viruses, bacteria, fungi, parasites) contain nucleic acids (DNA or RNA), genetic material Huntington's Disease a neurodegenerative disease with a very clear genetic basis. affects 1 in 10, 000 ppl caused by a single mutation in the Huntingtin gene, which results in misfolding of the huntingtin protein. this mutation is dominant (only need 1 bad copy of the gene, the long version) huntingtin protein is highly expressed in basal ganglia. aggregation (clumping) of this protein causes parts of the basal ganglia to degenerate symptoms occur between 30-50, death follows 15-20 years later - characterized by increasingly severe lack of coordination, uncontrollable jerky limb movements, eventually dementia, followed by death movements in Huntington's disease look like fragments of purposeful movements but occur involuntarily process : - we get 2 copies of each gene ( 1 from mom 1 from dad) - the huntingtin gene has a section of it where there's multiple CAG nucleotide repeats (CAG string of nucleic acids that encodes for the amino acid glutamine), in this gene, theres usually 30 CAG repeats in a row (healthy version) unhealthy version : too many repeats in a row, becomes really problematic when you have more than 39 (the protein has more than 39 glutamine amino acids in a row) = long version - enzyme comes & tries to cut it up = leaves a fragment that is very prone to clumping, they form little clumps in the brain Antisense Therapy presently no cure/treatment (for immune system to fight these clumps) - some optimism about the potential for antisense gene therapy, but 2 clinical trials recently failed researchers administer antisense DNA (or RNA) into spinal cord antisense DNA complements mRNA, when they bind together = mRNA not translated into protein they hope for this approach (or viral-mediated gene delivery & gene editing technologies) to become a practical & effective approach to altering gene expression in brains of living Parkinson's Disease - another degenerative "movement" disorder, does not have an obvious genetic basis - results from degeneration of dopamine neurons in the midbrain - specifically in the substantia nigra : there are typically aggregates of misfolded alpha-synuclein protein left behind, which is killing dopamine neurons - very common, affects 1% of population, symptoms usually appear after 60 - as dopamine neurons die off, because alpha-synuclein clumping together, basal ganglia is getting less dopamine, which initially leads to motor problems ; ( muscle rigidity, slowness of movement, shaking, difficulty walking, eventually dementia) - without treatment, ppl have increasing difficulty initiating purposeful movement - no cure, but many ways to alleviate the motor problems (up to a decade) - cognitive, emotional & sleep disturbances develop as well, no good treatments for these symptoms Alpha-synuclein : (the protein aggregating) - its heavily expressed in midbrain dopamine neurons. abnormal accumulations associated with dopamine neuron degeneration - cause of protein aggregation unknown Lewy Body : aggregates of misfolded alpha-synuclein protein found in the cytoplasm of midbrain dopamine neurons in ppl with Parkinson's disease rare mutations in the alpha-synuclein gene have been identified to promote the formation of Lewy bodies - these mutations not present in most cases (pretty rare) Types of mutations ; (cells are aware misfolding happens) - they have enzymes whose jobs are to recognize this 1: Parkin enzyme goes around looking for misfolded proteins 2: When Parkin recognizes one, it adds molecules of ubiquitin to the end of the misfolded protein 3: Proteasome breaks misfolded protein that have ubiquitin tag, into their constituent amino acids Parkin : protein (enzyme) that plays a critical role in ubiquitination. mutated parkin is one cause of familial Parkinson's disease. If parkin defective = misfolded proteins accumulate, aggregate, eventually kill the cell Ubiquitin : protein that is added to faulty/old/misfolded proteins, which targets (tags) them for degradation. Ubiquitinated proteins get brought to proteasomes, which breaks them into their constituent amino acids for recycling Proteasome : Organelle responsible for destroying ubiquitinated proteins within a cell Sometimes ppl have a gene mutation in the alpha-synuclein protein, that makes it so Parkin enzyme doesn’t recognize that its misfolded Mutations in the DNA, causing ; Toxic Gain of Function : when a dominant gene mutation produces a protein with toxic effects Ex. Mutations in alpha-synuclein gene can prevent the protein, when misfolded, from being ubiquitinated = results in Parkinson’s disease Mutations in huntingtin gene can cause the huntingtin protein to misfold = results in Huntingtin's disease Loss of Function : a recessive gene mutation (not making the protein it needs to) that when present on both chromosomes (on both copies of the gene) = results in the absence on a necessary protein Ex. Loss of function mutations in the parkin gene can make it unable to ubiquitinate misfolded alpha-synuclein protein Treatment - elevating dopamine signaling in the brain alleviates the motor symptoms - dopamine receptor antagonists work to some extent, but cause too many side effects (in the PNS) - dopamine does not cross blood brain barrier, but precursor of dopamine (L-dopa) can, where its converted to dopamine in brain - daily administration of L-dopa can diminish motor symptoms for many years (not more than 5) - brain lesions & deep brain stimulation (DBS) ; main targets for lesions & DBS are parts of basal ganglia that become overactive in Parkinson's disease ; the globus pallidus & subthalamic nucleus - damaging the globus pallidus or disrupting subthalamic nucleus activity seems to relieve symptoms by removing one of the brakes on motor behavior Dementia progressive impairments to memory, thinking & behavior due to a neurological disorder that affect one's ability to perform everyday activities common causes are neurodegenerative diseases, its seen in MS, multiple strokes, repeated brain trauma - culprit thought to be beta Amyloid protein, that is misfolding throughout the brain, clumping up & causing widespread neural degeneration when its beta Amyloid protein causing it... we call it ; Alzheimer's Disease a neurodegenerative disorder that causes progressive memory loss, motor deficits & eventually death - occurs in about 10% of population above 65, and 30% in above 90 - associated with aggregates of misfolded beta Amyloid protein & severe degeneration within + around the hippocampus & neocortex, spreads everywhere Beta Amyloid : (the problematic protein) - aggregates of misfolded beta Amyloid protein are present in brains of ppl with Alzheimer's Amyloid Plaque : extracellular aggregation of beta Amyloid protein surrounded by glial cells & degenerating neurons Tau Protein : microtubule protein that becomes hyper-phosphorylated in Alzheimer's disease, disrupting intracellular transport Neurofibrillary tangle : intracellular accumulation of twisted Tau protein in dying neurons Beta Amyloid precursor protein (APP) - the protein that is the precursor for beta Amyloid protein - the gene for this protein is located on chromosome 21 (its a transmembrane protein), in the APP protein's normal life cycle, 2 enzymes come & cut it up in 2 spots (the secretase enzymes) = you have 3 fragments, when they cut it up, the middle section, healthy version of it is 40 amino acids long, but sometimes secretase come in and cut it in wrong section = 42 amino acids long (the long fragment is sticky & it aggregates) Secretase : class of enzymes that cut the beta Amyloid precursor protein APP into smaller fragments - made up of diff proteins that make that enzyme ; 1 : Presenilin : protein that forms part of the secretases that cut APP mutations in presenilin cause it to preferentially generate the abnormal long form of beta Amyloid, which causes early onset Alzheimer's 2 : Apolipoprotein E (ApoE) : a protein that regulates cholesterol in the blood - glycoprotein that transports cholesterol in the blood & plays role in cellular repair presence of E4 allele of the ApoE gene increases risk of late-onset Alzheimer's Other than age... strongest risk factor is TBI - other factors ; obesity, hypertension, diabetes, high cholesterol (things regulating cholesterol) - seems less prevalent in well-educated people, those that keep their minds & bodies active - no cure, some medications reduce symptoms a bit, but dont significantly stop the neurodegeneration - most promising ones are a form of immunotherapy, where we inject antibodies that directly bind to beta amyloid protein or tau protein, marking them for destruction by the immune system ALS-FTD (Amyotrophic lateral sclerosis) - ALS aka Lou Gehrig's disease / motor neuron disease - ALS attacks motor neurons in both spinal cord & cranial nerves - symptoms include ; Spasticity (increase muscle tension causing stiff, awkward movements), exaggerated stretch reflexes, progressive weakness & muscular atrophy, followed by paralysis & then death - 90% of cases are sporadic (causes is unknown), but 10% cases is inherited from parents in rare cases, simple gene mutation are the dominant cause - appears out of 3 in 100 000. typically starts after 50, lifespan after diagnosis 2-4 years, but some ppl live much longer (Stephen Hawking lived for 40+ years) - ALS & frontotemporal dementia (FTD) are considered to be part of a common disease spectrum (FTD-ALS) because of genetic, clinical & pathological similarities Common Harmful Gene Variants Prion, Huntington's & ALS-FTD diseases are somewhat rare Parkinson's & Alzheimer's are common Heart disease, strokes & cancer are common There is a strong genetic component to all these conditions there are common gene variants in the population that increase ppl's risk - the question remains : why have these gene variants not been eliminated through evolution? why are they so common? Reproductive Success - 15% of women, 40% of men never have a biological child - who has children is not exactly random : physical & mental health issues impact ppl's likelihood of having kids - hard to classify who has a severe mental illness, researchers estimate it at around 4% of the population, their fertility rate reaches 1/2 the national average - having a severe mental illness dramatically reduces reproductive success - according to theory of evolution & natural selection, gene variants increasing risk of developing a severe physical or mental health issue : should expectedly get eliminated from the gene pool across generations - yet, every disease & disorder that plagues humanity seems to have a genetic basis how does this make sense? Genetic Variation - gene mutations arise with each generation - gene mutations result in either diff versions of a gene or diff versions of a gene promoter region : theres are multiple alleles (multiple versions) of that gene - tons of diff alleles in human population are relatively common : 1 in 100 ppl have the allele if more than 1% of population has a specific allele (specific gene variant) - its unlikely that allele is uniformly detrimental to reproductive success - its also unlikely that allele is uniformly beneficial to reproductive success (or everyone would have it) Bad Genes - natural selection eliminates harmful genes from the gene pool over time - very harmful gene mutations get eliminated quickly. rarely passed down across multiple generations given they greatly reduce reproductive success very harmful gene mutations are rare & in recent origin (arise with each generation but quickly get selected out) Slightly harmful gene mutations : eliminated more slowly (tend to be inherited across multiple generations) - only slightly reduce reproductive success - slightly harmful gene mutations = more common in population & old in origin, but still unlikely to persist in gene pool forever - gene mutations that slightly reduce reproductive success (by 1% or smt) would only persist in human gene pool for 100 generations or so before being selected out Good Genes - as harmful alleles get eliminated, prevalence of beneficial alleles increase until everyone gets them - we say "a gene has gone to fixation" when the same version is found in nearly 100% of population. If an allele slightly increases reproductive success, it should spread to entire population within 100 generations - generally, most genes in human genome have gone to fixation (virtually 100% prevalence in human population), bcus they promoted survival & reproduction in ancestral conditions better than other gene variants did - such genes comprise the species-typical human genome, & its normal neurodevelopmental product is human nature Genetic Basis of Disease - when we analyze the genomes of ppl letter by letter (nucleotide by nucleotide), we see a variety of alleles (different versions of a gene) that are quite common - some alleles confer an increased risk of developing a disease/disorder, while other ones are protective - there is strong evolutionary pressure acting on these gene variants - the good genes go to fixation, the bad ones get selected out - BUT, why are harmful gene variants so common today??? How did they persist over the last 200 000 years of human history??? Main Factor : our environment & lifestyles have changed very quickly & very dramatically in recent history Gene-Environment Interactions - when the environment is stable for hundreds of generations, the only maintained alleles are the ones that are beneficial or completely neutral - the prevalence of neutral alleles drifts randomly across generations - many alleles that were neutral or beneficial 50 generations ago aren’t anymore = they are now harmful, there is no clear offsetting benefit of them - when allele is neutral in one environment but not another : there is a genre-environment interaction - many of gene variants currently associated with disease show classic hallmarks of gene- environment interactions : they are common in human population, but prevalence rates vary widely across cultures & recent history - in many cases, there are obvious environmental explanations for the variability in the prevalence of these diseases The prevalence rates of these disorders vary widely across cultures & recent history, the environmental risk factors associated with them were not present in ancestral environments - obesity & diabetes : sudden abundance of cheap, unnaturally delicious food - asthma : sudden changes in air quality, exposure to pollutants & antigens - drug addiction : sudden abundance of highly purified synthetic drugs - heart disease, strokes, cancer : sudden changes in lifespan, diet, lifestyle - late onset neurodegenerative disorders : sudden changes in lifespan, diet, lifestyle - depression & anxiety : sudden changes lifestyle Mental Illness - some mental disorders do NOT show the classic hallmarks of gene-environment interactions Ex. Schizophrenia & autism are heritable, but prevalence rates do NOT vary widely across cultures or recent history "severe" mental disorders... - reduce reproductive success (1/2 as many children) - are heritable (genetic explains much of the variance in diagnoses) - are very common (4% of population) "severe" mental illnesses are genetic disorders, but associated alleles are widespread & seemingly are not being eliminated through natural selection. What is going on??? Why are harmful heritable mental disorders so common & persistent??? Schizophrenia Schizophrenia Susceptibility Genes - we have identified hundreds or relatively common gene variants that each individually confer a very small statistical increase in the risk of developing schizophrenia - the combinations of these gene variants create conditions where mental illness is likely - the concordance rate for schizophrenia among genetically identical twins is about 50% - 1 twin has schizophrenia, other one has 50% chance of having it too - (less than 1% in general pop) - so clearly there can be a genetic predisposition for schizophrenia, but what actually triggers it? - to asses environmental risk factors (role of the environment), we compare rates of schizophrenia among identical twins that were either raised tgt or separated at birth results : it doesnt matter : still 50% chance regardless - there are environmental risk factors, but they exert a very small influence overall. schizophrenia primarily reflects a genetic predisposition & bad luck Why are schizophrenia susceptibility genes so common in the gene pool? 1 theory says : certain combinations of schizophrenia susceptibility genes may improve reproductive success (somehow making ppl smarter) - there may be good combinations of these gene variants that boost reproductive success Do the siblings of ppl with schizophrenia have tons of kinds?... NO... have same fertility rate as the general population Researchers have not yet identified any offsetting benefit of schizophrenia susceptibility genes Mental Disorder Susceptibility Genes the common gene variants associated with increased risk of developing schizophrenia are also associated with increased risk of developing bipolar disorder, depression, autism, OCD & ADHD Risk conferred by gene variants are not specific to traditional diagnostic boundaries, they are not "schizophrenia genes" or "autism genes" - the gene variants reflect a vulnerability to developing some kind of mental illness, not a specific mental illness, nor a specific symptom within a diagnostic category "you have a higher chance of developing a mental illness, we just cant tell you which one" Its all the same genes, and they’re predisposing ppl to some mental illness, not a specific one Mental illnesses are not randomly scattered in the population : they tend to aggregate within people, clusters of mental illnesses within ppl, 1 diagnosis = more likely to get another Diagnostic Categories We have these templates in our head of the classic representations, but the truth is : the presentations are so variable there is too much - heterogeneity (variety) within diagnostic categories - comorbidity across categories (2 conditions at same time) - continuity with normality for mental disorders to qualify as well-defined, distinct disorders its a continuum, we draw lines to tell ppl they need help - our diagnostic categories grew out good faith efforts to describe clusters of symptoms that tend to appear together - they reflect historical conventions more than known biological differences : no match to the actual biology - diagnostic categories are somewhat helpful for treatment decisions, still clear that similar behavioural symptoms can arise from completely diff neural circuit disruptions, they just happen to present in the same way, but the underlying problems are different Mental Disorder Susceptibility Genes - many gene variants associated with increased risk of mental illness regulate brain development & neural plasticity - the gene variants do not directly cause mental illness : they seem to collectively compromise the evolved interactions of various proteins & cell types in the brain, slightly altering the dynamic interactions of the thousands of proteins expressed in the brain, reducing overall robustness of brain development & function - issue not as simple as 1 bad gene, bad protein, or dysregulated brain region, nothing consistent across people, not a simple problem we can point to - ppl with mental illness have more brain peculiarities overall, but few if any of those are consistent across ppl with similar diagnoses - ppl who present seemingly similar types of mental illness rarely share the same gene variants Brain Development is highly complicated, also robust (not delicate) - there is certain amount of unavoidable randomness at the molecular level that impacts brain development & maturation, but our genome evolved to buffer many insults (environmental variation, genetic variation, molecular noise) - our genome contains redundancies, error checking mechanisms, quality control efforts = to ensure healthy brain development and brain function - gene mutations can be a source of stress for the developing brain, but robustness in our genetic instructions allows gene variations to accumulate in the population if individual mutations are not too severe Neurodevelopmental Robustness the bodies of bilateral creatures (animals with nervous systems) are largely symmetrical, the 2 sides develop independently from the same set of genomic instructions - highly symmetrical bodies reflect clear genetic instructions - random uncommon asymmetries suggest the underlying genetic instructions are a bit confusing, may indicate some amount of developmental instability - body symmetry may be indicative of the robustness of genetic instructions, which must contend with the environmental variation & molecular noise - body symmetry slightly correlates with intelligence, physical attractiveness & physical health - all traits that have a genetic basis - these gene variants are maybe indicative of some kind of neurodevelopmental robustness (very clear genetic instructions that can withstand environmental variation & molecular noise) Mutation-Selection Balance - mental disorder susceptibility genes : being continually selected out through evolution, but new mutations keep arising - 20 000 protein-encoding genes in our genome. 1/2 of our genes are expressed in the brain at some point during development or adulthood - mutations in any of these genes can put a strain on brain development & brain function - mental illness : not result of specific gene mutations, just an unfortunate combination of gene mutations (across the genome) that altogether slightly disrupt neural network dynamics - prevalence/persistence of mental illness may reflect a gene mutation-selection balance, to some extent. harmful mutations eliminated through natural selection, but new gene mutations arise each generation - not specific key genes that are important. 1/2 our genome impacts brain development & function. mutations anywhere may increase someone's risk of developing a mental illness - best advice for maintaining a healthy brain & healthy body ; stay active physically & mentally (exercise, socialize, set goals) eat well (more vegetables, less sugar) reduce stress, lower blood pressure maintain good sleep habits limit alcohol intake, avoid Tabacco & hard drugs Future Directions - identifying gene variants & neural circuit disruptions associated with mental illness, hope to develop new treatment & prevention strategies - developing gene editing techniques that could be used in living ppl or in vitro - hope for better disease management through pharmacological treatments (that directly target intracellular signaling cascades) - evaluating efficacy of deep brain stimulation targeted to diff areas of the brain - increasingly testing closed-loop stimulation strategies (implanted metal wire used to record brain dynamics & deliver stimulation when necessary to correct neural circuit irregularities) Schizophrenia characterized by social withdrawal, disorganized thinking, abnormal speech, inability to understand reality - affects nearly 1% of population symptoms typically come on gradually, begin in young adulthood, never resolve in many cases (20% of ppl still do quite well eventually) 30-50% of ppl with schizophrenia dont believe they have an illness or comply with their recommended treatment onset generally between 15-30 years for men & women, women have increased risk in their late 40's - time periods correlate with periods where brain has to dramatically adapt Schizophrenia Symptoms grouped into 3 categories ; Negative : Absence of behaviours - social withdrawal, reduced emotional expression, poverty of speech, reduced motivation Cognitive : Disorganized & irrational thinking, deficits in learning & memory, poor abstract thinking, poor problem solving Positive : Presence of delusions (delusions of persecution, grandeur, control beliefs that contradict reality) & hallucinations (perception of stimuli that are not actually present) - negative symptoms typically emerge first, followed by cognitive symptoms, then years later positive symptoms - many patients also exhibit neurological symptoms like poor control of eye movements & unusual facial expressions - Schizophrenia also associated with subtle differences in brain structure, but are quite variable Schizophrenia Heritability estimated at around 80% heritability measures the fraction of phenotype variability that can be attributed to genetic variation. Concept of heritability can be expressed in from of a question ; " What is the proportion of the variation in a given trait within a population that is not explained by the environment or random chance? " Concordance rates : someone’s likelihood of having schizophrenia 50% : if identical twin has it 50% : if both parents have it 13% : if one parent has it 8% : if one sibling has it 5% of cases attributed to rare gene copy number variations (duplicated or missing genes), which often result in schizophrenia comorbid with autism & intellectual disabilities - these highly penetrant gene mutations are rare Schizophrenia Environmental Factors : most of these relate to the developing embryo's (environment in the wound) - mother's nutrition during pregnancy - mothers stress during pregnancy - certain infections (particularly during pregnancy) - birth month - being raised in a city - childhood trauma - social isolation - perinatal hypoxia/brain damage somewhat related to environmental factors that can affect development in utero ; like season of birth, viral epidemics, population density, parental smoking Seasonality Effect : a disproportionately large number of schizophrenic ppl born in February, March, April, May Twin Studies Prenatal environments of monochorionic twins (share one placenta) are more similar than those of dichorionic twins - evidence suggest the concordance rate for schizophrenia is higher for monochorionic twins than for dichorionic twins = suggest prenatal environment is an important factor Evidence for abnormal brain development - symptoms of schizo not normally seen in childhood, but behavioural & anatomical evidence indicates that abnormal prenatal development is associated w schizo Behavioural : children who go on to develop schizo display less sociability & deficient psychomotor functioning as kids Anatomical : minor physical abnormalities often seen in children who go on to develop schizo, like partial webbing of the two middle toes & a high- steepled palate Treatment of Schizophrenia there is no cure main treatment is medication, often in combination w psychological & social support - many drugs relieving the positive symptoms have been developed they typically block dopamine D2 receptors : antipsychotics or neuroleptics focus on : alleviating symptoms Dopamine receptor agonists, (crystal meth, cocaine) often elicit certain aspects of the positive symptoms of schizo in ppl who do not even have the disorder (the dopamine system seems involved) ; Block dopamine signaling = get rid of hallucinations & delusions Boost dopamine signaling = develop hallucinations & delusions The Dopamine Hypothesis : of schizophrenia - excessive dopamine D2 receptor activity (in nucleus accumbens), underlies the positive symptoms of schizophrenia Dopamine D2 receptor antagonists reduce positive symptoms of schizophrenia (delusions & hallucinations) but not the negative symptoms (reductions in motivation, speech, emotionality & sociality) - negative symptoms account for a large part of the long-term disability & poor functional outcomes of ppl with schizo - some evidence suggests the negative symptoms result from abnormal activity in the prefrontal cortex - negative symptoms similar to those of ppl with damage to the prefrontal cortex, schizo ppl do poorly on neuropsychological tests that are sensitive to prefrontal brain damage - generally, negative symptoms may be cause by hypofrontality (decreased activity of the frontal lobes - dorsolateral prefrontal cortex), which may relate to hypoactivity of local excitatory dopamine D1 receptors excess dopamine signaling in the striatum associated with the positive symptoms, its possible that reduced dopamine signaling in prefrontal cortex underlies some of the negative symptoms - might be associated with too little dopamine in prefrontal cortex, and too much dopamine elsewhere - the atypical antipsychotic clozapine (2nd gen drug/dirty drug), has been found in monkeys to simultaneously decrease dopamine levels in the striatum & increase dopamine levels in the prefrontal cortex Atypical Antipsychotics 2nd generation antipsychotics that aim to reduce both positive & negative symptoms Clozapine : 1st of the atypical antipsychotic medications blocks dopamine D2 & serotonin 2A receptors, among other actions Aripiprazole : also Abilify or Aristada acts as a partial agonist at dopamine D2 & D3 receptors, as well as at serotonin 1A receptors - thought to simultaneously reduce dopamine receptor activity in the striatum while boosting it in the prefrontal cortex by acting as a partial agonist at dopamine receptors, Aripiprazole thought to reduce dopamine receptor activity in striatum while simultaneously boosting dopamine receptor activity in the prefrontal cortex Partial Agonist : drug with very high affinity for a receptor, but it activates it less then the normal ligand does so a partial agonist can boost receptor activity in regions where there is low concentration of the normal ligand, while simultaneously reducing receptor activity in regions where there is high concentration of the normal ligand Autism, ADHD & Depression people often make distinction between neurodevelopmental disorders & mental illnesses 1 : mental illnesses can occur at any age, they can be temporary or episodic 2 : neurodevelopmental disorders, clearly evident in childhood or at birth, they are lifelong disabilities neurodevelopmental disorders : autism, intellectual disability, ADHD & motor disorder's (Tourette’s) Sex Differences - some mental illnesses affect males & females at similar rates (schizophrenia & bipolar disorder rates similar between sexes) Mental Illnesses more common in women ; Anxiety disorders, major depressive disorders, OCD, PTSD ; 2X more common Anorexia 3X more common Bulimia 10X more common Mental Illnesses more common in males ; Autism 4X more common ADHD 4X more common Intellectual disability 2X more common Tourette's syndrome 3X more common One theory about sex differences = they just aren't real the biology is similar between the sexes - all has to do w culture & socialization 1 : maybe were underdiagnosing anxiety& depressive disorders in males 2 : maybe were underdiagnosing neurodevelopment disorders in females Truth : we do have certain