Brain dysfunction

1. Brain dysfunction Jinghua Jin Department of Neurobiology jhjin@zju.edu.cn

2. What you have learned about human brain? • Anatomy? • Brain structure? • Histology? • Cell types? • Physiology? • Brain function? • Pharmacology? • Central nervous system drugs ?

3. Outline • I: General conception about human brain • II: Cognitive disorder • III: Consciousness disorder • IV: Summary

4. 1.Structural Characteristics • It is located inside the skull, protects brain from injury, confines the brain • It is composed of neurons and glial cells • The blood supply is from twin vertebral arteries and carotis interna • The brain blood barrier protects brain from invasion of toxic insults

5. Human Brain To understand the dysfunction of the brain, it’s important to know a bit about the brain… • The Brain’s Vital Statistics • Adult weight: • about 3 pounds (~1.5kg) • Adult size: • a medium cauliflower • Number of neurons: • 100 billion • Number of synapses: • 100 trillion

6. Inside the Human Brain

7. Cell Types of the Brain Neurons Glia

8. Structure of Neuron

9. Neurons Specialized Regions of Neurons Carry out Different Functions Hippocampus（海马） Structure of typical mammalian neurons

10. Glia

11. Cellular Functions • Neuron is in charge of different functions • Glia nourishes and protects the neurons

12. Spine How are neurons connected? • Synapses!!

13. How does the Synapse carry the signal? 1. Electrical current travels down the axon • Vesicles with chemicals move toward the membrane • Chemicals are released and diffuse toward the next cell’s plasma membrane 4. The chemicals open up the transport proteins and allow the signal to pass to the next cell

14. 2. Characteristics of Metabolism • The most active organ in energy metabolism • Glucose is almost the only source of brain energy • The storage of glucose in the brain is very limited

15. 3. Characteristics of Brain Disease • Region-dependent consequences to injuries • When the cerebral cortex is damaged, the degree of dysfunction is proportionate to the extent of the damage: The more extensive the damage, the more severe the dysfunction is likely to be. However, when the brain stem is damaged, a relatively small amount of damage may cause complete loss of consciousness and even death.

16. When Specific Areas of the Brain Are Damaged

17. 3. Characteristics of Brain Disease • Limited capacity for self repair Three characteristics of the brain help it compensate and recover after it has been damaged: • Redundancy: More than one area can perform the same function. • Plasticity: Nerve cells in certain areas can change so that they can perform a different function. • Adaptation: Areas with somewhat overlapping functions can sometimes compensate for lost functions.

18. Brain responses to Injuries • Cellular responses: • Neuron death (necrosis, apoptosis) • Degeneration (axon/dendrites retraction, atrophy ) • Inflammation (microglia, astrocytes) • Demyelination (oligodentrocytes) • Functional responses: • Acute brain damages will cause disturbance in consciousness: Consciousness disorder • Chronic lesions usually lead to cognitive dysfunction: Cognitive disorder

19. Outline • I: General conception about human brain • II: Cognitive disorder • III: Consciousness disorder • IV: Summary

20. 1.Cognition • The ability of the brain to process and store information in order to solve problems. • It involves a series of voluntary psychological and social behaviors, such as study, memory, language, thinking, emotion etc.

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

22. Function of cerebral cortex • Frontal cortex: voluntary movements, complex intellectual activities such as writing, memory, creativity, judgment, vision and social responsibility. • Lesions in this area will result in contralateral hemiplegia (偏瘫), agraphia （失写症）and frontal dementia （痴呆）. • Damage in Broca’s area (44 and 45) result in motor aphasia (Broca’s aphasia)

23. Function of cerebral cortex • Parietal cortex: plays major role in high level process and integration of sensory information. • Lesions in this area produce controlateral sensory deficits. • Lesions in the angular gyrus (角回) result in alexia (失读症). • Lesions in the supamarginal gyrus (缘上回) result in astereognosis (实体感觉缺失).

24. Function of cerebral cortex • Temporal cortex: sensory receiving area for auditory impluses. • Lesions in area 22 (auditory association cortex) can lead to Wernicke’s aphasia • Lesions in temporal hippocampus can produce spatial or emotional memory impairment

25. Function of cerebral cortex • Occipital cortex: vision • Lesions in the primary visual cortex result in visual fields defects. • Lesions in the visual association cortex result in a lack of recognition of objects and in distinguishing the difference of animals (cat vs. dog).

26. 2. Cognitive Disorder • The disturbance of the mental process related to learning and memory, reasoning and judgment, accompanied by aphasia (失语), apraxia (失用), agonasia (失认) or disturbance in executive functioning

27. Major Manifestations • Learning and memory disorders • Aphasia • Agonosia • Apraxia • Dementia

28. Case: Patient H.M. • Patient HM suffered from epilepsy to his medial temporal lobe (MTLs). On September 1, 1953, surgeons removed parts of HM's medial temporal lobe on both sides of his brain. HM lost approximately two-thirds of his hippocampal formation, parahippocampal gyrus, and amygdala. His hippocampus appeared entirely nonfunctional because the remaining 2 cm of hippocampal tissue appears atrophic and because the entire entorhinal (which forms the major sensory input to the hippocampus) was destroyed. Some of his anterolateral temporal cortex was completely destroyed. • After the surgery he suffered from severe anterograde amnesia: although his short-term memory was intact, he could not commit new events to long-term memory. According to some scientists, HM is impaired in his ability to form new semantic knowledge but researchers argue over the extent of this impairment. He also suffered moderate retrograde amnesia, and could not remember most events in the 3-4 day period before surgery, and some events up to 11 years before, meaning that his amnesia was temporally graded. However, his ability to form long-term procedural memories was still intact; thus he could, as an example, learn new motor skills, despite not being able to remember learning them.

29. Learning and memory deficits: Patient HM: MRI HM’s lesion includes medial temporal lope structures in addition to hippocampus (amygdala, entorhinal cortex…)

30. HM’s good news and bad news The surgery had a profound effect on declarative memory Severe anterograde amnesia Mild retrograde amnesia Disability to transfer new short-term memory into long-term memory But there was no effect on: Personality Attention Intelligence Many forms of memory were spared (short-term memory, motor, implicit memory, etc).

31. 3. Etiology and Pathogenesis • Chronic brain damage • Chronic systemic diseases • Mental and psychic disorder • Other factors

32. Chronic Brain Damage • Imbalance of regulating molecules in the brain • Protein aggregation in the brain • Chronic cerebral ischemic injury • Environmental and metabolic toxins • Cerebral trauma • Brain aging

33. (1) Imbalance of Regulating Molecules • Dopamine • Norepinephrine • Acetylcholine (Ach) • Glutamate • Aberrant neuropeptide • Lack of neurotrophic factors

34. Dopamine Dopamine Pathway

35. Dopamine Synthesis and Storage Tyrosine  L-DOPA  DA

36. Distribution：Dopamine pathway

37. Parkinson Disease

38. (2) Protein Aggregation in the Brain • Gene mutations • Abnormal post-translational modification • Infection of slow virus in the brain

39. 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

40. Mutant a-synuclein in Parkinson’s disease

41. Alzheimer Disease

42. Alzheimer’s Disease • 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

43. Senile plaques Neurofibrillary tangles

46. (3) Chronic Cerebral Ischemic Injury • Energy exhaustion and acidosis • Intracellular calcium overload • Free radical injury • Excitatory toxicity • Inflammatory reaction by cytokine

47. Glutamate

48. Excitatory toxicity • A general pathologic process beginning with the energy and metabolic dysfunction caused by cerebral ischemia and anoxia, which then result in inhibition of Na+-K+-ATPase in plasma membrane, elevation of extracellular K+ and depolarization of neurons. These changes then cause overdosed release of EAA (excitatory amino acids) into the synaptic cleft and overacitvation of EAA receptor, ultimately over excitement and death of neurons.

49. Pathogenesis of Cognitive Disorder

50. 4. Principles for Treatment of Cognitive Disorders • General neuroprotective treatments • Maintenance of normal neurotransmitter level • Surgery