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Attention & Brain Rhythms Attention & Brain Rhythms • • • • Arousal Attention Body Rhythms Rhythm Disorders Arousal • The Reticular Activating System (RAS), a diffuse collection of various nuclei in the pons, medulla and brainstem including: – Locus coeruleus (pons, NE) • Activated by novel & meaningful sensory stimuli. • Excitory effect on rest of brain. – Raphe nuclei (pons, medulla, 5-HT) • Mostly inhibitory. Particularly important in sleep. – Substantia Nigra, Ventral tegmental area (DA) – Cholinergic basal forebrain and brainstem nuclei (ACh) • Excitatory Arousal • The Reticular Activating System (RAS) projects to the basal forebrain, which then projects to the entire cortex. – ACh – promotes behavioral arousal • Adenosine (AMP metabolite) builds up during waking, and acts to inhibit arousal. Caffeine inhibits adenosine receptors, and acts like a stimulant. • Histamine from hypothalamus excites arousal. – GABA – inhibits the thalamus and cortex and inhibits behavioral arousal. Arousal • Stimulation of the RAS in sleeping cats (Moruzzi & Magoun, 1949) produced a waking pattern of electrical activity in the cerebral cortex. Lesions caused sleep state. • RAS acts as the on/off switch for the brain. – On = conscious – Off = unconscious – Prolonged off state = coma Attention • The ability to preferentially ignore some distracting sensory inputs, i.e. the “cocktail party effect.” • Why do we have attention systems? – – – – We can’t possibly process every sensation. To make optimal use of limited resources. Detection is enhanced. Reaction times are speeded. Attention • Attention is generally limited to one sensory stream at a time. • There is some evidence for independent hemispherical attention, but the left hemisphere is more attentive. • Attention requires arousal (by RAS), but just enough. Insufficient arousal leads to inattention. Attention • Attention is a like a spotlight, highlighting one somato- or enviro-topic area by inhibiting surrounding areas. • The pulvinar nucleus of the thalamus and the parietal lobes help directs attention by inhibiting irrelevant information. • The cortex controls inhibition of ascending sensory information to preferentially select input from one particular side or feature type (ex. particular audio frequencies). ADD/ADHD • Attention Deficit Hyperactivity Disorder (ADHD) – Inattentive type (~55%) • Meso-libmic dopamine system, motivation – Impulsive-hyperactive type (~15%) • Meso-cortical dopamine system, disinhibition – Combined type (~30%) • Affects 7-8% of children (DSM-IV), 3:1 M:F • Chronic – persists to 4-5% of adults, <2:1 M:F • Strongly genetic: MZ=80-90%, DZ=25-35% ADD/ADHD • Comorbidities: – CD (20-50%) – OCD (40-80%, Hyperactive only) – Substance Abuse (~35%) – Anxiety (10-40%) – Depression (0-45%) ADD/ADHD • Non-genetic predispositions – Maternal smoking, drinking (2.5:1) – Maternal anxiety or high phenylalanine – Prematurity of birth (45%+ have ADHD) • Post-Natal – – – – Hypoxia Lead poisoning Streptococcus infection (basal ganglia) Frontal lobe trauma (inattention only) ADD/ADHD • Genetics – DAT1 (5p15.3) 10-R dopamine transporter polymorphisms are strongly related and highly predictive of ADHD hyperactivity and impulsivity, but not inattention. Dopamine is reuptaken with increased efficiency. – Dopamine-beta-hydroxylase (DBH) (9q34) variants are related. More efficient enzyme. – DRD4 receptor (11p15.5) 7-R subsensitive. – All act to decrease arousal by dopamine. ADD/ADHD • Neuroanatomical correlates – Filipek, et al (1997) reported 10% decreased volume in anterior superior (posterior prefrontal, motor association) and anterior inferior (basal ganglia) areas. – Castellanos, et al (1996) reported 10% decreased volume in the right anterior frontal, caudate and globus pallidus areas and loss of normal symmetry. – No significant difference by gender • “A hypofunctioning smaller brain” ADD/ADHD • Commonly treated with stimulants: – amphetamines • Benzedrine 1937, Dexadrine, Adderall – methylphenidate • Ritalin, Concerta, Metadate • Ineffective in homozygous 10 repeat DAT1 allele – pemoline (Cylert) – buproprion (Wellbutrin) – All these drugs inhibit dopamine reuptake transporters in the basal ganglia, raising synaptic dopamine levels. Rhythms of the Brain • • • • • • • Body rhythms Brain rhythms Ultradian rhythms Circadian rhythms Monthly rhythms Seasonal/yearly rhythms Rhythm disorders: epilepsy Body Rhythms • Heart has its own pacemaker. – Normally runs too fast. – Vagus nerve (X) slows it down (parasympathetic). – Epinephrine speeds it up (sympathetic). • Breathing – Controlled by pacemaker in the medulla. • Temperature – Controlled by its own circadian clock, usually synced to the circadian clock. Also in medulla. Rhythms of the Brain • Pairs of excitatory and inhibitory neurons can form neural oscillators. – Any network of strongly interconnected neurons is prone to oscillation. • Some thalamic neurons have special sets of voltagecontrolled ion channels that allow it to self-modulate. Rhythms of the Thalamus • Large thalamic rhythms are generated during sleep. – These project to all areas of the cortex and are thought to shut down all sensory information to and motor information from the cortex. • Cortical rhythms while awake are thought to help synchronize and bind various kinds of information which are to be associated. Ultradian Rhythms • “Faster than a day” • 90 minutes – Infants feed, urination, sleep sub-cycles. – This clock appears to be in the medulla. • 12 hour – Most people have wakefulness lows at 6 and 18 hours after rising, and are most wakeful at 0 and 12 hours after rising. Circadian Rhythms • • • • Circadian (= “about a day”). Circadian behaviors are inborn, not learned. Primarily control sleep/wake cycle. Secondarily control temperature, enzyme levels (i.e. liver enzymes), genetic expression, etc. Circadian Clock • Located in the suprachiasmic nuclei of the hypothalamus, directly above the optic chiasm. – SCN lesions disrupt circadian cycles, fetal SCN tissue transplants restore circadian cycles. • SCN contains about 10,000 neurons, each with its own clock, all synced to light/dark cycle. • SCN projects to hypothalamus, midbrain, and the pineal gland. The pineal gland releases the hormone melatonin at night. Circadian Clock Genetics • SCN neurons use genetics to oscillate on a long time period, just like two interconnected neurons can oscillate. – The production of the first protein stimulates the increased production of the second. – The second protein inhibits the first. • Cycle lasts about 26 hours in humans, but is resynchronized by the onset of daylight every 24 hours. Circadian Clock • The SCN clock is synchronized to the onset of light, shortening cycle to 24 hours. • Dilemma: some blind people still sync to daylight. • Melanopsin - newly discovered opsin (chromophore / B2) in the inner ganglion layer of the retina (NOT in rods or cones!). • Frogs have photosensitive cells in skin, maybe humans do too. Circadian Clock • All mammalian species show about the same melatonin production cycle (high at night, low during the day), so melatonin only tracks time, not wakefulness. • Nocturnal animals interpret or respond differently to the melatonin cycles as diurnal animals. • Teenagers have phase shift vs. adults. • FASPS phase shift due to 2q point mutation. (affects per2) Monthly Rhythms • Primarily sex-related modulations – Hormonally controlled • Hypothalamus tells pituitary to release hormones. – Female ovulation cycle • Follicle Stimulating Hormone (FSH) causes follicle maturation. Maturing follicle produces estradiol. A large estradiol buildup causes release of Lutinizing Hormone (LH), which causes release of follicle. If egg is fertilized, progesterone is released. If not, prostaglandin causes menstruation. – Males have minor modulations. Seasonal Rhythms • SCN->PVN->SNS->Pineal gland implicated in seasonal patterns. • SCN/PVN lesions disrupt seasonal patterns. • Fetal SCN cell implants restore circadian patterns but not seasonal patterns. • Seasonal variations not generally found in humans, except in severe cases, like SAD. Seasonal Affective Disorder • The length of melatonin produced at night remains constant all year in normal people. • People with SAD produce melatonin for about an hour longer during periods of prolonged reduced photoperiod. • Since melatonin and serotonin are both made from the same precursor, more melatonin generally means less serotonin. Lowered serotonin is linked with depression. Seasonal Affective Disorder • SAD is about 70% genetic. There are both predispositions and protections. • SAD is geographical: almost unheard of in equatorial areas, with increasing prevalence towards the poles. • Light therapy is usually an effective treatment, and early morning light is much more effective than evening light. Sleep • Must be important! – Takes up 1/3 of our lives, more than any other activity. – Other than breathing, sleep is the most insistent drive. – What function does it serve? – Why is it so important? – What controls it? Sleep Function and Need • Sleep appears to let the brain rest. – Possibly to allow regeneration of depleted neurotransmitters. • Sleep appears to be necessary for survival. – All vertebrates and reptiles sleep, and fish and amphibians show periods of quiescence. – Sleep has not disappeared even where it interferes with survival, but not without adaptations. • Uni-hemisphere sleep, multiple naps, etc. (Beta 13-30 Hz, awake, alert) Alpha (8-12 Hz) Theta (3.5-7.5 Hz) Theta + spindles and K complexes Delta (<3.5 Hz) Delta REM (like beta) Sleep Stages Dement: REM (1): a “hallucinating brain in a paralyzed body.” Delta (4) : an “idling brain in a moveable body.” • REM (Rapid Eye Movement) – – – – – Dement: “hallucinating brain in a paralyzed body.” Dreaming occurs during this phase. Complete muscle relaxation/paralysis. “Paradoxical Sleep” because of beta activity. Can be easily awakened by meaningful stimuli (i.e. their name) and will appear alert and attentive. – Physical arousal of the sexual organs. • REM sleep is important to learning. – Periods of REM are longer following intense learning episodes. – REM deprivation interferes with learning tasks. – Non-REM deprivation does not interfere with the same learning tasks. Dreams • Dreams seem to be the cortex trying to make sense of random lower brain firings. • Dreams are usually high in visual imagery, but poorly organized with respect to time. • Madsen, et al (1991) found high cortical activation in the visual association cortex and low activation of the frontal lobes. Dreams • REMs seems to be related to visual scanning of a scene - EEG patterns match visual scanning, not just eye movements. • Cortical and subcortical brain mechanisms that would be involved if the dream were real seem to be activated during dreaming. – Broca’s area is activated during “speech.” – Wernicke’s area is activated during “listening.” – Motor areas are activated during “movement.” Sleep Theories • Recuperation Theory – Body needs time to “rebuild” after a hard day’s work. • Circadian Theory – Animals are active at the best times of the day to promote their survival. • Mostly circadian with some recuperation. Recuperation Theory Pros • REM sleep seems to be necessary. • REM sleep is made up if deprived, non-REM is not. • Function seems to be memory housekeeping: flush useless clutter and consolidate new memories and information with existing memories. Recuperation Theory Cons • There is a problem with recuperation theory: • Lack of sleep does not seem to interfere with human capacity for physical exercise. – Quadriplegics and forced bed rest subjects do not show decreased or altered sleep. – Exception: exercise that significantly raises the brain’s temperature (and metabolic rate) seem to cause increased need for slow wave sleep. Sleep Deprivation Predictions • Recuperation: – Missed sleep will cause physiological and psychological disturbances, which will get worse with time. – Much of missed sleep will be made up. • Circadian: – No ill effects, except due to falling asleep. – Sleep desire will display circadian cycle. – Little or no sleep compensation. Sleep Deprivation Studies • Kleitman (1963) – Sleep deprived lab subjects functioned normally during the day, with greatest drowsiness between 3-6 AM. • Gardner/Dement (1978) – Randy Gardner, 17, decided to break world record for staying awake, lasting 11+ days. – Only slept 14 hours for one night, then 8. • Both support circadian theory. Sleep Deprivation • Sleep deprivation increases sleep efficiency. – – – – Increased percentage of REM sleep. Increased slow wave sleep. As much time in stages 3 & 4 as with longer sleep. Seems to indicate slow wave sleep has some sort of recuperative features. – Protein synthesis seems to be accelerated during slow wave sleep. Sleep and Affective Disorders • New research shows: – Sleep deprivation can bring a person out of depression. – Sleep deprivation can cause a stable bipolar patient to go (hypo)manic. – Prolonged sleep intensifies a depression. – Children with early onset bipolar disorder show marked ultradian cycles. Epilepsy • Epilepsy – Oldest known brain disorder (over 2000 years) – Def: repetitive seizures (abnormally synchronous brain activity) – 7-10% have at least one seizure. 1% have epilepsy. – More a symptom than a disease. Epilepsy • Seizures – Undamped oscillation between hemispheres – Generalized (grand-mal) • Involves the entire cortex of both hemispheres. • Split-brain procedure used in the worst cases. – Partial (petite-mal) • Only a circumscribed area of the cortex is involved. • Often treated with drugs, or by removal of the area. – Often preceded by auras (minor, partial seizures) • Tension, smell, sound, temperature, visual Epilepsy • Treatment – GABA antagonists are good convulsants. – Anticonvulsants: • barbiturates and benzodiazapenes prolong the inhibitory effects of GABA. – (barbiturate and alcohol withdrawal can trigger seizures) • gabapentin (Neurontin) increases brain GABA. • phenytoin (Dilantin), carbamazapine (Tegretol), valproate (Depakote), clonazepam (Klonopin) and oxycarbazapine (Trileptal) decrease high-frequency firing by nerves. – Surgical resection or splitting