1. BRAIN DAMAGE AND HUMAN NEUROPSYCHOLOGICAL DISEASES Outline 1. Causes of Brain Damage a. Tumors b. Cerebrovascular Disorders c. Closed-Head Injuries d. Infections e. Neurotoxins 2. Neuropsychological Diseases a. Epilepsy Kindling Model of Epilepsy b. Alzheimer’s Disease Transgenic Mouse Model of Alzheimer’s Disease c. Parkinson’s Disease MPTP Model of Parkinson's Disease

2. Causes of Brain Damage: Tumors A tumor (neoplasm) is a group of cells growing independently of the rest of the body a tumor can be Encapsulated (grow within their own membrane) usually benign (can be removed without further risk of growth) Infiltrating (grow diffusely through surrounding tissue) Usually malignant (difficult to remove or destroy and likely to spread) Metastatic tumors are tumors that originate in one organ and spread to another the symptoms of multiple cerebral tumors are often the first signs of lung cancer 20% of brain tumors are meningiomas that grow in the meninges they are encapsulated and benign

5. Cerebrovascular Disorders “Stroke" is commonly used to refer to any cerebrovascular disorder of sudden onset Two types 1) cerebral hemorrhage the bursting of aneurysms (balloon-like dilations of weak areas of blood vessels) is a major cause of intracerebral bleeding aneurysms can be congenital or the result of infection, toxins etc.

6. Cerebrovascular Disorders 2) Cerebral ischemia is a disruption of blood supply to an area of the brain Three main causes (1) in thrombosis a plug (a thrombus) becomes lodged at its site of formation the plug may be due to a blood clot, fat, cancerous cells, etc. (2) in embolism a plug (an embolus) travels from its site of formation and becomes lodged in a smaller blood vessel (3) in arteriosclerosis the blood vessel walls thicken and the space inside narrow usually from the accumulation of fat

7. Cerebral Ischemia The brain damage caused during an ischemic episode is believed to be due to an excessive release of excitatory amino acids Glutamate, the brain’s most prevalent excitatory amino acid neurotransmitter, is released in excessive quantities when blood vessels are blocked

8. Cerebral Ischemia The excessive glutamate over-activates glutamate receptors on postsynaptic membrane sites NMDA (N-methyl-D-aspartate) receptors Thus, too many Na+ and Ca++ ions are allowed to enter the postsynaptic neuron The over abundance of Na+ and Ca++ triggers (a) an excessive release of glutamate, causing a cascade of this toxic effect (b) triggers a sequence of reactions that kills the postsynaptic neuron They are excited to death

10. Cerebral Ischemia The brain damage caused by ischemia takes a while to develop (days) Does not occur equally in all regions of the brain Hippocampus is particularly vulnerable Researchers are currently studying the ability of NMDA receptor blockers administered directly after a stroke to reduce subsequent brain damage

11. Closed-Head Injuries A brain contusion is an injury in which there is bleeding from the brain in the absence of a laceration the bleeding results in a hematoma (a bruise or collection of clotted blood) contusions are caused by the brain hitting the skull, and they are often contre coup (on other side of brain from blow) Concussion is the diagnosis when a blow to the head disrupts consciousness, but no evidence of physical damage can be found the punch-drunk syndrome is general dementia due to an accumulation of many concussions The case of Jerry Quarry

12. Infections Encephalitis is the general term for inflammation of the brain resulting from infection Bacterial infections can be treated with antibiotics, but if left untreated they can cause meningitis (inflammation of meninges) brain abscesses (pockets of pus), general paresis (a syndrome of weakness and dementia) Syphilis – passed through contact with genital sores Can remain dormant for several years, then turn virulent and attack many parts of the body, including the brain General paresis

13. Infections Viral infections include infections that preferentially attack the nervous system (e.g., rabies virus) infections that show no preference for the nervous system but still sometimes attack it (e.g., mumps and herpes viruses) Viruses may play a key role in the etiology of many neuropsychological disorders Their role is often hard to study because they may lie dormant not produce symptoms until years after they invade the nervous system

14. Neurotoxins Brain damage can be produced by a variety of toxins in the environment "mad hatters" were the result of mercury poisoning Mercury in the felt "crackpots" were originally those who drank tea from cracked ceramic pots with lead cores Sometimes drugs used to treat a disease can have neurotoxic effects Tardive dyskinesia is a disorder produced by prolonged exposure to certain antipsychotic medications

19. Questions for Film What are symptoms of Parkinson’s Disease? What happens in the brain that produces Parkinson’s disease? What causes Parkinson’s disease? What was the initial treatment for Parkinson’s disease that was discussed in the film. L-Dopa – what is it? What was the problem with this treatment? Where did the Mexican surgeons get the cells they implanted in the Parkinson’s patients? Where did the Swedish surgeons get the cells they implanted in the Parkinson’s patients? Where did the Swedish surgeons implant the stem cells in the MPTP patient’s brains? – Caudate and Putamen Why there and not the Substantia Nigra? Why did the procedure work better for MPTP patients than for traditional Parkinson’s patients? What was one of the big advantages of discovering the MPTP molecule? Animal models – deprenyl – monoamine agonist = MAO inhibitor Why was it that the Swede’s did not use Connie as a subject at first.