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Brain dysfunction
Zhihua Gao
Neuroscience Institute
Outline
• Biology of the brain
• Cognitive disorders
• Conscious disorders
• Summary
4
Biology of the Brain
• inside the skull• skull provides protectio
n• but confines the brain
Basics of human adult brain:
• Weight: ~3 pounds
• Size: ~a medium cauliflower
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.
Blood brain barrier ( 血脑屏障)
BBB consists of:tight junctions around the capillariesendothelial cells a thick basement membraneastrocyte endfeets
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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
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
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.
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
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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
Brain function
• Central control of the human body• Maintain cognition• Maintain consciousness
•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
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
Outline
• Biology of the brain
• Cognitive disorder ( 认知障碍 )
• Conscious disorder ( 意识障碍 )
• Summary
16
Cognition and cognitive disorder
• Cognition--the process of the brain to sens
e, handle and acquire informationInvolves a series of voluntary psychological and socia
l behaviors, such as study, memory, thinking, judgme
nt and emotion.
Relies on the normal function of the cerebral cort
ex.
• Cognitive disorders--the disturbance of the
process related to cognition
Structural Basis of Cognition
Brodmann Mapping (52 areas)
Cerebral cortex
Structural Basis of Cognition
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
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
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•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
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Learning and memory defects
Henry Molaison (HM) Patient
An epileptic patient
24
HM’s lesion includes medial temporal lope
structures in addition to hippocampus
(amygdala, entorhinal cortex…)
Surgery removal of the temporal lobe
25
HM’s good news and bad news• The surgery had a profound effect on declarativ
e memory – Severe anterograde amnesia (he lives in the present!) – Mild retrograde amnesia (only instant memory) – unable to commit new short-term memory into long-t
erm memory
• But there was no effect on:– Personality– Attention– Intelligence (normal IQ)– Motor skill learning
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
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 )
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Etiology and Pathogenesis
• Chronic brain damage
• Chronic systemic diseases
• Mental and psychic disorder
• Other factors
Pathogenesis of cognitive disorderPathogenic factors
Changes in neurotransmitters,
receptors, neuropeptides and
neurotrophic factors
Genetic abnormalitie
s
Chronic viral infection
Chronic ischemia
Metabolic abnormalities
Protein aggregation
Abnormal protein modificati
ons
Reduced ATP production, acidosis,
elevation of calcium, free radicals and inflammatory
factors, Chronic brain damage
brain dysfunction
Cognitive disorder
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Chronic Brain Damage
• Alterations in regulatory molecules • Aberrant protein aggregation• Chronic cerebral ischemic injury• Environmental and metabolic toxins • Cerebral trauma• Brain aging
Alterations in regulatory molecules
Abnormal levels in
Neurotransmitters and receptors –Dopamine–Norepinephrine–Acetylcholine (Ach)–Glutamate
Neuropeptides
Neurotrophic factors
Dopamine Pathw
ay
Dopamine
Distribution: Dopamine pathway
Parkinson Disease
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
• 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
QQ QQQ QQ
Q Q
Mutant Huntingtin in Huntington’s disease
Mutant -synuclein in Parkinson’s disease
Alzheimer’s Disease
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
Sen
ile p
laq
ues
Neu
rofib
rillary tan
gle
s
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
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
Principles for Treatment of Cognitive Disorders
• General neuroprotective treatments
• Restore and maintain the normal levels
of neurotransmitters and regulatory mol
ecules
• Surgery
Outline
• Biology of the brain
• Cognitive disorders
• Conscious disorders
• Summary
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
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
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
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。
Major manifestationsof conscious disorder
Delirium
Confusion
Stupor
Coma
谵妄
精神错乱
昏睡
昏迷
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
Pathogenesis of conscious disorderPathogenic factors
Acute brain lesion Brain intoxication Brain tumor
Direct damages to neuronsAxonal injury, cell
swelling
Abnormal neurotransmitters
Suppress the brai
n and brai
n stem
Abnormalities in the cortex and BSRF function
Conscious disorder
Abnormalities in energy
metabolism
Abnormalities in plasma
membrane
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Principles in Prevention and Therapy
• Urgent management• Making a definitive diagnosis ASAP (as
soon as possible)• Monitoring vital signs and conscious• state• Brain protections
Outline
• Biology of the brain
• Cognitive disorders
• Conscious disorder
• Summary
55
Glossary
• Cognition, cognitive disorder, • Broca’s aphasia, Wernicke’s aphasia,
dementia• Conscious disorder, delirium,
excitatory toxicity
2. Questions
• What is the characteristics of brain disorders?
• What is the pathogenesis of cognitive disorder?
• What is the pathogenesis of consciousn disorder?
1. Broca’s aphasia is caused by lesions in which of the following region:
A. Temporal lobeB. Parietal lobeC. Frontal lobeD. Occipital lobe 2. Ischemia causes cognitive disorder likely by the following
mechanisms:A. Energy exhaustion and acidosisB. Intracellular calcium overloadC. Free radical injuryD. Excitatory toxicityE. All of the above
Quizz
3. The following signs manifest the consciousness disorder EXCEPT:
A. DeliriumB. ConfusionC. ComaD. Aphasia 4. Memory loss can result from lesions in which of the following
region:A. Temporal lobeB. Parietal lobeC. HypothalamusD. Occipital lobe
Quizz
Thank you!