Brain dysfunction

Jinghua Jin Department of Neurobiology

jhjin@zju.edu.cn

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 axon2. Vesicles with chemicals move toward the membrane 3. Chemicals are released and diffuse toward the next cell’s plasma

membrane4. 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

Parkinson DiseaseParkinson Disease

(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

QQ Q

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

Senile plaquesSenile plaques

Neurofibrillary tangles

Neurofibrillary tangles

(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?