Download Conscious disorder

Brain dysfunction
Zhihua Gao
Neuroscience Institute
Outline
• Biology of the brain
• Cognitive disorders
• Conscious disorders
• Summary
Biology of the Brain
Basics of human adult brain:
•Weight: ~3 pounds
•Size: ~a medium cauliflower
• inside the skull
• skull provides
protection
• but confines the brain
4
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 capillaries
endothelial cells
a thick basement membrane
astrocyte endfeets
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
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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.
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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.
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How do neurons communicate?
Functional unit in the brain-synapse
A synapse is a structure that permits neurons to transmit
the electrical or chemical signal from one to another.
How does the synapse transmit the signal?
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
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Brain function
• Central control of the human body
• Maintain cognition
• Maintain consciousness
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Brain lesions: some principles
•Diffusive or localized lesion ?
•Location determines the symptom.
•Acute or chronic?
•Phases determines the symptom.
•Acute
•Chronic
conscious disorder
cognitive disorder
•Brain has very limited capacity for selfrepair
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
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Outline
• Biology of the brain
• Cognitive disorder (认知障碍)
• Conscious disorder (意识障碍
)
• Summary
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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
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Structural Basis of Cognition
Cerebral cortex
Brodmann Mapping (52
areas)
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
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.
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Parietal lobe
•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
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Temporal lobe
•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)
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Learning and memory defects
Henry Molaison (HM) Patient
An epileptic patient
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Surgery removal of the temporal lobe
HM’s lesion includes medial
temporal lope structures in
addition to hippocampus
(amygdala, entorhinal
cortex…)
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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 longterm memory
• But there was no effect on:
–
–
–
–
Personality
Attention
Intelligence (normal IQ)
Motor skill learning
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Occipital lobe
• 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?
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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)
Etiology and Pathogenesis
• Chronic brain damage
• Chronic systemic diseases
• Mental and psychic disorder
• Other factors
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Pathogenesis of cognitive disorder
Pathogenic factors
Changes in
neurotransmitters,
receptors, neuropeptides
and neurotrophic factors
Genetic
abnormalities
Chronic viral
infection
Abnormal protein
modifications
Metabolic abnormalities
Protein aggregation
Chronic brain damage
brain dysfunction
Cognitive disorder
Chronic
ischemia
Reduced ATP
production, acidosis,
elevation of calcium,
free radicals and
inflammatory factors,
Chronic Brain Damage
• Alterations in regulatory molecules
• Aberrant protein aggregation
• Chronic cerebral ischemic injury
• Environmental and metabolic toxins
• Cerebral trauma
• Brain aging
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Alterations in regulatory molecules
Abnormal levels in
Neurotransmitters and receptors
–Dopamine
–Norepinephrine
–Acetylcholine (Ach)
–Glutamate
Neuropeptides
Neurotrophic factors
Dopamine
Dopamine
Pathway
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
Mutant Huntingtin in Huntington’s disease
Q Q
QQ Q Q Q
Q Q
•Cleaved to generate N-terminal polyQ fragments
•Aggregates form in cytoplasm and in nucleus-amyloidlike conformation
•Controversy over whether aggregates are toxic or
protective
•Gain of toxic function and/or loss of protective function
Mutant a-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
Senile plaques
Neurofibrillary tangles
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
molecules
• Surgery
Outline
• Biology of the brain
• Cognitive disorders
• Conscious disorders
• Summary
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
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Structural Basis for Consciousness
cerebral
cortex
thalamus
Dynamics between ARAS and ARIS and their
Brain association with cerebral cortex determines
stem the state of consciousness.
reticular
formation
47
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 manifestations
of conscious disorder
Coma
昏迷
Stupor
昏睡
Confusion
精神错乱
Delirium
谵妄
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 disorder
Pathogenic factors
Acute brain lesion
Abnormal
neurotransmitters
Direct damages to neurons
Brain intoxication
Abnormalities in
energy metabolism
Abnormalities in
plasma membrane
Axonal injury, cell
swelling
Abnormalities in the cortex
and BSRF function
Conscious
disorder
Brain tumor
Suppress
the brain and
brain stem
Principles in Prevention and Therapy
• Urgent management
• Making a definitive diagnosis ASAP (as
soon as possible)
• Monitoring vital signs and conscious
• state
• Brain protections
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Outline
• Biology of the brain
• Cognitive disorders
• Conscious disorder
• Summary
Glossary
• Cognition, cognitive disorder,
• Broca’s aphasia, Wernicke’s aphasia,
dementia
• Conscious disorder, delirium,
excitatory toxicity
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2. Questions
• What is the characteristics of brain
disorders?
• What is the pathogenesis of cognitive
disorder?
• What is the pathogenesis of
consciousn disorder?
Quizz
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
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
Thank you!