2. Brain dysfunction Zhihua Gao Neuroscience Institute

3. Outline Biology of the brain Cognitive disorders Conscious disorders Summary

4. 4 Biology of the Brain inside the skull skull provides protection but confines the brain Basics of human adult brain: Weight: ~3 pounds Size: ~a medium cauliflower

5. How does the brain get fed? Blood supply from twin vertebral arteries and carotis interna provides the brain nutrition. However, nutrients have to pass through the blood brain barrier to get into the brain.

6. Blood brain barrier ( 血脑屏障 ) BBB consists of:  tight junctions around the capillaries  endothelial cells  a thick basement membrane  astrocyte endfeets

7. 7 Blood brain barrier (BBB) provides a selective filter for the brain BBB allows essential metabolites, e.g. oxygen and glucose to diffuse from the blood to the brain, but blocks most molecules (>500 Dalton). Protects the brain from "foreign pathogens, e.g. viruses and bacteriaviruses bacteria Shields the brain from hormones and neurotransmitters Maintains brain homeostasis

8. 8 Brain Metabolism The most active organ in energy metabolism (high demand for blood and oxygen supply). Glucose is the primary energy source; however, the storage of glucose in the brain is very limited. Brain is highly sensitive to hypoxia and ischemia.

9. 9 What consists of the brain? Biology of the Brain Neurons: executors of brain function Glial cells: supporters and sponsors Neurons and glial cells form a complex network to ensure normal brain function.

10. How do neurons communicate? A synapse is a structure that permits neurons to transmit the electrical or chemical signal from one to another. Functional unit in the brain-synapse

11. 11 Electrical current travels down the axon. Vesicles move towards the membrane and fuse into the membrane. Chemicals are released, diffusing towards the next cell ’ s membrane. The chemicals bind to the receptor and opens up channels, relaying the signal to the next cell. Pre-synaptic membrane Post-synaptic membrane How does the synapse transmit the signal?

12. 12 Brain function Central control of the human body Maintain cognition Maintain consciousness

13. Diffusive or localized lesion ? Location determines the symptom. Acute or chronic? Phases determines the symptom. Acute conscious disorder Chronic cognitive disorder Brain has very limited capacity for self- repair Brain lesions: some principles

14. 14 Brain responses to lesions Cellular level: –Neuronal death (necrosis, apoptosis) –Degeneration (axon/dendrites retraction, atrophy ) –Inflammation (microglia, astrocytes) –Demyelination (oligodentrocytes) Systemic level: –Cognitive disorder –Conscious disorder

15. 15 Outline Biology of the brain Cognitive disorder ( 认知障碍 ) Conscious disorder ( 意识障碍 ) Summary

16. 16 Cognition and cognitive disorder Cognition--the process of the brain to sense, handle and acquire information Involves a series of voluntary psychological and social behaviors, such as study, memory, thinking, judgment and emotion. Relies on the normal function of the cerebral cortex. Cognitive disorders--the disturbance of the process related to cognition

17. Structural Basis of Cognition Brodmann Mapping (52 areas) Cerebral cortex

18. Structural Basis of Cognition

19. Frontal lobe  Controls voluntary movement, memory, writing, thinking, creative thoughts, judgment, understanding and social responsibility and personal morals.  When damaged:  Loss of simple movement  Loss of flexibility in thinking  Changes in social behavior  Changes in personality  Inability to express language

20. 20 When frontal lobe is damaged:  Hemiplegia ( 偏瘫 ): paralysis of one side of the body  Aphasia ( 失语 ): partial or total loss of the ability to communicate verbally or using written words  Broca’s aphasia: inability to express language (areas 44&45)  Agraphia ( 失写 ): A form of aphasia characterized by loss of the ability to write.  Dementia( 痴呆 ): loss of mental ability that interferes with normal activities of daily living (> 6 months), without a loss or alteration of consciousness.

21. 21 Processes and discriminates between different sensory inputs When damaged: Agraphia ( 失写 ): inability to locate the words for writing Alexia ( 失读 ): Problems with reading Agnosia ( 失认 ): Inability to recognize objects Contralateral sensory deficits Parietal lobe

22. 22 Is involved in processing sensory (auditory and visual) input, language comprehension and new memories When damaged Wernicke’s aphasia ( 感觉性失语 ) (area 22 ， can speak, but meaningless) Spatial or emotional memory impairment caused by hippocampal lesion ( 空间与情感记忆障碍 ) Temporal lobe

23. 23 Learning and memory defects Henry Molaison ( HM) Patient An epileptic patient

24. 24 HM’s lesion includes medial temporal lope structures in addition to hippocampus (amygdala, entorhinal cortex…) Surgery removal of the temporal lobe

25. 25 HM’s good news and bad news The surgery had a profound effect on declarative memory –Severe anterograde amnesia (he lives in the present!) –Mild retrograde amnesia (only instant memory) –unable to commit new short-term memory into long- term memory But there was no effect on: –Personality –Attention –Intelligence (normal IQ) –Motor skill learning

26. 26 Visual sensing and processing –Lesions in the primary visual cortex result in defects in visual fields. – Lesions in the visual association cortex result in loss of objective recognition and of distinguishing the differences between animals cat or dog? Deer or horse? Occipital lobe

27. Major manifestations of cognitive disorder Learning and memory deficits Aphasia ( 失语 ) Hemiplegia ( 偏瘫 ) Agraphia ( 失写 ) Apraxia ( 失用 ) Alexia ( 失读 ) Agnosia ( 失认 ) Dementia ( 痴呆 )

28. 28 Etiology and Pathogenesis Chronic brain damage Chronic systemic diseases Mental and psychic disorder Other factors

29. Pathogenesis of cognitive disorder Pathogenic factors Changes in neurotransmitters, receptors, neuropeptides and neurotrophic factors Genetic abnormalities Chronic viral infection Chronic ischemia Metabolic abnormalities Protein aggregation Abnormal protein modifications Reduced ATP production, acidosis, elevation of calcium, free radicals and inflammatory factors, Chronic brain damage brain dysfunction Cognitive disorder

30. 30 Chronic Brain Damage Alterations in regulatory molecules Aberrant protein aggregation Chronic cerebral ischemic injury Environmental and metabolic toxins Cerebral trauma Brain aging

31. Alterations in regulatory molecules Abnormal levels in Neurotransmitters and receptors –Dopamine –Norepinephrine –Acetylcholine (Ach) –Glutamate Neuropeptides Neurotrophic factors

32. Dopamine Pathway Dopamine

33. Distribution ： Dopamine pathway

34. Parkinson Disease

35. Abnormal protein aggregation Generally seen in a range of neurodegenerative diseases, e.g. Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Prion disease Caused by –Gene mutations –Abnormal post-translational modifications –Infection of prion protein in the brain

36. Cleaved to generate N-terminal polyQ fragments Aggregates form in cytoplasm and in nucleus-amyloid- like conformation Controversy over whether aggregates are toxic or protective Gain of toxic function and/or loss of protective function Q QQ Q QQ Q Q Q Mutant Huntingtin in Huntington’s disease

37. Mutant  -synuclein in Parkinson’s disease

38. Alzheimer’s Disease

39. Gradual memory loss Decline in the ability to perform routine tasks Disorientation Difficulty in learning Loss of language skills Impairment of judgment and planning Personality changes

40. Senile plaques Neurofibrillary tangles

42. Chronic Cerebral Ischemic Injury Brain has low energy reserve. Brain is highly sensitive to ischemia and hypoxia. –Neurons die upon complete ischemia for 5 min. Ischemia causes cognitive disorder likely by the following mechanisms: –Energy exhaustion and acidosis –Intracellular calcium overload –Free radical injury –Excitatory toxicity –Cytokines induced inflammatory reactions

43. Excitatory toxicity Deficits in energy production, caused by ischemia and hypoxia, inhibits the activity of the Na+-K+- ATPase in plasma membrane, resulting in substantial elevation of extracellular K +, depolarization of neurons, accompanied by overdosed release of EAA (excitatory amino acids). This leads to the over activation of EAA receptors and neuronal over excitement and death. EAA: glutamate and aspartate IAA: GABA and glycine

44. Principles for Treatment of Cognitive Disorders General neuroprotective treatments Restore and maintain the normal levels of neurotransmitters and regulatory molecules Surgery

45. Outline Biology of the brain Cognitive disorders Conscious disorders Summary

46. 46 Consciousness and conscious disorder Consciousness refers to individual awareness of self thoughts, memories, feelings, sensations and environment Two aspects: –State of arousal (by subcortical regions) –Responsiveness (controlled by cortex) Consciousness disorder refers to the impairments in maintaining awareness of self and environment and responding to environmental stimuli

47. 47 Structural Basis for Consciousness cerebral cortex Dynamics between ARAS and ARIS and their association with cerebral cortex determines the state of consciousness. Brain stem reticular formation thalamus

48. Brain stem reticular formation 上行激动系统 (ARAS) 上行抑制系统 (ARIS) ARAS 的投射纤维终止于大脑皮层广泛区域 主要维持大脑皮层兴奋性，维持觉醒状态和产生意识活动 ARIS 发出的上行纤维行走于 ARAS 大体一致 主要对大脑皮层兴奋性起抑制作用 ARAS ARIS

49. 丘 脑 由多个核团组成 特异性核团 : 向大脑皮层传递各种特异性感觉信息 非特异性核团 : 接受脑干 网状结构上行纤维并向 大脑皮层广泛部位投射， 参与维持大脑皮层觉醒状态 损害可致长期昏睡。

50. Major manifestations of conscious disorder Delirium Confusion Stupor Coma 谵妄 精神错乱 昏睡 昏迷

51. Etiology and Pathogenesis Acute brain injury –e.g. Diffuse encephalic infection, diffuse brain trauma, subarachnoid hemorrhage, etc. Acute brain intoxication Endogenous poisonous lesion Exogenous poisonous lesion Intracranial extrusion and destructive lesion Rapidly expanding or destructive lesions

52. Pathogenesis of conscious disorder Pathogenic factors Acute brain lesion Brain intoxication Brain tumor Direct damages to neurons Axonal injury, cell swelling Abnormal neurotransmitters Suppress the brain and brain stem Abnormalities in the cortex and BSRF function Conscious disorder Abnormalities in energy metabolism Abnormalities in plasma membrane

53. 53 Principles in Prevention and Therapy Urgent management Making a definitive diagnosis ASAP (as soon as possible) Monitoring vital signs and conscious state Brain protections

54. Outline Biology of the brain Cognitive disorders Conscious disorder Summary

55. 55 Glossary Cognition, cognitive disorder, Broca’s aphasia, Wernicke’s aphasia, dementia Conscious disorder, delirium, excitatory toxicity

56. 2. Questions What is the characteristics of brain disorders? What is the pathogenesis of cognitive disorder? What is the pathogenesis of consciousn disorder?

57. 1. Broca’s aphasia is caused by lesions in which of the following region: A. Temporal lobe B. Parietal lobe C. Frontal lobe D. Occipital lobe 2. Ischemia causes cognitive disorder likely by the following mechanisms: A. Energy exhaustion and acidosis B. Intracellular calcium overload C. Free radical injury D. Excitatory toxicity E. All of the above Quizz

58. 3. The following signs manifest the consciousness disorder EXCEPT: A. Delirium B. Confusion C. Coma D. Aphasia 4. Memory loss can result from lesions in which of the following region: A. Temporal lobe B. Parietal lobe C. Hypothalamus D. Occipital lobe Quizz

59. Thank you!