Brain dysfunction

Zhihua Gao

Neuroscience Institute

Outline

• Biology of the brain

• Cognitive disorders

• Conscious disorders

• Summary

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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

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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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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?

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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

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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 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

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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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•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

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HM’s lesion includes medial temporal lope

structures in addition to hippocampus

(amygdala, entorhinal cortex…)

Surgery removal of the temporal lobe

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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

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• 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

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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

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

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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!