Brain dysfunction

2. Brain dysfunction Zhihua Gao Neuroscience Institute

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

4. inside the skull skull provides protection but confines the brain Biology of 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. 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 bacteria Shields the brain from hormones and neurotransmitters Maintains brain homeostasis

8. 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 Metabolism Brain is highly sensitive to hypoxia and ischemia.

9. Biology of the Brain What consists 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? Functional unit in the brain-synapse A synapse is a structure that permits neuronsto transmit the electrical or chemical signal from one to another.

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. How does the synapse transmit the signal? Pre-synaptic membrane Post-synaptic membrane

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

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

16. 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 Cognition and cognitive disorder

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

18. Structural Basis of Cognition

19. 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 Frontal lobe

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

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

25. 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 HM’s good news and bad news

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. 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) Major manifestations of cognitive disorder

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

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

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

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

32. Dopamine Dopamine Pathway

33. Distribution：Dopamine pathway

34. Parkinson Disease

35. 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 Abnormal protein aggregation

36. Mutant Huntingtin in Huntington’s disease Q Q Q Q Q Q Q Q Q • 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

37. Mutant a-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 Alzheimer’s Disease

40. Senile plaques Neurofibrillary tangles

42. 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 Chronic Cerebral Ischemic Injury

43. 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 Excitatory toxicity

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

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

46. Consciousnessrefers 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 Consciousness and conscious disorder

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

48. Brain stem reticular formation ARAS ARIS 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

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 Coma 昏迷 Stupor 昏睡 Confusion 精神错乱 Delirium 谵妄