Brain Damage & Recovery

1. Brain Damage & Recovery • Causes of brain damage • Some examples of brain damage • Effects of brain damage • Recovery from brain damage • Myelination disorders

2. Causes of Brain Damage • Genetic (not necessarily hereditary!) • Congenital • Environmental (toxins) • Neoplasms • Apoptosis (programmed cell death) • Cerebrovascular problems • Head impact injuries (closed head) • Infections

3. Hereditary Brain Damage • Passed from parent to child through DNA. • Several types: • Faulty chromosome duplication • Rare • Dominant gene disorders • Rare, tend to be self-limiting. • Recessive gene disorders • Not all children express the defect. • Polygenetic disorders • By far the most common.

4. Faulty Chromosome Duplication • Trisomies • Patau’s Syndrome (trisomy 13) • Cleft lip, polydactyly, heart, stillborn or die young. • Edward’s Syndrome (trisomy 18) • Multiple major abnormalities & MR • Down’s Syndrome (trisomy 21) • MR, Alzheimer’s • Others • Turner’s Syndrome (X0) • Klinefelter’s Syndrome (XXY)

5. Dominant Gene Disorders • Normally the disorders prevent their own reproduction, with two exceptions: • Disorder limited to rare environmental conditions. • Disorder manifests itself later in life. • Pubertal changes required for gene expression • Adult onset. • Huntington’s disease (Huntingtin, 4p16.3) • Early-onset Parkinson’s (pre-50, chr. 4 & 6) • (not all Parkinson’s cases are genetic)

6. Recessive Gene Disorders • Single defective gene is passed from parents to children, but only ~25% of children express (or know of) the disorder. • Often affects myelination of cerebral neurons. • Pelizaeus-Merzbacher brain sclerosis • PLP (proteolipid protein), Xq21.3-q22. • Adrenoleukodystrophy (ALD) • Xq28 mutation causes peroxisomes to lose the ability to breakdown very long chain fatty acids (VLCFAs). VLCFAs degrade both myelin and the adrenal gland.

7. Polygenetic Disorders • Requires the presence of multiple defective genes, along with environmental influences. • Most psychological disorders & personality traits. • Genetics can also protect against disorders.

8. Congenital Brain Disorders • In-womb damage • Typically due to maternal toxin exposure • Fetal Alcohol/Narcotic Syndrome (FAS/FNS) • Prescription drugs • Thalidomide – “seal limb” • DES (synthetic estrogen) – 50% vaginal cancer by age 10 • Birth Trauma • Hypoxia due to umbilical strangulation • Forceps damage during delivery • Gonorrhea and herpes infections

9. Environmental • Toxins • Ingested toxins (alcohol, drugs, etc.) • Heavy metal (mercury, lead, etc.) poisoning • Radiation (fallout, exposure, X-rays, etc.) • Radiation can cause genetic mutations. • Drugs • Drugs of abuse • Aspirin – Reye’s Syndrome • Nutritional problems

10. Neoplasms (Cancers) • Mass of new tissue (= “new growth”). • Physiologically useless. • Growth is usually not controlled. • Neoplasms account for a relatively high proportion of neurological disease. • Brain is 2nd only to uterus as tumor area. • Brain tumors typically not from nerves. • Gliomas account for 45% of brain neoplasms

11. Neoplasms • Two types of tumors • Benign (-omas) • Regular, well-defined shape. • Does not intrude into surrounding tissue. • Effects only by pressure on the brain. • Malignant (-carcinomas) • Irregularly shaped. • Intrudes (infiltrates) into surrounding tissue. • Tend to be recurrent.

12. Neoplasms • Astrocytomas • 40%, slow growing, good prognosis • Glioblastomas • 30%, M, >30, highly malignant, < 1 year. • Meduloblastomas • 11%, children only, 1.5-2 years • Meningioma • Most benign of brain tumors, well encapsulated. Glioblastoma

13. Neoplasms • Metastatic Tumors • Cancerous cells migrate from other parts of the body, normally the lung or breast. • It is not uncommon for lung cancers to first be noticed in the brain. • Normally multiple implant sites. • All malignant. • Very hard to treat.

14. Cell Death • Apoptosis • Death by suicide • Normal housekeeping • Shrivel and waste • Slow death, days • No inflammation • Nucleus affected from the beginning • More prevalent in early development • Necrosis • Externally caused • Death by injury • Cells swell and rupture • Death is swift, < 1 hour • Surrounding area becomes inflamed • Nucleus not affected until the very end

15. Cerebrovascular Damage • Brain is well-protected against vascular problems. • Bilateral independent arterial supply both front and back. • Circle of Willis

16. Cerebrovascular Damage

17. Cerebrovascular Damage • Aneurysms = weakened/expanded blood vessels • Take up space normally occupied by brain. • Ruptured aneurisms = hemorrhage • Stroke / cerebrovascular accident (CVA). • Arteriosclerosis • Hardening/narrowing of arteries. • Cerebral thrombosis • Lodged embolus causes ischemia and infarction.

18. Aneurysm • Weakened and/or expanded blood vessels, or pouches. • Can burst causing hemorrhage, infarction & ischemia.

19. Aneurysm of aortic arch

20. Arteriosclerosis • Arteries get clogged • Fat & cholesterol • Blocks oxygen delivery. • Partial obstructions require increased blood pressure to push blood past obstruction. • Elevated BP can rupture aneurysms.

21. Thrombosis • Floating body lodges in vessel. • A 70-year-old woman presented to the emergency room with an acute onset of left arm weakness, difficulty walking and slurred speech. • DX: Acute cerebral infarct from right MCA thrombosis.

22. Thrombosis

23. Thrombosis

24. Cerebrovascular Damage • Formerly assumed that most damage was due to decreased oxygen and/or glucose. • Now appears that most cerebrovascular damage is due to excess glutamate release by blood-deprived neurons. • Excess Ca++ and Na+ influx, especially through NMDA receptors, kills cells. • Hippocampus is particularly affected. • Ca++ channel & NMDA receptor blockers helpful in preventing post-stroke damage.

25. Head Impact Injuries • Car accidents • Household accidents • Falling down stairs • Bike/scooter/Rollerblade accidents • Shaken baby syndrome • Physical abuse

26. Head Impact Injuries • Contusions (= bruise) • Damage to the vascular system. • Hematomas - localized collections of blood. • Subdural - beneath (inside) the dura • Epidural - on top of (outside) the dura • Many are contrecoup, opposite to blow.

27. Head Impact Injuries • Concussion • Disturbance of consciousness without evidence of contusion or other structural damage. • Common assumption is temporary disruption with no long-term damage. • Punch-drunk syndrome suggests otherwise. • Boxers show cerebral scarring with dementia.

28. Other CNS Injuries • Primarily spinal cord • Slipped disk • Intervertebral disk presses into cord. • Vertebral fracture • Spinal cord can be transected, with varying disabilities.

29. Infections • Bacterial • Streptococcus • Sore throat, OCD, ADHD • Syphilis (shown) • General pariesis – insanity and dementia • Neisseria meningitidis • Campylobacter jejuni • Common intestinal bacteria • Clostridium tetani (tetanus) • Neurotoxin that blocks cholinesterase

30. Infections • Viral • Rubella (German measles) • Rubeola (measles) • Varicella/Zoster (chicken pox/shingles) • Mumps • Poliomyelitis • Cytomegalovirus (CMV) • Epstein-Barr virus • Rabies • Herpes

31. Infections • Encephalitis - inflammation of brain • Bacteria and/or viruses – herpes (shown) measles, chicken pox, mumps, etc. • Sometimes passed by mosquitos or animals. • Can have high mortality rate.

32. Infections • Meningitis - inflammation of the meninges • Bacteria, viruses, funguses, toxins. • Bacterial form (Neisseria meningitidis) most common. • Viral form most deadly. • Often mistaken for flu: fever, aches, stiffness. • Drowsiness, stupor, seizures, then coma.

33. Effects of Brain Damage • Kill neurons • Damage to nerve itself • Damage to glial cells/altered environment • Damage to pre-/post-synaptic nerves • Crowd out or put pressure on the brain • Disable neurons • Often by interfering with myelin

34. Recovery of Function

35. Recovery of Function • What happens after (or during) brain damage? • Degeneration • Regeneration • Reorganization • Can anything be done to aid recovery?

36. Degeneration • Damaged neurons degenerate over days by the process of phagocytosis: • By astroglia in CNS. • By Schwann cells in the PNS.

37. Degeneration • Anterograde – segments distal to soma: • Always die thru Wallerian degeneration. • Swell within hours, fragment within days • Distal neurons can also be affected. • Retrograde – segments proximal to soma: • Might die, might live. • Early swelling = regeneration likely • Early shrinking = degeneration likely • Proximal neurons can also be affected.

38. Regeneration • Damaged neurons may regrow. • Regeneration is well developed in invertebrates. • Accurate in both the CNS and PNS. • Accurate even when not in a myelin channel. • Mammals seem to lose their regeneration capabilities during maturation. • Almost non-existent in mammalian CNS. • Hit-or-miss in mammalian PNS.

39. Regeneration • Regeneration in mammals depends on the balance of two competing factors: • Growth promoting factors (higher in PNS) • Neural growth factor (NGF) • Brain-derived neurotrophic factor (BDNF) • Growth inhibiting factors (higher in CNS) • Nogo • Myelin-associated glycoprotein (MAG) • Chondroitin sulfate proteoglycan (CSPG) • Oligodendrocyte myelin glycoprotein (OMG)

40. Regeneration in PNS • If myelin sheaths remain intact, nerve can regrow at mm/day to original destination. • If nerve sections are separated by more than a couple mm, they can grow back thru the wrong myelin tunnels. • If nerves sections are widely separated, both sections will die, or regenerating axon tips will grow wildly into a spaghetti patch.

41. Regeneration • Collateral sprouting • When axons degenerate, adjacent healthy neurons send out axon branches from terminal end or nodes of Ranvier to sites vacated by the dying neuron. • Appears to be mediated by neurotrophic factors released by the denervated target tissue.

42. Neural Reorganization • aka. Plasticity • The ability of the brain to remap its functioning. • 2 Mechanisms: • Rapid reorganization • Altered synaptic strengths • Gradual reorganization: • Establishment of new connections • Collateral sprouting, etc. • Damage repair

44. Neural Reorganization • The extent and mechanisms of neural reorganization are still being debated. • 3 general conclusions • Bona fide recovery is rare. • Small lesions are more likely to be recovered. • Recovery is more likely when young.

45. Therapeutic Implications • Promotion of recovery by neurotransplantation • PNS neurons secrete NGFs and will cause nearby CNS neurons to grow. • Cheng, Cao & Olson (1996) cut an optic nerve, spliced in a PNS nerve segment, and found retinal axon cells projecting to superior colliculus 4 months later. • NGF injection into human CNS promotes a little growth. Anti-nogo allows ~5% regrowth.

46. Therapeutic Implications • Promotion of recovery by rehabilitative training. • At least in motor cortex, greater use = less loss of function (or greater recovery). • Recovery of monkeys with hand motor cortex lesions improved with hand motor tasks. • Humans with spinal cord injuries learn to walk better with rehabilitative treatment than with just physiotherapy.

47. Therapeutic Implications • Promotion of recovery by genetic engineering. • The promise of the future. • Since CNS nerves do not grow because of lack of neural growth factor (NGF), the idea is to introduce some from stem cells or altered viruses. • Nogo also prevents the growth of nerves. Maybe it can be artificially inhibited. Experimental nogo antagonists have been found.

48. Myelination Disorders

49. Myelination Disorders • Dysmyelination – poor myelin formation • Early in life, mostly genetic. • Many disorders • Many affect connection between myelin layers. • Demyelination – myelin destroyed • Later in life, some genetic, mostly autoimmune.

50. Myelination Diseases • Dysmyelination • leukodystrophies (ALD, PMD, Krabbe) - CNS • Demyelination • Guillan-Barré Syndrome (GBS) - PNS • Acute Disseminated Encephalomyelitis (ADEM) CNS • Multiple Sclerosis (MS) - CNS • Combination • Charcot-Marie-Tooth Disease (CMT) – PNS