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Brain Damage and Recovery of Function 6 different categories of brain damage: tumors, seizures, head injury, infectious disease, cerebrovascular accident, degenerative diseases (first 5 described in detail here): 1) Tumors –mass of cells whose growth is uncontrolled. -no useful function Benign tumors – harmless, encapsulated Types: Meningiomas –cells that constitute the dura mater or arachnoid membrane. Malignant tumors – cancerous a) infiltrate surrounding tissue, and b) metastases – shed cells that grow new tumors in different locations. How do tumors damage the brain? a) compression b) infiltration c) blocking the flow of CSF Treatment – remove tumor, irradiation. 2) Seizures –sudden synchronized excessive activity in neurons. Two types i) Generalized seizures, ii) Partial Seizures i)Generalized seizures symptoms a)grand mal –severe, - convulsions. -prior to seizure - an aura, -begins with tonic phase (forceful contractions of muscles) -then clonic phase (trembling and jerking of muscles). -ends with a state of confusion and exhaustion. b) “absence” or Petit-mal seizures. -stares unresponsively. ii)Partial seizures symptoms – definite focus a) Complex partial seizures –restricted to temporal lobes, unaware but engage in compulsive repetitive, simple (doing/undoing a button) or complex (hop, skip, jumping) behaviors. b). Simple partial seizures – primarily sensory or motor or both (Jacksonian seizures) Causes: -
Genetics (eg decrease release of GABA or mutated GABA receptors) or environmental toxins scarring, due to brain injury, stroke, tumor. infections that create a high fever alcohol/barbiturate withdrawal, i.e.
Treatment: a) anticonvulsant drugs - increase GABA at inhibitory synapses, -or block the flow of sodium across the cell membrane. b) surgery -anterior temporal lobectomy -cut corpus callosum 3) Head injury Cause: sharp blow to the head. -results in contusion (bruising) and localized edema (increased fluid) Cause: Car accident (acceleration injury) or fall (deceleration injury)
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-subjects the brain to rotational forces that drive brain tissue against the skull. -results in/damages the brain by – contusions, hemorrhaging, diffuse axonal injury 4) Infectious diseases. Transmitted by– bacteria, fungi, parasites, viruses. Eg a) meningitis –inflammation of the meninges. Symptoms – headache, stiff neck, convulsions, confusion, loss of consciousness, death. Causes: – spread of infection into the brain, -from middle ear, head injury, heart Brain is damaged because the flow of blood or CSF is blocked. Treatment – antibiotics b) Encephalitis – infection of the brain. Causes – virus transmitted by mosquito Occasionally herpes simplex virus. Symptoms – from mild to severe, headache, fever, nausea, convulsions, delirium, coma, paralysis. Treatment – antiretroviral drug (acyclovir) for Herpes Other forms - 70% fatal -50% left with severe neurological deficits 5) Cerebrovascular accident (CVA) -temporary loss of blood flow to a region in the brain -likelihood – increases with age. Major types of CVA: a) Obstructive, b)hemorrhagic, c) total interruption (heart stops: 1 min. neurons stop, > 4 min. irreversible damage occurs) -For (a) & (b) damage depends on size and location of blood vessel. eg middle cerebral artery, provides blood supply to motor cortex and language areas. a) Obstructive (Ischemic)– blocks an artery therefore prevents the flow of blood. Causes i) Embolism o Blood clot o Bacterial/fat debris ii)disease of the arterial wall - cholesterol deposits Damage due to reduced oxygen and glucose. Treatment – medications to dissolve blood clot (tPA) or increase blood flow (eg anticoagulants), surgery to remove blood clot. b)Hemorrhagic – bleeding inside the skull damages brain tissue Causes: i) intracerebral hemorrhage in brain. ii) Subarachnoid hemorrhage in meninges. iii) Subdural hematomas caused by head injury i) interacerebral hemorrhage: Damage due to -blood vessel weakened by high blood pressure/age -blood seeps out, accumulates, -or blood vessel dilation puts pressure on surrounding brain tissue Damage - varies from negligible to massive. Eg Symptoms – severe headache, loss of vision, confusion, paralysis, nausea, seizures, loss of consciousness.
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Treatment drugs for high blood pressure surgery to repair blood vessel ii) subarachnoid hemorrhage bleeding between pia mater and arachnoid membrane Cause – rupture of an aneurysm in cerebral artery or malformed blood vessel Symptoms: warning signs – headache, facial pain, double vision. -after rupture – severe headache, confusion, paralysis, coma, death. Treatment of an aneurysm – analgesics (opioids), non steroidal anti-inflammatory (not aspirin) -surgery – isolate and/or support the blood vessel wall (eg coiling procedure slows blood flow through aneurysm, promotes clot formation and seals aneurysm off). How do CVA’s cause brain damage? In general: stops or floods blood, kills cells in immediate region then cells within the penumbra (surrounding region) die within the next few days Important Cascade of events: a) obstructive = decrease Oxygen & glucose Hemorrhagic= increase Oxygen & calcium b)Sodium-potassium pump slows -K+ accumulates outside neuron -Na+ accumulates inside neuron -causes edema ( absorb water and swell). -inflammation attracts - glia , -eg., astrocytes that engage in phagocytosis (engulfing and removing of debris) -attracts white blood cells which adhere to and block capillaries c)reverses neuronal glutamate transporters - Glial cells dump glutamate -over stimulates NMDA receptors -Na+K+ pump impaired -calcium enters the postsynaptic cell - extra ions swells/bursts neuron -activates enzymes that destroy molecules vital for normal cell function. d)damaged mitochondria -produces free radicals (molecules with unpaired electrons that act as oxidizing agents) -these destroy proteins, fatty acids & nucleic acids. e) toxic cascade is spread f) glial cells proliferate, remove debris, create scar tissue. CVA case study: Why are CAT scans unable to detect changes in the brain after a stroke? Minimization of brain damage: i)soon after onset (1.5 - 3 h) try to dissolve blood clots eg., “tissue plasminogen activator” (tPA) ii)try to prevent the death of cells in the penumbra -anti-inflammatory agents -affect glutamate: decrease release, block receptors -block calcium or open K+ channels -inactivate free radicals
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-cool the brain Recovery of Function General observations: -effects arising from brain damage may be confused with recovery -recovery is precarious at best -brain damage will manifest itself during, stress, exhaustion, drinking and with age -likelihood of recovery changes with age and/or place of damage -smaller lesions more likely associated with recovery How does age influence recovery? 1)in children: establish new connections with spared neurons (Kennard principle) -due to collateral’s sprouting, dendrite branching, and redirection of axons -different patterns of connections are not necessarily better ones. 2)different effects due to slowly maturing neurons. Eg frontal lobes in young How does Timing of lesions influence recovery? -serial lesion effect – damage occurs in several stages with time to recover between each. -even after massive cumulative damage, function is still possible. Due to: - collateral sprouting or - surviving abilities are used in better ways. Potential mechanisms of recovery: a) behavioral intervention -compensation -exercise eg., sensory stimulation i.e., highly stereotyped repetitive training (Muir & Steeves, 1997) b) stimulate surviving neurons -prevents diaschisis (reduced activity of surviving neurons) -amphetamine + physiotherapy c) stimulate regeneration PNS: Schwann cells guide and direct - neurotrophic factors (promote growth) & - cell-adhesion molecules (provide path). Guidance may be: i) correct if axon /myelin is just crushed ii) incorrect if axon is severed by a few mm, or iii) not at all if axon is severed by a greater distance. -however, could build bridges to support nerve growth through gap, eg Spidrex or modified spider silk to be used as scaffold for neuronal growth. Priestly 2006) CNS: regeneration possible or not? -blocked by glycoproteins released by oligodendrocytes -could try grafting PNS glia into CNS + axon growth blocked by proteins eg Nogo -blocking Nogo in rats, allows spinal neurons to regrow and rats to behave normally (ie swim, balance, climb (Schwab, 1990’s) -similar/better results observed by blocking Nogo’s receptor (Strittmatter, 2001) scar tissue –dealing with a physical barrier - use chondroitinase ABC (bacterial enzyme dissolves barrier) - could inject filled biodegradable nanospheres
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-but also dealing with chemical barrier eg., astrocyte inhibitor proteins. - If block chemicals, either see abnormal behavior, little growth (Fawett et al.., 2001) vs., behavioral recovery/neuroplasticity (Seymour et al.., 2005). Other strategies to save cells/promote regeneration: Create genes synthesizing neurotrophins carried through viruses injected into target site -alter stem cells to create neurotrophins.
d) collateral sprouting from undamaged axon -may be useful, useless, or harmful. -eg gangliosides? e) denervation /disuse supersensitivity increase receptor sites postsynaptically = > sensitivity to neurotransmitter. How does denervation supersensitivity affect rats behavior? Eg with neurotoxin that destorys DA neurons damaged in left hemisphere of rats. f) reorganization of sensory representation -cells no longer receiving input respond to other sections of somatosensory cortex. -due to collatoral sprouting or denervation supersensitivity Not always positive effects Eg phantom limb pain g) Brain Grafts : replacing dead brain cells with living ones. -historically in rats learned that reasonable connections could be established and that rarely are CNS transplants rejected. Neurotransplantation protocols in humans currently involve i)stimulate and redirect regeneration in CNS eg transplant Schwann cells (Aguayo et al., 1987) ii)replace dysfunctional tissue eg Parkinson’s Disease -transplant DA-releasing fetal cells -does it work? (eg Freed, Fahn et al., 2001)
However, routine for new medical techniques- to be investigated firstly in tissue cultures, rats, primates (and than with knowledge of risks and benefits) - lastly in humans. -problem – no guarantee of successes transferred between species, ethical constraints on primate studies. Hope for modest changes (eg bladder control)