brain dysfunction jinghua jin department of neurobiology [email protected]
TRANSCRIPT
What you have learned about human brain?
• Anatomy?– Brain structure?
• Histology?– Cell types?
• Physiology?– Brain function?
• Pharmacology?– Central nervous system drugs ?
Outline
• I: General conception about
human brain
• II: Cognitive disorder
• III: Consciousness disorder
• IV: Summary
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
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
Inside the Human Brain
Cell Types of the Brain
Neurons
Glia
Structure of Neuron
NeuronsSpecialized Regions of Neurons Carry out Different Functions
Structure of typical mammalian neurons
ippocampus（海马）
Glia
Cellular Functions
• Neuron is in charge of different functions
• Glia nourishes and protects the neurons
How are neurons connected?
• Synapses!!
Spine
How does the Synapse carry the signal?
1. Electrical current travels down the axon
2. Vesicles with chemicals move toward the membrane
3. 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
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
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.
When Specific Areas of the Brain Are Damaged
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.
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
Outline
• I: General conception about
human brain
• II: Cognitive disorder
• III: Consciousness disorder
• IV: Summary
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.
Structural Basis of Cognition
Brodmann Mapping (52 areas)
Cerebral cortex
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)
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 ).
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
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).
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
Major Manifestations
• Learning and memory disorders
• Aphasia
• Agonosia
• Apraxia
• Dementia
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.
Learning and memory deficits:Patient HM: MRI
HM’s lesion includes medial temporal lope
structures in addition to hippocampus
(amygdala, entorhinal cortex…)
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).
3. Etiology and Pathogenesis
• Chronic brain damage
• Chronic systemic diseases
• Mental and psychic disorder
• Other factors
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
(1) Imbalance of Regulating Molecules
• Dopamine
• Norepinephrine
• Acetylcholine (Ach)
• Glutamate
• Aberrant neuropeptide
• Lack of neurotrophic factors
Dopamine Pathway
DopamineDopamine
Dopamine Synthesis and StorageTyrosine L-DOPA DA
Distribution ： Dopamine pathway
(2) Protein Aggregation in the Brain
• Gene mutations
• Abnormal post-translational modification
• Infection of slow virus 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 Q QQ Q
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Mutant Huntingtin in Huntington’s disease
Mutant -synuclein in Parkinson’s disease
Alzheimer 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
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(3) Chronic Cerebral Ischemic Injury
• Energy exhaustion and acidosis
• Intracellular calcium overload
• Free radical injury
• Excitatory toxicity
• Inflammatory reaction by cytokine
GlutamateGlutamate
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.
Pathogenesis of Cognitive Disorder
4. Principles for Treatment of Cognitive Disorders
• General neuroprotective treatments
• Maintenance of normal
neurotransmitter level
• Surgery
Outline
• I: General conception about
human brain
• II: Cognitive disorder
• III: Consciousness disorder
• IV: Summary
1. Consciousness
• The sense of awareness of self and the environment.
• It consists of two aspects:– State of arousal and content of
consciousness.
2. Consciousness Disorder
• Parenchymal mental disorders in which there is impairment of the ability to maintain awareness of self and environment and to respond to environmental stimuli.
Structural Basis for Consciousness
Structural Basis for Consciousness disorders
• Dysfunction of brain stem reticular formation
• Dysfunction of thalamus
• Dysfunction of cerebral cortex
Major Manifestations
DeliriumDelirium
Confusion
Drowsiness
Coma
3. Etiology and Pathogenesis
• Acute brain injury– eg. Diffuse encephalic infection, diffuse brain
trauma, subarachnoid hemorrhage, etc.
• Acute brain intoxication
• Intracranial extrusion and destructive lesion
Acute Brain Intoxication
• Endogeneous toxins injury– Alteration in neurotransmitter– Aberrant energy metabolism– Nerve cell membrane injury
• Exogenous toxins injury
Etiology and Pathogenesis of Consciousness Disturbance
4. Principles of Prevention and Therapy
• Urgent management
• Making a definite diagnosis as soon as possible
• Monitoring vital signs and consciousness state
• Brain protections
Outline
• I: General conception about
human brain
• II: Cognitive disorder
• III: Consciousness disorder
• IV: Summary
1. Glossary
• cognition, cognitive disorder, Broca’s aphasia, Wernicke’s aphasia, hemiplegia, agraphia, apraxia, agonasia, alexia, astereognosis, dementia, consciousness disorder, delirium, confusion, drowsiness, coma, excitatory toxicity.
2. Questions
• 1. What is the characteristics of brain disease?
• 2. What is the pathogenesis of cognitive disorder?
• 3. What is the pathogenesis of consciousness disorder?