CNS Pathophysiology

Feelings of sadness that persist on a daily basis beyond a few weeks. Accompanied by multiple sx severe enough to cause distress & impair psychosocial function.

Depression with 1 or 2 sx that lasts 2 yrs or more

Impact on appetite, sleep, lobido, motor functions, anxiety and aggression.

Impact energyDecreased memoryImpaired anhedonia - inability to experience pleasure

Increase in cortisolFlight or fright sx turned on - increased HR/breathing rate

A neurodevelopmental disorder assoc with 2nd trimester influenza (N-CAMS)-obstetric complications- neonatal hypoxia

Results in excessive D2 activity- disorganized speech- unusual speech- odd behavior- delusions- hallucinations

Results in deficit in D1 activity- social withdrawal and isolation- lack of initiative (avolition)- dull or blunted emotioal affect(anhedonia)- poverty of speech ( algonia) bcos of brain lesion- posturing- autism

Monoamine hypothesis - excess NE & DA activity leads to mania- DA antagonist & alpha-2 adrenergic agonists decrease catecholamines & mania- deficits of NE, DA &/or 5-HT lead to depression- NE, DA &/or 5-HT reuptake inhibitors & MAOIs increase NT activity & decrease depression

Food triggers - alcohol, bananas, caffeine, tyramine pdts, chocolateEnvironmental triggers - tobacco smoke, strong smells, glare, loud noisesBehavioral-Physiologic triggers - stress, fatigue, menstruation, overexertionMedication - analgesic overuse, BZD withdrawal, oral contraceptives, decongestant overuse

Migraine triggers or CSD can activate trigeminal nerve axons, which then release neuropeptides from axon terminals near the meningeal & other blood vessels

Cholinergic cell lossReduced activity of choline acetyltransferase(ChAT)ChAT is the enzyme responsible foe synthesizing acetylcholine from choline & acetyl CoAIn AD cholinergic pwys are damaged esp neurons inthe nucleus basalis of meynert located at the base of the forebrainAxons from these cholinergic neurons prj to the frontal cortex & hippocampus, areas strongly assoc with memory & cognition

Neurofibrillary tangles (NFTs)- composed of paired helical filaments that aggregate in dense bundles- Helical filament is formed from tau proteins- Tau proteins bind & help stabilize microtubules- In AD chemically altered tau, twists into the hallmark NFTs

Cholinergic cell loss is the source of memory & cognitive impairment of AD

Cholinergic loss is not the disease prding eventCholinergic neurons are one of many neuronal pwys destroyed in ADSimply replacing acetylcholine can't compensate for the loss of neurons, receptors & NTs

- Promotes neural growth- Prevents oxidative damage- Estrogen is co-localized w/ receptors for nerve growth factor on cholinergic terminals on the hippocampus, cerebral cortex & basal forebrain- supplementation increases Ach- increases NMDA receptors in areas of the brain involved in forming new memories

GABAAchATP (functions as an inhibitory NT in certain areas of the brain)Glutamate

• Na+
• Ca++
• K+

Glutamate is removed from synapse by reuptake thru presynaptic transporterPrb w/ transporter can cause glu to remainin synapse long enough to overexcite neurons & become neurotoxicTransporter prb can be caused by:- hypoxia- interrupted bld supply- genetic defect in transporter

They prd electric charges that must fire regularly in order for a steady current to pass from one nerve cell in the brain to anotherGenetically damaged ion channel produces a chemical imbalance that can cause misfiring & seizures

Initially a sm # of neurons fire abnormallyNormal membrane conductance & inhibitory currents decreaseExcessive excitatoryspreads - locally for partial or focal - propagates via local cortical connections- widely for generalized seizure - propagates via long assoc or commissural pwys such as the corpus callosum

Partial seizures- begin in one hemisphere- asymmetric motor dysfunction- w/ or w/o loss of consciousnessGeneralized seizures- involves both hemisphere- bilateral motor dysfunction- loss of consciousness

Occurs when simple partial seizure precedes a complex partial seizureXterized by the ff sx:- HA, lerthargy, myoclonic jerking, palpitations, mood alterations, epigastric sensationsThese sx precedes the seizure by several hrs

Short durationXterized by brief contractions of bodily muscles, which usually occur at the same time on both sides ofthe body

Xterized by sudden & complete loss of muscle toneCommon for indiv to have falls & injuries

Xterized by jerking of muscle gps

Xterized by stiffness os muscle gps

Begins with stiffening of the limbs (the tonic phase) ff by jerking of the limbs & face( the clonic phase)

By dorsal raphe nucleus - serotonergicLocus ceruleus & nucleus peribrachialis leterisNoradrenergic - facilitation of arousal & wakefulness:- ascending reticular activating sys (RAS)- posterior hypoyhalamus

Electroencephalograms-EEGElectro-oculograms EOGElectromyograms EMG of the mentalis & submentalis muscles

Low-amplitude mixed frequency EEGAbsence of muscle toneBursts of bilateral rapid eye m'vts

Cessation of airflow at the nose & mouth lasting @ least 10 secQuantified using polysomnograghy (PSG)

Central SAObstructive SA

• Involves impairment of resp driveMakes up 10% of apneas
• Most cases are idiopatic
• Some causes include:- nasal obstruction-
• ANS lesions (cervical cordotomy)-
• neurological disease (poliomyelitis, encephalitis)- CHF

Xterized by parasthesias that are felt deep in the calf muscles & cause the urge to keep the legs jn motion

• Uremia
• Anemia
• Pregnancy
• Sensation is bilateral occuring during rest & inactivity & relieved by walking or moving legs

• Dopaminergic agents
• Bzds
• Opioids
• Anticonvulsants

Schizophrenics have more DA in their brains & this excess DA causes the sx of the disease

Amphetamine prds psychotic-like sxAntipsychotics are post-synaptic DA antagonists

Amphetamine psychosis only mimics the + sxAntipsychotic drugs only effective on the + sx

• Block DA recptr. Mostly D2 which are inhibitory
• Any drug that blocks DA activity will decrease (+) sx of schiz

(+) sx related to DA-recptr hyperactivity in the caudate nucleus - increased density of D2 recptr(-) sx related to DA recptr hypofunction in the pre frontal cortex & caudate nucleus - decreased density of D1 & D2

• Neurons have excessive dendritic pruning
• Mostly affects neurons that bind glu

• Enlarged 3rd and lateral ventricles
• Decreased in brain size
• - temporal lobe
• - brain asymmetry more pronounced on left side

Increase DA & NE activity contributes to hyperactivity and psychosis of severe maniaDecreased DA & NE activity causes depression

• Low GABA causes mania
• GABA decreases NE & DA activity

Excessive glutamine causes mania

• 1-5 attack/month (migraineur)
• Occur early morning
• Pain gradual in onset - peaks over min to hr of onset, lasts 4-72 hrs

Pain usually involves fronto-temporal region, but can occur anywhere in the face or headPain is typically unilateral, throbbing or pulsating in nature90% experience GI sx, nausea & emesis

HA lasts 4-72 hrs. HA pain may be- unilateral or bilateral- pulsating- moderate or severe intensity- can be aggravated by routine physical activityMay have- nausea, vomiting or both- photophobia and phonophobiaAura fulfils criteria for typical aura, hemiplegic aura or basilar-type aura

Aura consisting of fully reversible motor weakness & >= 1 of:fully reversible visual sx including (+) &/ (-) features: flashing lights / spots etc. Or loss of vision or part of visual fieldFully reversible sensory sx including + &/ - features: pain/pins & needles or loss of sensationFully reversible dysphasic speech disturbance (difficulty finding the right words)

Migraine: + Aura severe, throbbing unilateral generalized N&V women>men, offen w/ mensesCluster : episodic, no throbbing forehead, eye tears, ptosis seek dark, quiet pace, beat head- men > women, seasonalTension: constant "Tight band", no throbbing, bilateral, not worse w/ activity

Scintillations-bright flickers of light, 5-10 cycles/secPhotopsia-a blind spot in the visual field that is bordered by shimmering or flashing lightTeichopsia or fortification spectra- the sansation of a luminous appearance b/4 the eyesScotoma - blind spotsHemianopsia - blindness in one half of the visual field

Tobacco - #1 cause of preventable death in USAHeavy alcohol use or abuse- 12-16 million AmericansCaffiene- most widely used behaviorally active substance in the world

Abnormalities in the ff axes: hypothalamic-pituitary-gonal, hypothalamic-pituitary-adrenal, hypothalamic-pituitary-thyroidOther possibilities: NT dysfunctions (serotonin, NE, DA), genetics, psychological, athletics.

• Reduction is caused by: excessive pre-synaptic uptake; stress related down regulation of postsynaptic recptrs
• HPA axisRegulation of circadian rhythm
• Note: diff types of 5-HT recptr have diff effects e.g. Type 1 less aggressive and certain type 2s can lead to suicide.

• Levels of NE &/ 5-HT increase w/i 6-24 hrs after drug administration; however, antidepressant effect takes several wks to develop
• Delayed therapeutic response to antidepressants is caused by adaptive changes in adrenergic recptr sys.
• Chronic use of antidepressants cause desensitization & down regulation of NE recptrs
• Down regulation/desensitization correlates to clinical time course of antidepressant effectsEg alpha-2 & beta-recptrs must be down regulated & desensitized in order for antidepressant to wk.

45%-60% of pts have neuroendocrine abnormalityHypersecretion of cortisolLack of cortisol suppression after dexmethasone administration - indicates dysregulation of the hypithalamic-pituitary-adrenal axis ( should suppress cortisol for 24 hrs)Sleep: earlier onset of REM sleep, decreased slow-wave deep sleep stages 3&4, increased awakenings during sleep & early morning. These are not diagnostic for major depression

Diagnostic work-upUsually have one or more episodes of major depression during lifetimeAt least 5 of the DSM-IV-TR criteria & at least one sx must be depressed mood or loss of interest or pleasure

• Depressed mood
• Diminished interest or pleasures
• Significant weight loss
• Insomnia or hypersomnia
• Psychomotor agitation or retardation
• Fatigue or loss of energy
• Feelings of worthlessness or excessive or inappropriate guilt
• Diminished ability to think or concentrate
• Recurrent thoughts of death, w/ suicide thoughts & attempts
• B. Sx cause clinically sig distress, impairment of social functioning
• C. Sx not due to direct effects of subs abuse or medical condition
• D. Sx not due to bereavement, persist longer than 2 mo or are xterized by marked functional impairment.

ANS in anxious pts is hypersensitivite & overreacts to stimuliIn response to stress LC activates NE release which stimulates CNS & PNSIn certain anxiety disorders like GAD, the central noradrenergic sys is chronically activated causing down regulation of alpha-2 adrenorecptrsAnxiogenic drugs increase LC activation (Yohimbe - alpha-2 antagonist)Yohimbe is a psychoactive plant which contains the tryptamine alkaloid yohimbeAnxiogenic drugs decrease LC activation - BZD , antidepressants, clonidine

PET studies: increased glucose metabolism at rest in frontal cortex & cingulates cortex areas assoc w/ worry & hypervigilanceAlterations observed inGABA recptrs, serotonin sys, BZD recptrs, NE sys, HPA axis activation, cortisol

• Increasing age
• WidowedUnmarried
• Unemployed
• Living alone
• Substance abuse
• Family history
• 8th leading cause of death in the US, all pts shd be assessed for suicidal thoughts

Low 5-HT activity can lead to dysregulation of other NTsSerotonin dysregulation & anxiety may occur due to prbs w/: presynaptic autorecptrs (5-HT 1A/1D), SERT (serotonin reuptake transporter site), effect of 5-HT @ postsynaptic recptrs (5-HT1A, 5-HT2A, 5- HT1c)5-HT activation decreases NE activity in the LC => decrease in panic & anxiety

Affects nearly 1% of the pop over age 50, regardless of ethnicity or sexTypucal age of onset is 60 yrsIncidence increases w/ age from 20/100,000 b/n 50-60 yrs to 90/100,000 b/n 70-80 yrs

Results from degeneration of the pigmented dopaminergic neurons found in the substantia nigra & other areas of the brain to a lesser extent

IdiopathicAcquired - typically caused by: infection, intoxication, traumaDrug-induced parkinsonism by: phenothiazines eg chloropromazine, prochloroperazine and thioridazine; Butyrophenones eg haloperidol

• Genes
• Neurotoxins
• Oxyradicals
• Excitotoxicity
• Apoptosis
• Chronic infection

Genes- id in developing parkinsonismAlpha-synuclein gene: abundant in presynaptic neurons, major component of Lewy bodies (lewy bodies decrease the action of Ach & DAParkin- plays a role in protein degradation & clearance: mutation in this gene is assoc w/ abnormal protein accumulation in the neuron

MPTP which is converted by MAO-B to toxic MPP+MPTP administration caused a loss of dopaminergic cells in substantis nigra pars compacta, which led to a reduction in the levels of DA in the striatumMPP+ is toxic to neurons by interfering w/ mitochondrial metabolism

• Rewards (motivation)
• Pleasure, euphoria
• Motor function (fine tuning)
• Compulsion
• Perseveration

• Mood
• Memory processing
• Sleep
• Cognition

The nigrostriatial tract from the substantia nigra to the striatum accts for most of the brain's DAThe Tuberoinfundibulad tract from the arcuate nucleus of the hypothalamus to the pituitary stalk, which has a controlling effect on the release of the hormones prolactin thru tonic inhibition via D2 recptrsThe mesocortical tract from the ventral tegmental area to the neocortex, particularly the prefrontal area. DA cells prj topographically to the areasThe mesolimbic tract from the ventral tegmental area to many parts of the limbic sys (nucleus accumbens is part of the basal ganglia)

Ach - substance P can modulate release of AchDA - Adenosine when adenosine recptr blocked DA goes up ( caffeine blocks ad recptr) coffee may protect against PDGABA - serotonin may reduce the release of GABAGlutamate - Enkephalins in same neuron axon terminals

Lewy bodies - inclusion bodies w/i dopaminergic cells of the SNClinical signs are observed when there is a 70% - 80% decrease in nigrostriatal DA neuronsThere is a correlation b/n the extent of nigrostriatal DA loss & clinical sx

• Apo E2
• Apo E3
• Apo E 4

• Risk depends on number of E4 copies, age, ethnicity and gender
• 40% of pts w/ late onset Alzheimer's disease have 1 coph
• 90% of indiv w/ 2 copies will develop late onset AD by age 80
• Increased risk of AD in caucasions & femailes w/ 1 copy of apo E4 genotype
• Although apo E4 increases risk, it is not diagnostic or essential to get the disease.