Lecture 16

-Learning & Memory

Learning refers to the process by which experiences change our nervous system and hence
our behavior.
We refer to these changes as memories (memory traces or memory engrams). Memories can
be transient or durable, explicit or implicit, personal or impersonal.
Accessing memories is known as memory retrieval.
The cellular basis of long-term memory is neuronal plasticity 神经元可塑性, which refers to
the ability of the nervous system to change and adapt.
-Neuronal Learning & Memory
To identify neuronal plasticity, researchers typically measure：
Intrinsic excitability - the number of action potentials a neuron exhibits in response to an
influx of positive current (physical change)
Synaptic strength - the amount of positive (or negative) current that enters the postsynaptic
neuron when a presynaptic cell has an action potential.
A change in the strength of the synaptic connection between two neurons is called synaptic
plasticity.
-Measurement of intrinsic excitability
Intrinsic excitability is determined by the number and type of ion channels (leak channels and
voltage-gated channels) expressed by the neuron.
If a neuron starts making fewer potassium leak channels, its resting membrane potential will
be slightly depolarized, which means the neuron will be more excitable in general (i.e., it will
exhibit more action potentials in response to the same excitatory synaptic input).
-Synaptic Plasticity
Synaptic plasticity refers to changes in the strength of the synaptic connection between two
neurons.
Enduring changes in synaptic strength are referred to as long term potentiation (LTP) or long
term depression (LTD,associated with weaker synapse)
EPSPs (excitatory postsynaptic potentials) are membrane depolarizations that are driven by
neurotransmitter release and postsynaptic receptor activation.
Synaptic plasticity can involve pre- and postsynaptic changes.
On the presynaptic side, the amount of voltage-gated calcium channels on presynaptic
membrane influences how many vesicles will be released following an action potential.
On the postsynaptic side, the amount of neurotransmitter receptors influences the sensitivity
of the postsynaptic cell to neurotransmitter.
-Non-Associative Learning 非联想学习: Habituation vs Sensitization 习惯化（反应随重复减
小）和敏化（反应随重复增强）
The aplysia 海兔 is an invertebrate sea slug with a simple nervous system. It has a large gill
腮 for respiration, and a siphon 虹吸管 through which it expels water. If the siphon is lightly
touched, the gill withdraws reflexively. Repeated touching of the siphon will reduce the
magnitude of the reflex until the Aplysia completely ignores this stimulus. This is an example
of habituation - reduced physiological or behavioural responding to a repeated stimulus.
In contrast, the sea slug’s response to an electrical shock often becomes greater with
additional exposures. Increased sensitivity to a stimulus is sensitization.
-Habituation of Aplysia Gill Withdrawal Reflex
Does the sensory neuron become less sensitive to touch? No, it depolarizes the same amount.
Has the excitability of the sensory neuron changed? Yes, fewer action potentials (1 vs 2)
occur when the siphon is touched.
Has the synaptic connection weakened between the sensory and motor neurons? Yes.
(Less presynaptic vesicles docked? Vesicles have less glutamate in them? Presynaptic voltage-gated calcium
channels don’t open as easily or for as long? Fewer postsynaptic glutamate receptors?Postsynaptic glutamate
receptors less sensitive to glutamate or don’tt open as much or for as long?)
Has the motor neuron become less excitable? No, it spikes the same amount when
depolarized.
Has the synaptic connection weakened between the motor neuron and gill? No, the gill is as
sensitive to an action potential in the motor neuron as before.
-Neuronal Learning & Memory
Cell excitability and synaptic strength can be directly measured in brain slice recordings.
(mammals)
If we block all synaptic activity so there's no synaptic release of neurotransmitter cells respond, often within a few
hours, by expressing tons of neurotransmitter receptor if it's not receiving any synaptic input. If it's not hearing
anything, it fills up its membrane with neurotransmitter receptors, desperate to get any information it can. We also
know that if we stop a cell from spiking ever, if we hyperpolarize it so much it never has an action potential, well,
then it's going to make more proteins to try to depolarize itself so it becomes more excitable. Or if we go in and
inject so much current it's spiking all the time, it will make proteins to try to hyperpolarize itself to become less
excitable.

-The deep neural nets used in artificial intelligence for pattern recognition have a:
Structure (number of nodes and layers as well as how each node gets activated)
Objective function (the goal; for example, to label things in the input or to predict what the
next input will be or to identify the best action given the input)
Learning function (method of adjusting the strength of each connection to better achieve the
objective function)
-Synaptic Plasticity
Long-term potentiation (LTP): Long-term increase in the strength of the connection between
two neurons (i.e., increased synaptic strength). Repeated high-frequency (tetanic) stimulation
of the inputs to a neuron often induces LTP. Commonly used is 100 Hz stimulation for 1
second (repeated 4 times). LTP is often initiated on the postsynaptic side (with more
neurotransmitter receptors) but retrograde signaling of nitric oxide (NO) can drive presynaptic
modifications (e.g., more vesicles of neurotransmitters).
Long-term depression (LTD): Long-term decrease in the strength of the connection between
two neurons (i.e., decreased synaptic strength). Persistent low-frequency stimulation of the
inputs to a quiet neuron often causes LTD. Commonly used is 1 Hz stimulation for 10
minutes. -LTD is often initiated on the postsynaptic side (with less neurotransmitter receptors)
but retrograde endocannabinoid signaling can drive presynaptic modifications (e.g., less
calcium-influx per action potential).
-Synaptic Plasticity:LTP & LTD
High frequency stimulation (~100 Hz) for 1 second, repeated a few times every 10 seconds
often produces LTP.
The same number of stimulations delivered at a slow rate (1 Hz) over 5-10 minutes often
produces the opposite effect: LTD. Why??
It turns out that LTP and LTD are a function of the number of times the synapse was activated
as well as whether the postsynaptic neuron fired at those precise times.
For LTP to occur, the release of neurotransmitter must coincide with a substantial
depolarization of the postsynaptic cell (normally associated with an action potential).
High frequency axon stimulation often causes postsynaptic neurons to spike (summation of
EPSPs brings the neuron across threshold). Low frequency stimulation on its own is often not
sufficient to get a postsynaptic neuron to spike.
-The NMDA Receptor-a coincidence detector
NMDA receptors plays a large role in learning and memory. They are located in almost every
glutamatergic synapse in the brain.
The NMDA receptor is a neurotransmitter- and voltage-dependent ion channel. (a)When the
postsynaptic membrane is at the resting potential, Mg2+ blocks the ion channel, preventing
Ca+ from entering. (b) When the membrane is depolarized, the magnesium ion is evicted.
Thus, the attachment of glutamate to the binding site causes the ion channel to open, allowing
calcium ions to enter the dendritic spine.
-Role of NMDA Receptors
NMDA Glutamate receptor – A coincidence detector
The NMDA receptor is an ionotropic glutamate receptor that has a large ion pore. When the
NMDA receptor binds glutamate and opens, magnesium ions (Mg2+) try to pass through its
pore, but they get stuck in it and block all current flow. The Mg2+ blockage of the NMDA
receptor only occurs when the membrane potential is below threshold (< -40mV), such as
when the cell is at rest.
If the membrane is depolarized (i.e., more positive than -40 mV) because of other synaptic
inputs, then Mg2+ ions will not try to enter though the NMDA receptor, and thus they won’t
clog the pore.
So, current flow through the NMDA channel is gated by both glutamate and membrane
voltage. Na+ and Ca2+ ions will enter a cell through NMDA receptors, but only when these
receptors are bound to glutamate and Mg2+ is not clogging the pore.
-Mechanisms of Synaptic Plasticity
AMPA receptor: The glutamate receptor that mediates most excitatory fast synaptic currents
in the brain. It is ionotropic and opens upon glutamate binding. It lets in sodium ions which
cause EPSPs (excitatory postsynaptic potentials) that depolarizes neurons. Most glutamate
synapses in the brain have AMPA and NMDA receptors.
NMDA receptor: Ionotropic glutamate receptor that only passes current upon glutamate
binding when the membrane potential is slightly depolarized. If glutamate binds when the cell
is hyperpolarized, the pore will get blocked by Mg2+. Open, unblocked NMDA receptors
allow sodium and calcium ions through.
CaMKII: Type II calcium-calmodulin kinase. It is an enzyme that is activated by calcium
influx through NMDA receptors. It plays a role in the intracellular signaling cascade that
establishes long-term potentiation, by increasing the number of postsynaptic AMPA receptors
(in excitatory glutamatergic synapses).
LTP can also be expressed through changes on the presynaptic side of things, but postsynaptic
neurons often initiate the process. Many experiments suggest that nitric oxide (NO) can act as
a retrograde messenger (released from postsynaptic membrane and detected by presynaptic
membrane) to promote LTP.

-Synaptic Plasticity: Long-Term Potentiation

Associative long-term potentiation: The increase in synaptic strength that occurs in weak
synapses when they are active right around the time when stronger inputs caused the
postsynaptic neuron to spike. 联想长期增强:当较强的输入导致突触后神经元激增时，较弱的突
触活跃时，突触强度就会增加。
If the weak stimulus and strong stimulus are applied at the same time, the synapse activated
by the weak stimulus will be strengthened.
If the activity of strong synapse is sufficient to trigger an action potential in the neuron, the
dendritic spike will depolarize the membrane of dendritic spines, priming NMDA receptors so
that any weak synapse active at that time will become strengthened.
Hebb’s rule: Hypothesis proposed by Donald Hebb that the cellular basis of learning involves
the strengthening of synaptic connections that are active when the postsynaptic neuron fires
an action potential. This is known as: Fire together, wire together…more strongly than before.
The synaptic connection does have to initially exist.
认为学习的细胞基础包括突触连接的加强，当突触后神经元发出动作电位时，突触连接就会活
跃起来。这被称为:一起发射，一起连接……比以前更牢固。突触连接必须在最初就存在。
-Types of Learning
Perceptual learning：Learning to recognize stimuli as distinct entities.
Motor learning：Learning to make skilled, choreographed movements. Procedural learning.
Relational learning ： Learning relationships among individual stimuli. Stimulus-Stimulus
learning. (after you've perceived something. I perceive that that's a ball, and I perceive that that's a
person. First step is perceiving things, but then in relational learning you're learning the
relationships between stimuli across. Space and time that when I see this I often see it with something
else in space or something else in time. And it's these relational learning that we use to create the
episodes of our life)
Stimulus–response learning ： Learning to perform a particular behavior when a particular
stimulus is present. Includes classical and instrumental conditioning.

Lecture 17
-Types of Memory: Implicit vs explicit
Unconscious memory (implicit memory, nondeclarative memory)
Memories that influence behavior in an automatic, involuntary manner
Relates to automatic adjustments to perceptual, cognitive, and motor systems that occur
beneath the level of conscious awareness
To probe these memories, we say “show me”. Examples include
procedural memories (how to ride a bike). perceptual memories (how to tell identical twins
apart, unconsciously) stimulus-response memories (salivating in response to a tone)
Consciously accessible memory (explicit memory, declarative memory)
Memories of events and facts that we can think and talk about. To probe these memories, we
say “tell me”. Includes
Episodic memory: Personal experiences associated with a time and place. Autobiographical
memory that involves contextual information and is learned all at once.
Semantic memory: Encyclopedic memory of facts and general information, often acquired
gradually over time. This knowledge need not be associated with the time or place in which
we learned the information.
Perceptual learning -implicit memory:The basis of recognition & categorization. Largely
dependent on the neocortex – sensory association areas
Motor learning (procedural learning) -implicit memory:The basis of motor skills (bike riding,
ball throwing, etc.…)Involves different brain areas involved in movement
Relational learning (stimulus-stimulus learning) - explicit memory: The basis of declarative
memory (episodic and semantic). Largely dependent on the hippocampus and neocortex
Stimulus–response learning -implicit and explicit memory: The basis of classical (Pavlovian)
and instrumental (operant) conditioning. Involves different brain areas depending on the
stimulus and response.
-Stability of memory
Sensory memory (perceptual memory; lasts only a couple seconds or less)
Allows an individual to retain the experience of the sensation slightly longer than the original
stimulus. Occurs in each of the senses. For example, people often reflexively say “what?”
when they hear something while distracted, but then they quickly realize they did hear what
was said.
Short-term memory (lasts for seconds to minutes)
Only a small fraction of sensory information enters short-term memory. The memory capacity
of short-term memory is limited to a few items, such as the digits in a phone number or the
letters in a name. The length of short-term memory can be extended through rehearsal. For
example, you might be able to remember the phone number longer if you repeat it to yourself
until you write it down.
Long-term memory (persists after getting distracted and even after a nap)
Information that will be retained from short-term memory is consolidated into long-term
memory. Long-term memories can be retrieved throughout a lifetime and strengthened with
increased retrieval.
-Perceptual Learning
Perceptual learning enables us to recognize and identify object or situations. It is a pattern
recognition system. Through perceptual learning we can recognize changes or variations in
familiar stimuli and respond to those changes.This unconscious, implicit learning involves
changes in the strength of connections between neurons in primary and association sensory
cortices.
-Visual agnosia and memory
Visual Agnosia
Damage to regions of brain involved in visual perception not only impair ability to recognize
visual stimuli but also disrupt people's memory of visual properties of familiar stimuli.(they
can see lines, dots,after distracting, can’t draw)(right is drawn from moments later)

-Motor learning
Motor learning involves learning to make a sequence of coordinated movements. We get
feedback from our movements from our joints, vestibular system, eyes, ears, etc. We use this
information to improve and optimize our movements. As with all forms of learning, there is a
rapid component to motor learning as well as a slower process called between-session
learning, where improvements in motor behavior are seen following a period of the memory
consolidation (in part during sleep). The cerebellum, thalamus, basal ganglia, and motor
cortex are all involved in motor learning.
-Stimulus-response learning: Classical conditioning VS Instrumental conditioning
Classical conditioning (also known as Pavlovian Learning)
US UR
Unconditioned Stimulus: a stimulus that has inherent value, like food or a painful shock.
Unconditioned Response: a behavioural response that is largely innate, hard-wired
(unlearned, unconditioned). (When things fly at your face, you kind of blink these.)
CS CR
Conditioned Stimulus: a stimulus that was initially perceived as neutral (e.g., a tone) but now
is perceived as predictive of an US.
Conditioned Response: a behavioural response that occurs in response to a CS. The behaviour
is often similar to the UR that was elicited by the US during training.(But it doesn't seem like
the brain necessarily draws this connection. And this way it's like relational learning. You're learning a
tone predicts a shock. You can consciously learn that in a relational learning manner. You can say I
explicitly know the tone predicts a shock, and if you know it consciously, your behavior. Will be
pretty different. You'll respond to that tone quite dramatically, but you don't have to have
this conscious association all over the brain.We're learning these unconscious responses, and what the
brain seems to be learning is when you hear a tone, close your eye or start to produce saliva, or have
your heartbeat faster and create a fear response.)
A key aspect of classical conditioning is that the animal has no control over its environment.
The animal can react to things (and we measure these reactions to infer learning), but the
animal’s actions do not influence the course of events.
-Reinforcement learning(AKA:Instrumental conditioning, Operant conditioning)
Learning from the consequences of your actions, from the receipt of reinforcement or
punishment. The likelihood of you repeating an action depends on whether it was previously
reinforced or punished. Animals are always exploring their environment and sometimes their
actions have consequences. Instrumental behaviours start off as flexible, volitional
exploratory behaviors. In contrast to Classical (Pavlovian) learning, operant conditioning
requires that the animal can move and make decisions that influence their environment (i.e.,
decisions that have consequences).
Reinforcing stimulus: Appetitive stimulus. When it follows a particular behavior, it increases
the likelihood the animal will repeat the behaviour. Reinforcement makes the behavior more
likely to occur.
Punishing stimulus: Aversive stimulus. When it follows a particular behavior, it decreases the
likelihood the animal will repeat the behaviour. Punishment makes the behavior less likely to
occur.

The process of reinforcement strengthens a connection between neural circuits involved in

perception (sight of the lever) and those involved movement (the act of lever pressing).
(When people start doing drugs, they often are initially, you know, totally in control, and they have this idea I want to take. Drugs, they do them, and that has a reinforcing

effect regardless of what you consciously say. The drugs in the brain act as a reinforcement signal to say this was something good. And consciously people still think they're making a

decision for a long time. They think I'm doing drugs because this is a conscious decision. But what's unconsciously happening is we're strengthening the link between the idea of having

drugs and the action of taking drugs. And the addiction catches people off guard because they're. Control. They're in control and then suddenly they realize they have this intense

craving, this like kind of lose control over this decision processes and they're not aware of it until it's too late. They're not aware. They don't have control until that's evident to them

that they just can't stop. And it's because what's actually controlling this learning is unconscious processes. What are your priorities? What are you going to create? This isn't something

you consciously say, this is my priority.)

-Instrumental conditioning
The are two major pathways between sensory association cortex and motor association
cortex.
Direct transcortical connections: (connections from one area of the cerebral cortex to
another) are involved in acquiring complex motor sequences that involve deliberation or
instruction(思考或指示)
The basal ganglia integrates sensory and motor information from throughout the brain. It is
important for habit formation. At first the basal ganglia is a passive “observer ”. But as
behaviors are repeated again and again, the basal ganglia begins to learn what to do.
Eventually, the basal ganglia takes over most of the details of the process, leaving the
transcortical circuits 皮质外回路 free to do something else. At this point, we don’t need to
consciously think about what we are doing.
The strength of cortical inputs to the basal ganglia is regulated by dopamine signaling . The
major input nucleus of the basal ganglia is the striatum 纹状体(or neostriatum). It consists of
the caudate, putamen, and nucleus accumbens.
Dopamine input to the Striatum
Dopamine neurons in the midbrain (substantia nigra and ventral tegmental area) project to
the striatum (caudate, putamen, and nucleus accumbens) and seem to signal reinforcement
and punishment.
In general, the overall amount of dopamine in the striatum seems to correspond to
motivation and the value of moving in and engaging with the environment . 纹状体中多巴胺的
总量似乎与动机和融入环境的价值相对应 Transient fluctuations in dopamine signaling seem to
drive learning by signaling how unexpectedly good or bad the current moment is . 多巴胺信号
的短暂波动通过传递当前时刻意外的好或坏来驱动学习。
-the Striatum
Different areas of the striatum process different types of information. For example, the
nucleus accumbens (in the ventral striatum) receives input from limbic areas such as the
hippocampus, amygdala, and parts of PFC. It seems to regulate people’s priorities.
-Role of the Basal Ganglia
As action sequences (and thought patterns) are repeated again and again, they become more
and more habitual, ingrained and automatic. Across this transition, different circuits within
the basal ganglia become involved in the action selection and action execution 执 行
processes. Lesions of the basal ganglia disrupt reinforcement learning and habit learning, but
they do not strongly affect perceptual learning or stimulus-stimulus(relational) learning.
-Background - Hippocampus
Henry Gustav Molaison (HM) – first described by Brenda Milner in 1957
Doctors cut out his hippocampus bilaterally to cure his epilepsy. It worked, but he lost the
ability to form new explicit memories (severe anterograde amnesia). He also suffered from a
graded retrograde amnesia (events that occurred within 1 or 2 years were lost as well as some
events that happened even longer ago than that). He still had a brief working memory and a
high IQ, but he could not learn new words or names or learn to navigate a new space .
Researchers have been recording neural activity in the hippocampus for over 50 years now,
trying to make sense of the firing patterns.
-Human Anterograde Amnesia
Korsakoff's syndrome: Permanent anterograde amnesia caused by brain damage, usually
resulting from chronic alcoholism. Korsakoff’s patients are unable to form new memories but
can still remember old ones before the brain damage occurred.
Confabulation 虚 构 : Reporting of memories of events that did not take place without
intention to deceive. Seen in people with Korsakoff's syndrome
-Relational Learning
Without a functional hippocampus, animals cannot form new episodic or semantic memories.
Their short-term, working memory is generally fine. They can also remember previously
learned semantic information if it was consolidated prior to the hippocampal damage. But
they generally live in the moment. They don’t really reminisce about previous episodes in
their life, nor do they imagine future possibilities. They live in the here and now. The
hippocampus is not the location of either short-term or long-term memories. It seems to be
involved in converting short-term memories into explicit long-term memories, a process
known as memory consolidation 记忆巩固.
-Memory consolidation
Most psychologists believe that learning consists of at least two stages: short-term memory
and long-term memory.Simplest model of the memory process. Sensory information enters
short-term memory, rehearsal keeps it there, and eventually, the information makes its way
into long-term memory, where it is permanently stored.

-Memory Encoding
During any given moment, a unique pattern of neural activity (spread across the cerebral
cortex) reflects the constellation of sensory input, thought processes, and emotion you are
currently experiencing. Perhaps the cortical activity 皮 质 活 动 associated with any given
moment can be indexed in some manner in the hippocampus. It is generally thought that
memories are not stored in the hippocampus, but that the hippocampus forms a hub, node, or
index that is capable of both representing and reactivating the sensory systems that initially
encoded any given event/experience.
Memory Encoding (pattern storage): Cortical sensory systems Hippocampus
Memory Retrieval (pattern completion):
Partial cue Hippocampus Cortical sensory systems
So, for example, you have lunch today. Everything associated with that event, where you are, how it tasted, the food was all there, there was

experience, your brain was living it. With all these different neural activity, the hippocampus takes a snapshot or creates an index or a lookup table of this

event. Later, hours later, something reminds you of this event. Somebody says what you have for lunch, or you think about the meal or some queue that

triggers the memory. This partial queue will be often one of the aspects of that original event comes to your attention when this partial queue, let's say it's

something you see or here, it's processed in the cerebral cortex and goes into the hippocampus and the hippocampus says, the last time I saw that cure, it

was a part of a larger event, and the hippocampus has the ability to reactivate. The entire cerebral cortex to relive that event. So when you've lived it the first

time, all these things were naturally activated because the sensory experience was there and present. But later this is just imagine you are imagining the

event again because the hippocampus is reactivating all the elements that were activated, and what drove it was a partial cue that came in of the Event Act

went into the hippocampus reactivated this node.

-Memory Encoding
Over time (years in humans), memory gradually becomes less and less dependent on the
hippocampus, which simply means the memory will still be there if you lose your
hippocampus.
What is happening in the years when memories are dependent on the hippocampus?
A prominent theory is that hippocampal activity (during recall events and during sleep) is
“training” the cortex, causing a reorganization of the synaptic weights in the cortex so that
intra-cortical connections can support memory recall on their own.
Some people argue that the cortex only contains semantic information (facts). In this model,
all memory starts off as episodic memory, which is always dependent on hippocampal nodes
interacting with the cortex. Over time, as facts emerge from repeated episodic experiences,
these semantic memories are permanently stored in the cortex in a hippocampal-independent
manner.(semantic transformation theory)
Functional imaging revealed that the retrieval of the youngest long-term memories activated
the hippocampus more than the cortex of the superior frontal gyrus, but retrieval of older and
older memories activated the hippocampus less and the cortex more, 9 years same.
-Memory consolidation
Where in the brain are spatial memories stored?
After training a rat to solve a maze…
Rodents need a functional hippocampus to remember newly learned spatial information but
not information learned 30 days ago. Memories are consolidated and stored in the cerebral
cortex during this time. This kind of memory consolidation occurs over several years in
humans.
-Amnesia
Anterograde amnesia(K and Confabulation) refers to the inability to learn new information
or retain new information ‘after’ brain injury. Memory for events that occurred before the
injury remain largely intact.
Retrograde amnesia refers to the inability to remember events that occurred ‘before‘ the
brain injury. Complete amnesia in either direction is rare.
-Relational Learning
Damage to the hippocampus or to regions of the brain that supply its inputs and receive its
outputs causes anterograde amnesia, but nondeclarative learning ability remains intact.
-Spared Learning Abilities
When amnesic patients are trained and tested, we find that they are capable of three of the
four major types of learning: perceptual learning, motor learning, and stimulus–response
learning. However, amnesic patients do not explicitly remember anything about what they
have learned.
-The T Maze

With minimal training, healthy mice often turn toward the “Place” goal on the “Probe” test.
With overtraining, however, mice mostly turn toward the “Response” goal.
These results suggest that what is initially learned is an explicit spatial memory (turn toward
the window), but overtime a stimulus-response memory starts to dominate (always turn to
the right).
Basal ganglia lesions disrupt implicit “Response” learning.
Hippocampal lesions disrupt explicit “Place” learning.

Lecture 18
-Speech Comprehension
Lateralization
Verbal behavior is lateralized function. Most language disturbances occur after damage to
left side of brain, regardless if people are left-handed or right-handed. The left hemisphere is
dominant for speech in 90 percent of the population. Right-hemisphere speech dominance is
seen in 4 percent of right-handed people and 27 percent of left-handed people.
-Prosody: Rhythm, Tone, and Emphasis in Speech
Human speech has a regular rhythm and cadence 抑扬顿挫
People give some words stress (i.e., pronounce them louder)
Pitch of the human voice indicates phrasing and distinguishes between assertions 断言 and
questions. Humans impart information about their emotional state through the prosody 韵律
(rhythm, emphasis, and tone) of their speech. Prosody is typically a function of the right
hemisphere, so people who don’t understand language because of left hemisphere damage
will typically still be able to appreciate prosody and extract information from it.
-Recognition of People's Voices
People can recognize the voices of particular individuals. Even newborn infants can
recognize the voices of their parents. Recognition of a particular voice is independent of
recognition of words and their meanings. People with left hemisphere damage might not be
able to understand words but they could still recognize voices. Phonagnosia is a disorder
where people have great difficulty recognizing voices. It results from localized brain damage
to the right superior temporal cortex.
A task that requires comprehension of metaphors such as “green lung of the city” (that is, a
park) activates right superior temporal cortex. Judging the moral of Aesop's fables (as
opposed to judging more superficial aspects of the stories) activated regions of right
hemisphere.

-Aphasia 失语症
Aphasia refers to a disturbance in understanding, repeating, or producing meaningful speech.
The difficulty must not be caused by simple sensory or motor deficits or by lack of
motivation. The deficit must be relatively isolated, such that the patient must be capable of
recognizing when others are attempting to communicate. The patient must be somewhat
aware of what is happening around them.
Damage to the frontal lobe causes deficits in speaking. The aphasia may be described as a:
anterior aphasia/motor aphasia/expressive aphasia/Broca’s aphasia/non-fluent aphasia
Damage to sensory association cortex causes deficits in understanding language . The aphasia
may be described as a posterior aphasia/sensory aphasia/receptive aphasia/Wernicke’s
aphasia/fluent aphasia

-Word Comprehension
The posterior language area is critical for language comprehension.
Neurons here probably activate the ensemble of neurons throughout sensory association
cortices that store the representations (the meanings) of specific words. For example,
activating the DOG neurons here would cause activity throughout sensory association
cortices (vision, hearing, touch, smell, taste, and even motor commands like petting) that are
associated with the word DOG.
-Word Comprehension
The posterior language area is located at the junction of the temporal, occipital, and parietal
lobes, around the posterior end of the lateral fissure. It is critical for language comprehension
(regardless of whether the words are heard, seen, or spoken).
Damage to the posterior language area causes: Transcortical Sensory Aphasia: Failure to
comprehend(and express) the meaning of words and an inability to express thoughts with
meaningful speech. Word perception and speaking might be fine (without any
comprehension of what is heard or spoken). For example:Word repetition (e.g., repeat after
me…) Reading (without understanding), Writing (without understanding)(clip 1, 答非所问)
-Conduction Aphasia
Characterized by an inability to repeat the exact words you hear. Other than that, you are
fine, that is you have meaningful, fluid speech and good speech comprehension. When asked
to repeat the word ‘house’, the person may say “home”. When asked to repeat a nonsense
word like ‘blaynge’, the person will be unable to do it. They will just say I didn’t hear you.
Conduction aphasia as the result of damage to the connection between Wernicke’s area and
Broca’s area known as the arcuate fasciculus 弓状纤维束.
-Wernicke's area
Wernicke’s area is involved in analysis of speech sounds and in recognition of spoken words.
Region of auditory association cortex on left temporal lobe of humans. Being able to hear is
one thing (primary auditory cortex); Recognizing words is another thing (Wernicke’s Area);
Comprehending them—understanding their meaning—is yet another thing (Posterior
Language Area) (Note that Posterior Language Area overlaps with Wernicke’s area)
-Wernicke aphasia
Is the result of damage to both Wernicke’s area and the Posterior language area, which means
you have features of transcortical sensory aphasia and pure word deafness.
The defining feature of Wernicke's aphasia (and transcortical sensory aphasia) is poor
language comprehension. These people can have fluent speech production, but what they say
is meaningless and typically filled with function words, such as a, the, in, about (as opposed
to content words that convey meaning, such as nouns, verbs, and adjectives).Their speech
seems natural and is filled with intonation and emphasis (prosody). Words seem to come
easy to them, but unfortunately what they say is meaningless, and they are typically not
completely aware of this problem.This disorder has been characterized as a receptive aphasia
or fluent aphasia, because the people have no trouble coming up with nonsense things to say;
it is just that words have no meaning to them.
-Pure word deafness
Is the result of damage to a small part of Wernicke’s area
Pure word deafness is a disorder of auditory word recognition, an inability to comprehend or
repeat spoken words. “I can hear you, but I don’t recognize the words you are saying. I even
have trouble repeating what you say.” It is caused by damage to Wernicke's area or
disruption of auditory input to this region. Speak intelligently, but they can’t recognize the
words they are saying by listening to themselves. Over time their speech becomes a bit
awkward, like when a deaf person speaks.
-Transcortical sensory aphasia versus Wernicke's aphasia
Patients with transcortical sensory aphasia have trouble with language comprehension, but
they can repeat what other people say to them; they can recognize spoken words.
Patients with Wernicke's aphasia have trouble with language comprehension and are
generally not capable of repeating what other people say to them.
Both of these aphasias are associated with damage in and around Wernicke’s area, including
Posterior Language Area. But these brain areas aren’t really separable, or rather the functions
of language comprehension and spoken word recognition are interweaved in and around
Wernicke’s area. It wouldn’t be able to differentiate between Wernicke’s aphasia and
transcortical sensory aphasia just by looking at a brain scan.
-Disorders of Reading : Pure Alexia
Damage to the visual word-form area (VWFA) disrupts the ability to perceive written words.
The visual word-form area is in the fusiform gyrus of the left hemisphere . (Face perception
is more dominant in the right hemisphere fusiform gyrus.) People with this damage (Pure
Alexia or Pure Word Blindness) cannot read, as they cannot recognize written words.
However, they can write just fine. They just can’t read what they write.
Toward an Understanding of Reading
Dyslexia 阅读障碍，阅读，拼写困难: means“faulty reading”. People with dyslexia have
difficulty reading.
Reading: Reading involves at least two different processes: direct recognition of the word as
a whole and sounding it out letter by letter
Whole-word reading: Reading by recognizing a word as a whole;“sight reading”
Phonetic reading: decoding the phonetic significance of letter strings; “sound reading”
Like the fusiform face area, which is critical for perceiving faces and differentiating between
similar looking faces, the visual word form area (VWFA) is critical for perceiving written
words.(cars vs ears)

Surface dyslexia:
An inability to recognize whole-words. The person can only read words phonetically.
Irregularly spelled words are difficult for these people to perceive, because sounding them
out doesn’t work: Pair, pear, pare
Phonological dyslexia: (problem with phonetic coding)
Reading disorder in which a person can read familiar words but has difficulty reading
unfamiliar words or nonwords: Blint, trisk, juff
-Toward an Understanding of Reading
Developmental dyslexia 发展型阅读障碍 is mostly a type of phonological dyslexia, and the
problem is largely genetic. People with developmental dyslexia have great difficulty learning
to read and some never become fluent readers, even though they are otherwise intelligent.
They also have trouble with grammar and spelling and have a hard time distinguishing the
order of sound sequences. The neural basis of developmental dyslexia is not well known.
-Direct Dyslexia
Some stroke patients have shown very specific deficits in their ability to extract meaning
from written words even though they can read out loud. This symptom is called Direct
Dyslexia. It is typically seen with larger deficits, like transcortical sensory aphasia where
there is limited language comprehension.
-Toward an Understanding of Reading
The most important cues to object recognition (which is the primary task of the visual
system) are those that remain relatively constant even when objects are viewed from
different angles.
Most reliable of these cues are ways that lines meet at vertices, forming junctions with
particular shapes, such as L, T, and X
-Speech Production
Damage to Broca’s area in the (left) inferior frontal lobe makes it difficult for patients to
express themselves verbally. This deficit is known as Broca's aphasia and it is characterized
by slow, laborious, and nonfluent speech. They have something to say, but have trouble
saying it. They are well aware of their condition and very frustrated it.
Broca’s aphasia encompasses three semi-distinct issues: articulation problems 发 音 问 题 ,
agrammatism 语法问题, anomia 忘名
Articulation 发音: Movement of tongue, lips, jaw, and other speech organs to make speech
sounds. Articulation problems might make it hard for someone to hear the words you are
saying. Or it could cause a sequencing problem: lipstick -likstip.
-Agrammatism
Difficulty comprehending or using grammatical devices, such as verb endings (-ed) and
word order (e.g., man bit dog).
People with agrammatism typically do not derive meaning from the sequence of words or the
grammar of sentences. Thus, they almost exclusively use content words (nouns, adjectives,
verbs, etc.) without any function words (the, on, about, etc.). People with Broca's aphasia can
comprehend speech much better than they can produce it, but there usually are some
comprehension deficits.
-Words
Content word: Noun, verb, adjective, or adverb that conveys meaning. People with Broca’s
aphasia have trouble coming up with content words, but that is how they communicate.
They rarely use function words.
Function word: Preposition, article, or other word that conveys little meaning but is
important for the grammatical structure of a sentence (a, the, in).
-Memory of Words: Anomic Aphasia
Anomia 失忆: Difficulty in finding (remembering) the appropriate word to describe object ,
action, or attribute; one of symptoms of Broca’s aphasia.
Anomic aphasia 失 语 : People with anomic aphasia have a hard time thinking of the word
they want to say. They can understand what other people say just fine. And they basically
talk just fine, but they often describe things in roundabout ways (circumlocution).
Circumlocution 绕 弯 : Strategy by which people with anomia find alternative ways to say
something when they are unable to think of most appropriate word.

Lecture 19
-Subvocal articulations
When we talk to ourselves in our head (our inner monologue), there is often subvocal
articulations (very slight movements of the muscles involved in speech that do not actually
cause obvious movement). When a person is asked to look at a pair of drawings and say
whether names of the items rhyme, functional imaging shows increased activation in region
of Broca's area because the person “says” the two words subvocally 潜声地.
-Toward an Understanding of writing
Writing depends on knowing/the words you want to use/proper grammatical structure
/specific motor commands that control the hand
Trouble with writing is called dysgraphia.(dyslexia is trouble with reading, phonological
dyslexia only can read familiar words)
There can be very specific deficits in motor programs caused by brain damage. For example,
people can have trouble writing: Letters but not numbers/ Lowercase but not uppercase
letters/ Vowels but not consonants/ Print but not cursive/ Letters in the correct order
When writing a word, spelling it can be accomplished by:Phonetically sounding out the word
Phonological dysgraphia is a condition where people cannot spell words by sounding them
out (common in Broca’s aphasia). They can only write words by imagining how they look.
Thus, they have to be very familiar with how the word looks or they cannot write it. They
cannot write non-words that sound fine, like blint or vak.
Visually imagining the word
Orthographic dysgraphia is a condition where people cannot spell words by visualizing them
(common in people with damage to VWFA visual word form area in visual association
cortex). They can only sound words out, which means they cannot correctly spell any words
that have an irregular spelling (half-haff; busy-bizzy).
-stroke
Incidence of strokes in the United States is approximately 750,000/year.
The likelihood of having a stroke is related to age – probability doubles each decade after 45
years of age and reaches 1–2 percent per year by age 75.
Atherosclerosis 动脉硬化; Process in which linings of arteries develop a layer of plaque 斑
块, deposits of cholesterol, fats, calcium, and cellular waste products 细胞 waste 沉积过程.
Risk factors include high blood pressure, cigarette smoking, diabetes, and high blood levels
of cholesterol.
Precursor to heart attacks (myocardial infarction) and strokes.
-Cerebrovascular Accidents
Atherosclerotic plaques often form in the internal carotid artery, which supplies most of the
blood flow to the cerebral hemispheres. 动脉粥样硬化斑块经常形成于颈内动脉，它为大脑半球提供大部分
的血液流动。

Narrowing can be visualized in an angiogram, produced by injecting a radiopaque dye into

the blood and examining the artery with a computerized X-ray machine.
通过向血液中注射一种不透光的染料，并用计算机 x 光机检查动脉，可以在血管造影中看到血管狭窄。

Plaques can cause severe narrowing of interior of artery 动脉, greatly increasing the risk of a
massive stroke.
-Stroke:Hemorrhagic stroke/Ischemic stroke
Hemorrhagic stroke 出血性中风: Rupture of a cerebral blood vessel
Ischemic stroke 缺血中风: Occlusion of a blood vessel, 87% of strokes are ischemic
-Stroke
Thrombus 血栓: Blood clot 血凝块 that forms within a blood vessel, which may block it
and reduce blood flow to the affected area.
Embolus 栓子: Piece of matter (such as a blood clot, fat, or bacterial debris) that dislodges
from its site of origin and occludes an artery. In the brain, an embolus can lead to a stroke.
-Cerebrovascular 脑血管 Accidents
Depending on size of the affected blood vessel, the amount of brain damage can vary from
negligible to massive. Strokes often cause permanent brain damage, but over days, months,
and years physical therapy, occupational therapy, and speech therapy often produce dramatic
improvements in brain function.
-Researchers have sought ways to minimize amount of brain damage caused by strokes
One approach has been to administer drugs that dissolve blood clots in an attempt to
reestablish circulation to an ischemic brain region. This approach has met with some success.
For example, administration of a clot-dissolving drug called tPA (tissue plasminogen
activator) after the onset of a stroke has clear benefits, but only if it is given within 3-4 hours.
-Risk reduction & treatment
Devices can be deployed through the vascular system to the site of an occlusion. The devices
use various strategies to secure and/or remove occlusions. The devices can include coils 线圈
(a), aspiration devices 吸气装置 (b), or be incorporated into stents 并入支架(c).
After Stroke Treatments: Drugs that reduce swelling and inflammation 消肿消炎/ Physical,
speech, and/or occupational therapy/ Exercise and sensory stimulation (constraint-induced
movement therapy)

-Tumors 肿瘤
Tumor: Mass of cells whose growth is uncontrolled and that serves no useful function.
肿瘤:生长不受控制且无任何作用的细胞团
Non-malignant tumor: Noncancerous, “benign” tumor. Has distinct border and cannot
metastasize.
非恶性肿瘤:非癌变的“良性”肿瘤。有明显的边界并且不会转移
Malignant tumor: Cancerous (literally, “harm-producing”) tumor. Lacks distinct border and
may metastasize.
恶性肿瘤:癌性
Metastasis: Process by which cells break off of a tumor, travel through the vascular system,
and grow elsewhere in the body
转移:细胞从肿瘤中脱落，穿过血管系统，在身体其他部位生长的过程
-Malignant vs non-malignant
The major distinction between malignancy and non-malignancy is whether the tumor is
encapsulated 包膜 (whether there is a distinct border between the mass of tumor cells and the
surrounding tissue)
If there is such a border, the tumor is non-malignant; the surgeon can cut it out, and it will not
regrow. However, if the tumor is cancerous it grows by infiltrating 浸 润 the surrounding
tissue, and there will be no clear-cut border between tumor and normal tissue. When surgeons
remove malignant tumors, some cancer cells are often missed, and these cells will produce
new tumors.
-Tumors
Any tumor growing in the brain, malignant or benign, can produce neurological symptoms
and threaten the patient's life.
Tumors damage brain tissue by two means: compression and infiltration. Even a benign tumor
occupies space and thus pushes against the brain.
Compression can directly destroy brain tissue, or it can do so indirectly by blocking flow of
cerebrospinal fluid and causing hydrocephalus 脑积水.
任何生长在大脑中的肿瘤，无论恶性或良性，都可能产生神经症状，并威胁患者的生命
肿瘤损伤脑组织的方式有两种:压迫和浸润。即使是良性肿瘤也会占据空间，从而压迫大脑
压迫可以直接破坏脑组织，也可以通过阻断脑脊液流动而间接破坏脑组织，导致脑积水
-Malignant Tumors
Gliomas 神经胶质瘤
Glioma is an example of a malignant brain tumor. The tumor initiating cells originate from
the neural stem cells that make glia. They rapidly proliferate and are more resistant to
chemotherapy and radiation than most tumor cells. The survival rate from malignant gliomas
is very low. 胶质瘤是恶性脑瘤的一个例子。肿瘤起始细胞来源于形成神经胶质的神经干细胞。它们迅速
增殖，比大多数肿瘤细胞更耐化疗和放疗。恶性胶质瘤的生存率很低。
-Non-malignant tumor
Meningioma 脑膜瘤 is an example of a non-malignant (encapsulated) tumor.
It is composed of cells that constitute the meninges – the dura mater or arachnoid membrane –
often right between the two cerebral hemispheres. 它由构成脑膜(硬脑膜或蛛网膜)的细胞组成，通
常位于两个大脑半球之间。
-A very problematic but technically Non-malignant meningioma
This meningioma (tumor of the cells of the meninges) may be encapsulated but it is still very
damaging. It has displaced the right side of the brain. The right ventricle is almost completely
occluded. 这种脑膜瘤(脑膜细胞的肿瘤)可能被包膜，但它仍然具有很大的破坏性。它转移了右脑。右心
室几乎完全闭塞
-Disorders Caused by Infectious Diseases
Encephalitis 脑 炎 :Inflammation of the brain caused by infection (bacterial or viral), toxic
chemicals, or allergic reaction. The first symptoms are headache, fever, and nausea.
由感染(细菌或病毒)、有毒化学物质或过敏反应引起的脑部炎症。最初的症状是头痛、发烧和恶心。
Meningitis 脑 膜 炎 : Inflammation of meninges caused by viruses or bacteria. The first
symptoms are headache and stiff neck. 由病毒或细菌引起的脑膜炎症。最初的症状是头痛和脖子僵
硬
Polio (acute anterior poliomyelitis)脊髓灰质炎: Viral disease that destroys motor neurons of
the brain and spinal cord. 一种破坏大脑和脊髓运动神经元的病毒性疾病。
Rabies 狂犬病: Fatal viral disease that causes brain damage; usually transmitted through the
bite of an infected animal. 导致脑损伤的致命病毒性疾病;通常通过被感染动物的咬伤传播。
Herpes simplex virus 单纯疱疹病毒: Virus that normally causes cold sores near the lips or
genitals. In rare cases, it instead enters the brain causing encephalitis and brain damage.
通常在嘴唇或生殖器附近引起唇疱疹的病毒。在极少数情况下，它会进入大脑，导致脑炎和脑损伤
-Traumatic Brain Injury 创伤性脑损伤(open and closed)
Closed-Head Injury
Caused by a blow to the head with a blunt object 被钝器击中所致
The brain comes into violent contact with the inside of the skull (coup). The brain then recoils
in the opposite direction and smashes against the skull again (contrecoup) 大脑与头骨内部猛烈
接触。然后大脑向相反的方向反冲，再次撞向头骨(撞击)
Open Head Injuries
Penetrating brain injuries (also called open head injuries) obviously cause damage to the
portion of the brain that is damaged by the object or the bone.
In addition, damage to blood vessels can deprive parts of the brain of their normal blood
supply. Accumulation of blood within the brain can cause further damage by exerting
pressure within the brain.
穿透性脑损伤显然会对被物体或骨头损伤的大脑部分造成损伤
此外，血管损伤会使部分大脑失去正常的血液供应 . 大脑内的血液堆积会对大脑施加压力，造成进一步的
损伤
-Traumatic brain injury (TBI)
In the United States, approximately 1.4 million people visit an emergency room for TBI,
270,000 people are hospitalized, and 52,000 people die from it. Almost a third of deaths
caused by injury involve TBI. In survivors, scarring often forms within the brain, around the
sites of injury, which increases risk of developing seizures. Many people receive brain injuries
but are not diagnosed. Even mild cases of TBI (mTBI) greatly increase a person's risk of
developing brain problems down the road. For example, the likelihood of Alzheimer's disease
is much higher in a person who has received blows to the head earlier in life.
-Seizure Disorders
Seizures have many causes
The most common cause is scarring, which may relate to an injury, a stroke, the irritating
effect of a growing tumor, or a developmental abnormality in the brain.
Other causes are high fevers (especially in young children) and withdrawal from GABA
agonists, such as alcohol and barbiturates.
Many cases are idiopathic (of unknown causes). Neural network instability and increased risk
of seizures can come about for genetic reasons, involving gene mutations that affect…
the amount or function of different ion channels in the brain/ the reciprocal wiring of
excitatory and inhibitory neurons/the rules that govern synaptic plasticity
Although there are some genetic factors that can promote seizures, most seizure disorders are
caused by nongenetic factors. In the past, many cases were considered to be idiopathic 先天
的 (of unknown causes, or literally “one's own suffering”). However, the development of
MRIs with more and more resolution and sensitivity has meant that small brain abnormalities
responsible for triggering seizures are more likely to be seen.
Seizure disorder: Preferred term for epilepsy. Sometimes, if neurons that make up motor
system are involved, a seizure can cause a convulsion 经 挛 / 抽 搐 , which is wild,
uncontrollable activity of the muscles. But not all seizures cause convulsions; in fact, most do
not.
Convulsion: Violent sequence of uncontrollable muscular movements caused by seizure.
Partial (focal) seizure(simple or complex): Seizure that begins at a focus and remains
localized, not generalizing to rest of brain. A simple partial seizure is a seizure that does not
produce loss of consciousness. A complex partial seizure is a seizure that produces a loss of
consciousness.
局部(局灶性)发作:发作始于某一焦点，并停留在局部，不扩散到大脑其余部分。简单的局部癫痫是一种不
会导致意识丧失的癫痫。复杂的部分性癫痫是一种导致意识丧失的癫痫。
Generalized seizure: Seizure that involves most of the brain (non-localized seizure). Includes
tonic-clonic seizures, atonic seizures, and absence seizures. 全身性发作:涉及大部分大脑的发作(非
局限性发作)。包括强直阵挛性发作，强直性发作和消失性发作。
-Grand mal seizure
Aura: Sensation that precedes a seizure. Its exact nature depends on the location of the seizure
focus.
Tonic- clonic seizure: A generalized, grand mal seizure that typically starts with an aura that is
followed by a tonic phase and then a clonic phase. This type of seizure involves convulsions.
Tonic phase: First phase of tonic-clonic seizure, in which all of patient's skeletal muscles are
contracted.骨骼肌收缩
Clonic phase: Second phase of a tonic-clonic seizure, in which patient shows rhythmic jerking
movements.
先兆:癫痫发作前的感觉。它的确切性质取决于发作焦点的位置。
强直阵挛性发作:一种全身性大癫痫发作，通常以先兆发作开始，随后是强直期和阵挛期。这种类型的癫
痫包括抽搐。
强直期:强直阵挛性癫痫的第一阶段，病人所有的骨骼肌收缩。
阵挛期:强直阵挛性发作的第二阶段，病人表现出有节奏的抽搐动作。
Children are especially susceptible to seizure disorders
Many do not have tonic-clonic episodes but instead have very brief seizures that are referred
to as spells of absence. Absence seizures are generalized complex seizures.
During absence seizures (also known as petite mal seizures), people stop what they are doing
and stare off into the distance for a few seconds, often blinking their eyes repeatedly.
许多人没有强直阵挛发作，而是有非常短暂的癫痫发作，...
在 absence(也被称为小癫痫发作)期间，人们会停下正在做的事情，盯着远方看几秒钟，经常会反复眨眼
Seizure disorders are treated with anticonvulsant drugs, such as benzodiazepines, many of
which work by increasing effectiveness of inhibitory synapses.
癫痫发作可以用抗惊厥药物治疗，如苯二氮卓类药物，其中许多是通过增加抑制突触的有效性而起作用的。
Most seizure disorders respond well enough to medications that the patient can lead a normal
life.
In a few instances drugs provide little or no help and the seizure foci remain so irritable that
brain surgery is required.
-Disorders of Development
Exposure to certain toxins, viruses, and drugs during pregnancy can impair fetal 胎儿 brain
development and cause intellectual disability. Dangerous toxins include organophosphates 有
机磷 (from insecticides 杀虫剂) and heavy metals such as lead 铅 and mercury 汞.Famous
viruses that alter brain development include the rubella virus 风疹病毒(German measles) and
the Zika virus (which spread fast in Brazil several years ago).
Alcohol might be the most dangerous drug during pregnancy. Babies born to alcoholic
women are typically smaller than average and develop more slowly. A particularly serious
condition associated with alcohol consumption during the 3rd and 4th week of pregnancy is
fetal alcohol syndrome 胎儿酒精综合征, which is associated with certain facial anomalies
and severe intellectual disabilities.
-Inherited Metabolic Disorders
Several inherited “errors of metabolism” can cause brain damage or impair brain development
Errors of metabolism” are genetic abnormalities in which recipe for a particular protein is in
error. Typically the cause is that an enzyme is not synthesized because of mutations in both
copies of the gene. If the enzyme is a critical one, results can be very serious.
There are hundreds of different inherited metabolic disorders that can affect development of
the brain. Here are two examples:
Phenylketonuria (PKU): Hereditary disorder caused by the absence of enzyme that converts
the amino acid phenylalanine to tyrosine 缺少将氨基酸苯丙氨酸转化为酪氨酸的酶. Accumulation
of phenylalanine causes brain damage unless a special diet is implemented soon after birth.
苯丙氨酸的积累会导致脑损伤，除非在出生后不久就实施特殊的饮食。
Tay-Sachs disease: Heritable, fatal, metabolic storage disorder. Lack of enzymes in lysosomes
causes accumulation of waste produces and swelling of cells of brain.
泰-萨克斯病:一种可遗传的、致命的代谢性储存障碍。溶酶体中缺乏酶会导致废物堆积和大脑细胞肿胀
Lecture 20(Down syndrome, MS, prion disease, Parkinson’s disease, Dementia, Alzhemer’s
disease, ALS)
-Disorders of Development: Down syndrome
Down syndrome is caused not by inheritance of a faulty gene but by possession of extra
twenty-first chromosome. Down syndrome is congenital 先 天 性 的 , which does not
necessarily mean hereditary; Congenital refers to a disorder that one is born with. It is
characterized by moderate to severe intellectual disability and often physical abnormalities.
After age 30, the brain of a person with Down syndrome begins to degenerate in a manner
similar to Alzheimer's disease.

-Autoimmune disorder 自身免疫性疾病

Multiple sclerosis (MS)多发性硬化症
Autoimmune demyelinating disease that usually occurs in people’s late twenties or thirties.
Certain genes increase one’s susceptibility for getting MS, but it is generally a sporadic
disease - one that is not obviously caused by an inherited gene mutation or an infectious
agent. At scattered locations within the central nervous system, myelin sheaths are attacked by
the person’s own immune system, leaving behind hard patches of debris called sclerotic
plaques
在中枢神经系统的分散位置，髓磷脂鞘受到人体自身免疫系统的攻击，留下坚硬的碎片斑块，称为硬化斑
块 Normal transmission of neural messages through demyelinated axons is interrupted
神经信息通过脱髓鞘轴突的正常传递被中断 Because the damage occurs in white matter located
throughout the brain and spinal cord, a wide variety of neurological disorders are seen
由于损伤发生在位于整个大脑和脊髓的白质中，可以看到各种各样的神经障碍
Symptoms of multiple sclerosis go through cycles where they flare up and then decrease after
varying periods of time. In most cases, this pattern (remitting-relapsing MS) is followed by
progressive MS later in course of disease. Progressive MS is characterized by a slow,
continuous increase in symptoms. There is not yet an effective treatment for multiple
sclerosis, but many drugs that help a little have been approved, including
interferon - a protein that modulates immune system activity
干扰素——一种调节免疫系统活性的蛋白质
glatiramer acetate – peptides that mimic myelin (decoy approach)
醋酸格拉替雷默——模拟髓磷脂的肽(诱骗方法)
People who spend their childhood in places far from equator are more likely to come down
with disease than are those who live close to equator. It is likely that some disease contracted
during childhood spent in region in which virus is prevalent causes person's immune system
to attack his or her own myelin.
-Degenerative Disorders
There are many different kinds of neurodegenerative disease, such as prion diseases,
Huntington's, Parkinson's, Alzheimer's, and ALS.
Some of these conditions injure particular kinds of cells, others are more widespread.
Degeneration is typically the result of apoptosis 细胞凋亡, which is triggered by collections
(aggregates) of misfolded proteins that disrupt normal cellular function. 它是由错误折叠的蛋白
质的集合(聚集)破坏正常的细胞功能触发的
Prion protein disease 阮蛋白病
Transmissible spongiform 海绵状 encephalopathy: Contagious brain disease (includes mad
cow and Creutzfeldt-Jacob disease) whose degenerative process gives the brain a sponge-like
appearance 传染性海绵状脑病:传染性脑病(包括疯牛病和克雅氏病)，其退化过程使大脑呈海绵状
Accumulation of misfolded prion protein is responsible for transmissible spongiform
encephalopathies.
Prion: Misfolded proteins with the ability to transmit their misfolded shape onto normal
variants of the same protein.
When a misfolded prion protein interacts with correctly folded prion proteins, it will cause
them to misfold as well. Accordingly, prion protein diseases spread from cell and cell and
animal to animal by means of contact with misfolded prion protein. It is the only infectious
agent 传 染 源 that is just a protein. All other infectious agents (viruses, bacteria, fungi,
parasites) contain nucleic acids.

Degenerative Disorders: Huntingtons’s Disease

Huntington’s disease is caused by one dominant mutation in the Huntingtin gene. Over time,
aggregates of huntingtin protein form in the basal ganglia, causing neurodegeneration. It
affects 1 in 10,000 people.
Symptoms usually begin between 30 and 50 years of age and death follows 15-20 years later.
It is characterized by an increasingly severe lack of coordination, uncontrollable jerky limb
movements 无法控制的肢体抽动, and eventually dementia followed by death. Movements
in Huntington's disease look like fragments of purposeful movements but occur involuntarily.
Huntingtin protein is heavily expressed in the input nuclei of the basal ganglia (the striatum -
caudate nucleus and putamen).
Mutated Huntingtin protein tends to aggregate (clump) 聚 集 and overtime this causes
degeneration of neurons in these regions.
There is presently no cure (or treatment really), but there is guarded optimism about the
potential of antisense gene therapy (even though two large clinical trials recently failed).
Antisense therapy
Antisense DNA (or RNA) can be administered intrathecally (in the spinal cord). Researchers
are hopeful that this approach (or viral-mediated gene delivery and gene editing technologies)
will one day become a practical and effective approach to altering gene expression in the
brains of living people.
-Parkinson’s Disease
Parkinson’s disease is another degenerative “movement” disorder. It is associated with
degeneration of dopamine neurons in the midbrain, specifically in the substantia nigra 黑质. It
affects 1% of the population. Symptoms usually appear after the age of 60. It is characterized
by shaking, muscular rigidity, slowness of movement, difficulty walking, and eventually
dementia. Without treatment, people have increasing difficulty initiating purposeful
movement.
The causes of Parkinson’s disease are largely unknown (partly genetic, partly environmental),
however the death of midbrain dopamine neurons seems to relate to aggregation of the protein
alpha-synuclein.
The protein alpha-synuclein, which is heavily expressed in dopamine neurons, tends to
aggregate (clump together) at some rate. Overtime these protein aggregates cause dopamine
neurons to undergo apoptosis. 这些蛋白质聚集导致多巴胺神经元发生凋亡。
Reduced dopamine signaling in the basal ganglia disrupts movement. There is presently no
cure, but there are many ways to somewhat successfully treat the motor problems. Cognitive,
emotional, and sleep disturbances eventually develop as well and there are currently no good
treatments for those symptoms.
Alpha-synuclein: Protein heavily express in midbrain dopamine neurons. Its function is not
entirely clear. Abnormal accumulations are associated with dopamine neuron degeneration in
Parkinson's disease.
Lewy body: Aggregate of misfolded alpha-synuclein protein; found in the cytoplasm of
midbrain dopamine neurons in people with Parkinson's disease.
Mutations in the alpha-synuclein gene can promote alpha-synuclein aggregation and cause
Parkinson’s disease. These mutations can be dominant 显 性 的 , in that only one bad gene
(from one parent) can cause the problem.
Ubiquitin: Protein that is put on faulty/old/ misfolded proteins, which targets them for
degradation. Ubiquitinated proteins get brought to proteasomes, which breaks them into their
constituent amino acids for recycling.
泛素:放在有缺陷的/老化的/错误折叠的蛋白质上的蛋白质，它的目标是使它们降解。泛素化的蛋白质被带
到蛋白酶体中，蛋白酶体将它们分解成组成它们的氨基酸，以便回收。
Parkin: Protein that plays a critical role ubiquitination. Mutated parkin is a cause of familial
Parkinson's disease. If parkin is defective, misfolded proteins accumulate, aggregate, and
eventually kill the cell.
帕金:在泛素化中起关键作用的蛋白质。帕金森氏病突变是家族性帕金森氏病的病因之一。如果帕金蛋白
有缺陷，错误折叠的蛋白质就会积累、聚集，最终杀死细胞。
Proteasome: Organelle responsible for destroying ubiquitinated proteins within a cell.
蛋白酶体:细胞内负责破坏泛素化蛋白质的细胞器。
Dopaminergic neurons 多巴胺能神经元 are especially sensitive to loss of parkin function
and alpha-synuclein aggregation.
Toxic gain of function: Genetic disorder caused by a dominant gene mutation that produces a
protein with toxic effects 由 产 生 具 有 毒 性 作 用 的 蛋 白 质 的 显 性 基 因 突 变 引 起 的 遗 传 障 碍 (e.g.,
mutations in the alpha-synuclein gene and huntingtin gene can produce proteins that create
problems, causing Parkinson’s and Huntingtin’s disease, respectively.)
Loss of function: Genetic disorder caused by a recessive gene mutation that fails to produce a
protein that is necessary to avoid problems 由隐性基因突变导致的遗传障碍，该基因突变无法产生
避免问题所必需的蛋白质(e.g., loss of or mutations in the parkin gene can cause misfolded alpha-
synuclein protein to not be degraded).
-Treatment
The main symptoms of PD are the result of reduced dopamine signaling. Dopamine does not
cross the blood-brain barrier, so it cannot be taken as a medicine to boost brain dopamine
levels. However, a precursor of dopamine, L-dopa, can enter the brain where it is readily
converted to dopamine. L-dopa treatments diminish the motor symptoms of PD.
Brain lesions and deep brain stimulation (DBS) devices are also common treatments for PD.
The main targets for lesions and DBS are parts of the basal ganglia that become overactive in
PD, the globus pallidus and subthalamic nucleus, respectively. 主要目标分别是在 PD 中过度活跃
的基底神经节、苍白球和丘脑下核。
Damaging the globus pallidus or disrupting subthalamic nucleus activity seems to relieve
symptoms of Parkinson's disease by removing one of the brakes on motor behaviour.
Dementia 痴呆
Progressive impairments to memory, thinking, and behavior that affect the ability to perform
everyday activities as a result of a neurological disorder
Common causes are neurodegenerative disease, MS, multiple strokes, and repeated brain
trauma (chronic traumatic encephalopathy).
Alzheimer's Disease
Alzheimer’s disease is a neurodegenerative disorder that causes progressive memory loss,
motor deficits, and eventual death. Occurs in approximately 10 percent of the population
above the age of 65 and almost 50 percent of people older than 85 years. It is associated with
aggregates of misfolded amyloid protein and severe degeneration within and around the
hippocampus and neocortex 新皮层.
Amyloid precursor protein (APP): Protein that is the precursor for β-amyloid protein.
The gene for this protein is located on chromosome 21, which is the one duplicated
(triplicated) in down syndrome.
Secretase 分 泌 酶 : Class of enzymes that cut the β-amyloid precursor protein into smaller
fragments, including β-amyloid.
Presenilin: Protein that forms part of the secretases that cut APP.
早衰素:构成切断 APP 的分泌酶的一部分的蛋白质。
Mutations in presenilin can cause it to preferentially generate the abnormal long form  β-
amyloid, which causes early onset Alzheimer's disease.
衰老素的突变会导致它优先生成异常的长形 β-淀粉样蛋白，从而导致早发性阿尔茨海默病。
Apolipoprotein E (ApoE): Glycoprotein that transports cholesterol in the blood and plays a
role in cellular repair.
载脂蛋白 E:在血液中运输胆固醇并在细胞修复中起作用的糖蛋白。
Presence of the E4 allele of the apoE gene increases risk of late-onset Alzheimer's disease
apoE 基因 E4 等位基因的存在增加了晚发性阿尔茨海默病的风险
β-amyloid (Aβ): Protein found in excessive amounts in brains of patients with Alzheimer's
disease.
Amyloid plaque: Extracellular aggregation of β-amyloid protein surrounded by glial cells and
degenerating neurons. 淀粉样蛋白的胞外聚集物，周围是胶质细胞和变性神经元。
Tau protein: Microtubule protein that becomes hyper-phosphorylated in Alzheimer's disease,
disrupting intracellular transport. 在阿尔茨海默病中过度磷酸化的微管蛋白，破坏细胞内运输。
Neurofibrillary tangle: Intracellular accumulation of twisted 扭 曲 Tau protein in dying
neurons.
Other than age, the strongest risk factor for Alzheimer’s disease is traumatic brain injury.
Impact of Lifestyle
Alzheimer's disease is less prevalent in well-educated people, especially those that keep their
minds and body highly active. It seems to be a use it or lose it phenomenon.Other risk factors
include obesity, hypertension, high cholesterol levels, and diabetes.
There is no cure for Alzheimer's Disease. Some medications reduce the symptoms a little bit,
but they don’t significantly stop the neurodegeneration. There are over 100 clinical trials
underway testing new potential treatments for Alzheimer's disease. The most promising ones
are a from of Immunotherapy. Many use an immunotherapy approach to get antibodies to
recognize and destroy Aβ protein (or Tau protein, or both), either by sensitizing the patient's
own immune systems to these proteins or by directly injecting antibodies that are made
elsewhere.
-Amyotrophic lateral sclerosis (ALS) 肌肉萎缩性侧索硬化症
AKA Lou Gehrig’s Disease or motor neuron disease
Degenerative disorder that attacks spinal cord and cranial nerve 颅神经 motor neurons
Incidence of this disease is approximately 3 in 100,000. The disease typically starts after the
age of 50.
Symptoms include spasticity (increased tension of muscles, causing stiff and awkward
movements), exaggerated stretch reflexes, progressive weakness and muscular atrophy, and,
finally, paralysis. 症状包括痉挛(肌肉紧张增加，导致僵硬和笨拙的动作)，夸张的拉伸反射，进行性虚
弱和肌肉萎缩，最后，瘫痪
90 percent of cases of Amyotrophic lateral sclerosis (ALS) are sporadic (probably new gene
mutations). Mutations in two or more genes are usually required to cause the disease.
10 percent of ALS cases are inherited. 10–20 percent of these cases are caused by a mutation
in the gene that produces the enzyme superoxide dismutase 1 (SOD1), found on chromosome
21. 其中 10 - 20%的病例是由 21 号染色体上产生超氧化物歧化酶 1 (SOD1)的基因突变引起的。
This mutation causes a toxic gain of function that leads to protein misfolding and aggregation,
impaired axonal transport, and mitochondrial dysfunction. 这种突变导致功能的毒性增加，导致蛋
白质错误折叠和聚集，轴突运输受损和线粒体功能障碍
ALS and frontotemporal dementia (FTD - another neurodegenerative disorder) are now
considered to be part of a common disease spectrum (FTD–ALS) because of genetic, clinical,
and pathological similarities. ALS 和额颞叶痴呆(FTD -另一种神经退行性疾病)由于遗传、临床和病理
上的相似性，现在被认为是常见疾病谱系(FTD - ALS)的一部分。
There is currently no cure for ALS. The only current pharmacological treatment is a drug that
reduces glutamate-induced excitotoxicity, which extends life by about two to three months.
Average life span following a diagnosis is 2-4 years, but some people live much longer than
that. For example, Stephan Hawking lived with the disease for over 50 years.
-Common but harmful gene variants
Most disorders associated with old age (including neurodegenerative disease, cardiovascular
disease, and cancer) have a strong genetic component to them.
Common gene variants in the human population are associated with higher risk of getting a
particular late onset disorder.
-Inherited Gene mutations
Gene mutations that reduce reproductive success tend to get eliminated from the gene pool
fairly quickly. Very harmful gene variants are typically eliminated within a few generations,
so they tend to be extremely rare and recent in origin. Mutations that cause small deleterious
effects are removed more slowly, so they tend to be more common and older – inherited from
parents, grandparents, and so forth. Still, mutations that cause a even a slight reduction in
fitness (say a 1% drop in reproductive success) may only persist in the population for a 100
generations on average before getting selected out.
-Gene Fixation
Over evolutionary time, natural selection favors higher-fitness genes.
Most genes in our genome have gone to fixation (virtually 100% prevalence in the human
population) because they promoted survival and reproduction under ancestral conditions
better than other genes did.
Such genes comprise the species-typical human genome. Its normal neurodevelopmental
product is human nature.
-Common gene variants
For common gene variants to be stable across generations, they must not confer an overall
advantage or disadvantage on reproductive success (i.e., they must have been neutral on
average across all ancestral environments).
Neutral gene variants can give rise to variations in human nature that are not clearly
associated with an overall change in reproductive success (like different personality traits).
Otherwise, across evolutionary timescales, gene variants are either selected for (such that
everyone would have them) or selected against (which would make them extremely rare).
-Common but Harmful gene variants
Since our environment, culture, and life span changed so dramatically in the last few hundred
years, it is likely that some common gene variants that were completely neutral across all
ancestral environments are now harmful.
Researchers have identified tons of these common gene variants.
They are associated with diseases that show the classic hallmarks of gene-environment
interactions (i.e., they are heritable, but prevalence rates vary widely across cultures and
recent history, and there are straightforward environmental explanations for the variability in
disease prevalence).
-Gene-environment interactions
The environmental risk factors associated with each the following disorders were not present,
in ancestral environments:
late onset disorders 迟发性疾病, due to rapid increase in human life spans
obesity and diabetes, due to the abundance and low price of unnaturally tasty food
asthma 哮喘, due to new types and unnaturally high levels of antigens and pollutants
addictions to highly purified synthetic drugs, such as heroin and meth
depression and anxiety – although the cause is unclear, prevalence rates have changed rapidly
in recent history and vary enormously between cultures.
The gene variants associated with an increased risk of these conditions were likely completely
neutral across our ancestral environments.
There is likely now strong evolutionary pressure on these gene variants.
-Mental Disorders
Psychiatric illnesses (like schizophrenia and autism) are …
a.heritable (20 to 80% of the variance in who has a given mental disorder is well explained by
genetics)
b.common (the frequency of severe mental disorders is around 4%)
c.harmful to reproductive success (the fertility rate for people with severe mental disorders is
about half the national average)
Mental Disorder susceptibility genes
Maybe some of the gene mutations associated with mental illness were neutral or
advantageous in ancestral environments.
Keep in mind though that if mental disorder susceptibility genes were neutral or advantageous
in most environments but not all, or in most cultures but not all, or in most people but not all,
then these gene variants would not actually be neutral.
And across evolutionary time they would either have been selected out or have gone to
fixation (i.e., either they would be extremely rare or everyone would have them).
The prevalence of schizophrenia 精神分裂 is about ~1% of the population, and this has been
highly consistent across cultures and recent history.
Genetic studies have found that schizophrenia is generally not associated with one bad gene,
one bad protein, or one dysregulated brain region. Rather, hundreds of relatively common
gene variants each individually confer a very small statistical increase in the risk of
developing schizophrenia.
One theory for the prevalence of these schizophrenia susceptibility genes is that certain
combinations of them may be advantageous for reproductive success. If this were true, the
siblings of schizophrenics who don’t have the disease should have increased reproductive
success on average, because they would be more likely to have the good combination of these
schizophrenia genes in comparison to the general population. However, siblings of
schizophrenics have the same reproductive success as the general population.

Lecture 21
-Mental Disorders
The large genetic studies of mental illness that have been done to date have associated
hundreds of common gene variants with increased risk of schizophrenia..., bipolar disorder,
depression, autism, OCD, and ADHD. The surprising thing is that the same gene variants
keep showing up in studies of different mental illnesses. The risks conferred by these gene
variants are not specific to traditional diagnostic boundaries. Rather, they seem to reflect a
vulnerability to mental illness in general, not a specific illness or specific symptom within a
diagnostic 诊 断 category. Accordingly, most of these gene variants cannot be labelled as
schizophrenia genes or autism genes or bipolar genes. There just seems to be hundreds of
common gene variants that increase one’s risk of developing some mental illness.
-Diagnostic Categories
Aren’t mental disorders discrete, unitary diseases? It doesn’t seem like it. There is too much
heterogeneity within diagnostic categories, comorbidity across categories 跨类别共病, and
continuity with normality,
for mental disorders to qualify as discrete, unitary diseases. Diagnostic categories partly
reflect historical convention, diagnostic convenience, and innate categorization biases in our
perception of behaviour. Diagnostic categories are useful for describing clusters of symptoms
that tend to appear together, but we now know that similar symptoms can arise form
completely different neural circuit disruptions.
-Mental Disorder susceptibility genes 易感基因
Why do gene variants that increase the risk of developing a psychiatric illness persist in the
population? Why haven’t they been selected out?
Many of the gene variants associated with increased risk of mental illness regulate brain
development and neural plasticity.
Their expression in the brain gives rise to altered patterns of neural activity throughout the
brain. The problematic protein variants slightly alter the dynamic interactions of the
thousands of proteins expressed in the brain across different cell types during development
and maturation.
Any mutation in a gene that is expressed in the brain can hinder healthy brain function. Why
do these gene variants persist?
-Mutation–selection balance
One popular theory is mutation-selection balance.
Mental disorder susceptibility genes are continually being selected out through evolution, but
new mutations keep arising. There are about 20,000 protein-encoding genes in the human
genome and about half of them are expressed in the brain at some point. All of us have gene
mutations associated with a slight reduction in “fitness” that arose within the last 100
generations or so of our family tree. Most bad genes are a family legacy, old mutations that
have yet to go extinct, rather than new mutations specific to the individual. These mutations
will get eliminated over time, but new ones keep coming.
-Inherited gene mutations
The human genome has evolved to buffer many insults 人类已经进化到可以避免很多器官
损 伤 – environmental variation, genetic variation, and molecular noise. This robustness
allows genetic variation to accumulate in the population if the individual mutations are not
too severe. 这种稳健性(不太严重)允许变异存在 Slightly bad gene mutations that do not
directly cause a disease can collectively compromise the evolved interactions of everything in
the brain, reducing the overall robustness of brain development and function.
-Brain development
Human brain development is extremely complicated. Despite the large number of
redundancies, error checking mechanisms, and quality control efforts that are put in place to
guide proper brain development, much depends on chance. There is so much unavoidable
randomness at the molecular level impacting brain development that even identical twins can
have very different brains (e.g., one may develop schizophrenia). 尽管有大量的冗余、错误检查机
制和质量控制指导大脑的正常发育，但很大程度上还是取决于运气。在分子水平上，有太多不可避免的随
机性影响着大脑的发育，甚至同卵双胞胎的大脑也可能非常不同(例如，其中一个可能会患上精神分裂症)。
-Neurodevelopmental robustness 神经发育稳健性
Some people argue that body symmetry is indicative of the robustness of the underlying
genetic instructions, which have to contend with environmental variation and molecular noise.
The two sides of the body develop independently from the same set of genomic instructions.
If the instructions are clear then the body should be symmetrical. If the instructions are a bit
confusing or open to interpretation, however, then the person may be more asymmetric. Body
symmetry is partially heritable and slightly correlates with intelligence, physical
attractiveness, and physical health. Genetic studies have identified hundreds of gene variants
that correlate with a very small statistical increase in intelligence. And, some of the gene
variants associated with intelligence overlap with the gene variants associated with physical
attractiveness, physical health, and longevity. These gene variants are thought to be indicative
of neurodevelopmental robustness (due to clear genetic instructions).
一些人认为身体对称表明了潜在的遗传指令的健壮性，这些指令必须与环境变异和分子噪声相抗衡。身体
两侧的发育独立于同一套基因组指令。如果说明清楚，那么身体应该是对称的。然而，如果这些指示有点
令人困惑或易于理解，那么这个人可能会更不对称。身体的对称性部分是遗传的，与智力、外表吸引力和
身体健康略有关联。遗传学研究已经确定了数百种基因变异，这些基因变异与智力统计上的微小增长有关 。
而且，一些与智力相关的基因变异与与身体吸引力、身体健康和寿命相关的基因变异重叠。这些基因变异
被认为是神经发育稳健性的标志(由于明确的遗传指令)。
-Should I have my genes tested?
Unfortunately, the identification of gene variants that confer an increased risk of developing
psychiatric illness has not been particularly helpful with regards to prevention or treatment.
For most psychiatric disorders, there are few preventive measures （几乎没有预防措施）
that can be taken beyond avoiding trauma and generally looking after oneself.
The best advice for maintaining a healthy brain and healthy body, based on the available data,
is to Stay active, physically and mentally (exercise, socialize, set goals) Eat well (more
vegetables, less sugar) Reduce stress, lower blood pressure Maintain good sleep habits Limit
alcohol intake and avoid tobacco and hard drugs.
-Future directions
By identifying the gene variants and neural circuit disruptions associated with mental illness,
researchers hope to develop new treatment and prevention strategies.
One idea is develop gene editing techniques 基 因 编 辑 技 术 that could be used in living
people, or as a part of in vitro fertilization 体外受精. There is also still hope for better disease
management through new pharmacological treatments, perhaps ones that directly target
intracellular signaling cascades rather than neurotransmitter signaling.
-Schizophrenia 精神分裂
Schizophrenia is is characterized social withdrawal 孤 僻 , disorganized thinking, abnormal
speech, and an inability to understand reality. It afflicts approximately 1% of world's
population. Symptoms typically come on gradually, begin in young adulthood, and in many
cases never resolve (although 20% of people eventually do quite well). About 30-50% of
people with schizophrenia do not believe they have an illness or comply 遵 守 with their
recommended treatment.
Schizophrenia symptoms
The symptoms of schizophrenia are often grouped into 3 categories:
Negative: the absence of behaviours - social withdrawal, reduced emotional expression,
poverty of speech, and reduced motivation
Cognitive: disorganized and irrational thinking, deficits in learning and memory, poor abstract
thinking, and poor problem solving
Positive: the presence of delusions (typically delusions of persecution, grandeur, or control -
beliefs that contradict reality) and hallucinations (perception of stimuli that are not actually
present)
Negative symptoms typically emerge first, followed by cognitive symptoms and, years later,
by positive symptoms.
Many patients with schizophrenia also exhibit neurological symptoms, such as poor control of
eye movements and unusual facial expressions, and the illness is associated with subtle
differences in brain structure.
Schizophrenia heritability
The causes of schizophrenia include environmental and genetic factors. Estimates of the
heritability of schizophrenia is around 80%. Heritability measures the fraction of phenotype
variability that can be attributed to genetic variation. Heritability measures the amount of
variation that can be attributed to genetics (i.e., the amount of variation that would be
eliminated if everyone had the exact same genes).
Risk of developing schizophrenia if: both of you parents have it (or an identical twin has it) is
~50%, one of your parents has it is ~13%, your sibling has it is ~8%. Around 5% of cases are
attributed to rare gene copy number variations (duplicated or missing genes), which are
frequently comorbid with autism and intellectual disabilities.
Environmental factors: mother’s nutrition during pregnancy, mother’s stress during
pregnancy, certain infections (particularly during pregnancy), birth month, being raised in a
city, childhood trauma, social isolation, perinatal hypoxia / brain damage
Evidence indicates that incidence of schizophrenia is related to several environmental factors
that could affect development in utero 子 宫 : season of birth, viral epidemics, population
density, and parental smoking.
The seasonality effect: A disproportionately large number of schizophrenic patients are born
in February, March, April, and May
The number of schizophrenic births in late winter and early spring is especially high if the
temperature was lower than normal during previous autumn. This condition keeps people
indoors and favors transmission of viral illnesses 病 毒 疾 病 的 传 播 . Schizophrenia is also
about three times more prevalent in people who live in the middle of large cities as compared
to those who live in rural areas. This result suggests transmission of infectious illnesses is
facilitated by increased population density.
Prenatal environments of monochorionic twins (i.e., they share one placenta) are more similar
than those of dichorionic twins. Some evidence suggests that the concordance rate for
schizophrenia is much higher for monochorionic twins and than in dichorionic twins, which
suggests the prenatal environment 产前环境 is an important factor.
-Evidence for Abnormal Brain Development
Symptoms of schizophrenia are not normally seen in childhood, but behavioral and
anatomical evidence indicates that abnormal prenatal development 产 前 发 育 异 常 is
associated with schizophrenia
Behavioural: Children who go on to develop schizophrenia display less sociability and
deficient psychomotor functioning as kids.
Anatomical 解剖结构: Minor physical abnormalities are often seen in children who go on to
develop schizophrenia, such as partial webbing of the two middle toes and a high-steepled
palate. 例如两个中脚趾部分呈蹼状，上颚呈高斜度。
-Treatment of Schizophrenia
There is no cure for schizophrenia. The main treatment is medication, often in combination
with psychological and social supports.
Many drugs have been developed that relieve the positive symptoms of schizophrenia. They
typically block dopamine D2 receptors and are called antipsychotics or neuroleptics.抗精神
病药或者安定药
In contrast, dopamine receptor agonists, like crystal meth and cocaine, tend to temporarily
elicit certain aspects of the positive symptoms of schizophrenia in people who do not have the
disorder. Thus…
The Dopamine Hypothesis: excessive dopamine D2 receptor activity, particularly in the
nucleus accumbens (striatum), underlies the positive symptoms of schizophrenia.
The Dopamine Hypothesis
Dopamine D2 receptor antagonists typically reduce the positive symptoms of schizophrenia
but not the negative symptoms.
Some evidence suggests that the negative symptoms of schizophrenia result from abnormal
activity in the prefrontal cortex
For example, the negative symptoms of schizophrenia are similar to those produced by
damage to the prefrontal cortex, and schizophrenic patients do poorly on neuropsychological
tests that are sensitive to prefrontal damage
In general, the negative symptoms of schizophrenia may be caused by hypofrontality 额叶减
退 , which is decreased activity of the frontal lobes, particularly the dorsolateral prefrontal
cortex, which may relate to hypoactivity of local dopamine D1 receptors.
While excess dopamine signaling in the striatum has been associated with the positive
symptoms of schizophrenia, reduced dopamine signaling in the prefrontal cortex has been
associated with the negative symptoms.
It is possible that schizophrenics have too little dopamine in the prefrontal cortex and too
much elsewhere.
The atypical antipsychotic clozapine has been found (in monkeys) to simultaneously decrease
dopamine levels in the striatum and increase dopamine levels in the prefrontal cortex.
Atypical antipsychotics 非典型抗精神病药物
Atypical antipsychotic medications: Recently developed medications which aim to reduce
both the positive symptoms and negative symptoms of schizophrenia. They typically
influence the activity of several neurotransmitter receptors (beyond blocking the dopamine
D2 receptor).
Clozapine: First of the atypical antipsychotic medications. It blocks both dopamine D2 and
serotonin 2A receptors.
Aripiprazole 阿立派挫: An atypical antipsychotic. It acts as partial agonist at the dopamine
D2 and D3 receptors. It is thought to reduce dopamine receptor activity in the striatum
(nucleus accumbens) but boost it in the prefrontal cortex.
The atypical antipsychotic Aripiprazole is a partial dopamine D2 receptor agonist.
A partial agonist is a drug with very high affinity for a receptor but it activates it less than the
normal ligand does. 局部激动剂是一种对受体具有非常高亲和力的药物，但它对受体的激活程度低于正
常 配 体 。 A partial agonist can act as an agonist in regions of low concentration of normal
ligand and as antagonist in regions of high concentrations. 局部激动剂可在正常配体浓度低的区域
作为激动剂，在高浓度区域作为拮抗剂

Lecture 22
-Autistic Disorder
Autistic spectrum disorder describes a wide range of developmental disorders that are
characterized by troubles with social interaction and communication, and by restricted and
repetitive behavior. The incidence of autism is around 1% of population. In many cases there
are clear cognitive impairments, intellectual disability, or reduced imaginative ability, but this
is not always the case. Parents usually notice signs during the first two or three years of their
child's life. Social impairments are often the first symptoms to emerge. Some infants with
autistic disorder do not seem to care whether they are held. Some arch their backs when
picked up, as if they do not want to be held.
Like intellectual disability, autism encompasses a large set of disorders with diverse
underlying causes. It is associated with a combination of genetic and environmental factors
that affect early brain development). Estimates of the heritability of autism are around 70%,
but as high as 90% for autism spectrum disorder. Many cases have been linked to
spontaneous 自 发 性 rare gene mutations that have severe effects. These include
chromosomal abnormalities involving deletions, duplications or inversions of genetic
material.遗传物质缺失或倒置 Other cases are associated with multigene interactions across
common gene variants. Some cases have been linked to maternal viral infections during
pregnancy.
Many people with autism have abnormal or even nonexistent language. About a third to a half
of individuals with autism do not develop enough natural speech to meet their daily
communication needs. They may echo what is said to them or they may refer to themselves as
others do—in second or third person. People with autism generally have atypical interests and
behaviors. They may show stereotyped movements, such as flapping their hand back and
forth or rocking back and forth. They may exhibit compulsive or ritualistic 仪 式 性
behaviour.
Mild forms of autistic spectrum disorder often do not include a delay in language
development or the presence of important cognitive deficits. Mild forms of autism (often
called Asperger’s syndrome) mostly just involve deficient or absent social interactions and
repetitive and stereotyped behaviors along with obsessional interest in narrow subjects.
Incidence of autistic disorder is around 1% of population. Disorder is four times more
common in males than in females. If only cases of autism with intellectual disability are
considered, the ratio falls to 2:1 (males:females). If only cases of high-functioning autism are
considered (those with average or above-average intelligence and reasonably good
communicative ability), the ratio rises to approximately 7:1 (males:females)
Within species, the heterogametic(XY-male for mammals and insects, ZW-female for birds,
butterflies,fish,reptiles) sex shows slightly more variability on all kinds of traits (from
morphology to academic performance).(homogametic, XX, ZZ)
There often appears to be significant abnormalities in the development of the brains of autistic
children. Kids who develop autism tend to have a slightly small brain at birth, but it grows
abnormally fast and by 2–3 years of age is often about 10% larger than a normal brain.
Following this early spurt, growth of the autistic brain slows down, and by adolescence it is
only about 1–2 percent larger than normal. Hypotheses for the cellular and molecular bases of
early brain overgrowth include the following: Altered neuronal migration during early
gestation/Abnormal formation of synapses and dendritic spines/Overconnectivity in key brain
regions/Unbalanced excitatory–inhibitory neural networks 妊娠早期神经元迁移改变/突触和树突
的异常形成/大脑关键区域的过度连接/不平衡兴奋-抑制神经网络
fMRI studies on people with autism have revealed marked abnormalities in brain activity.
For example, there is little or no activity in fusiform face area 棱状回面部区域 of autistic
adults looking at pictures of human faces.
-Autism treatment
The main goals when treating children with autism are to lessen the impact of the associated
deficits and family distress, and to increase quality of life and functional independence.
Intensive, sustained special education programs and behavior therapy early in life can help
children acquire self-care, communication, and life skills, and often improve functioning and
decrease symptom severity and maladaptive behaviors.
Medications generally do not address the core symptoms, but often help reduce the irritability,
inattention, and repetitive behaviors. All kinds of medications may be tried, including:
anticonvulsants (↑ GABA receptor activity), antidepressants (↑ serotonin receptor activity),
antipsychotics 抗 精 神 病 (↓ dopamine receptor activity), stimulants (↑ dopamine receptor
activity)
-Depression & bipolar
Major Affective Disorders
Affect: As a noun, affect refers to feelings or emotions. Just as the primary symptom of
schizophrenia is disordered thoughts, affective disorders (mood disorders) are characterized
by disordered feelings.
Mood (affective)disorder: Serious mood disorder. There are two principal types of mood
disorders: bipolar disorders 双相情感障碍 and major depressive disorder 重度抑郁.
-Mood Disorders
Affective disorders are prevalent and dangerous. A diagnosis of depression has a prevalence
of approximately 7% in women and 3% in men. Severely depressed people usually feel
unworthy, hopeless, and have strong feelings of guilt. People with mood disorders have a very
risk of self-harm and suicide.
-Bipolar disorder vs MDD
Bipolar disorder: Serious mood disorder characterized by cyclical periods of mania and
depression 周 期 性 的 狂 躁 和 抑 郁 . It affects 1% of the population. ~80% of the risk is
attributed to genetics.
Major depressive disorder (MDD): Serious mood disorder that consists of unremitting
depression or periods of depression (that do not alternate with periods of mania). 40% of the
risk is attributed to genetics.
Environmental factors for mood disorders include traumatic/abusive childhood experiences.
Bipolar disorder
Mania
Episodes of mania are characterized by sense of euphoria 欣快感 that does not seem to be
justified by circumstances. People with mania usually exhibit nonstop speech and motor
activity. Diagnosis of mania is partly a matter of degree; one would not call exuberance and a
zest for life pathological.
Biological Treatments for bipolar
Lithium 锂: Chemical element. Lithium salts (and anticonvulsants) are commonly prescribed
for bipolar disorder. Lithium is most effective for treating the manic phase of bipolar disorder.
Once mania is eliminated, depression usually does not follow. Therapeutic effect of lithium is
very rapid. The mechanism of action is unknown.
-Biological Treatments for MDD
There are several established and experimental biological treatments for major depressive
disorder (MDD)
Drugs that increase serotonin and/or norepinephrine 去甲肾上腺素 signaling by inhibiting
their enzymatic breakdown (e.g., monoamine oxidase inhibitors, MAOi) or by blocking their
reuptake (e.g., tricyclics and serotonin specific reuptake inhibitors, SSRIs).
Ketamine (NMDA glutamate receptor blocker), Electroconvulsive therapy (ECT), Deep brain
stimulation, Transcranial magnetic stimulation, Vagus nerve stimulation, Bright-light therapy
(phototherapy), Sleep deprivation
Tricyclic antidepressant: Inhibits reuptake of serotonin and norepinephrine but also affects
other neurotransmitters; Named for the molecular structure
Serotonin specific reuptake inhibitor (SSRI): A class of drugs that specifically inhibit the
reuptake of serotonin without affecting the reuptake of other neurotransmitters. The most
common one is Prozac (fluoxetine). Similar drugs are Celexa, Paxil, Zoloft, etc…
Serotonin and norepinephrine reuptake inhibitor (SNRI): Antidepressant drug that specifically
inhibits reuptake of norepinephrine and serotonin without affecting reuptake of other
neurotransmitters.
-Monoamine Hypothesis 单胺受体假说
Based largely on the success tricyclic and SSRI treatments, the monoamine hypothesis of
depression was developed. The idea is that depression is caused by insufficient monoamine
receptor activity (the monoamines are serotonin, norepinephrine, and dopamine). Because
symptoms of depression are generally not relieved by potent dopamine receptor agonists such
as amphetamine or cocaine, most investigators have focused their research efforts on the other
two monoamines: norepinephrine and serotonin.
Tryptophan 色氨酸 is the molecular precursor to serotonin. Giving people a low-tryptophan
diet + tryptophan-free amino acid “cocktail” lowers brain tryptophan levels and consequently
decreases their synthesis of serotonin (5-HT). This tryptophan/serotonin depletion procedure
can elicit a depressive episode in people susceptible to depression. 这种色氨酸/ 5 -羟色胺消耗过
程会导致易患抑郁症的人出现抑郁发作。 Although SSRIs and SNRIs increase the levels of 5-HT
and norepinephrine in the brain very rapidly, the drugs do not relieve symptoms of depression
until they have been taken for several weeks. This suggests that something other than a simple
increase in monoamine receptor activity is responsible for the normalization of mood. 除了单
胺受体活性之外还有其他因素
-Role of the Frontal Cortex
Functional Imaging Scans
Functional imaging scans have been done on many depressed patients, both before and after a
variety of successful treatments. There are few (if any) correlations. However, the argument
has been made that one area of the anterior cingulate cortex 前 扣 带 皮 层 (the subgenual
region known as area 25) becomes less active after successful treatments.
-Deep Brain Stimulation
Deep brain stimulation has been tried in the subgenual anterior cingulate cortex 膝下前扣带
皮 层 as well as in the nucleus accumbens 伏 隔 核 . Other promising approaches involve
transcranial magnetic stimulation (TMS) directed to areas of the PFC or vagal nerve
stimulation (VNS).
-Other Biological Treatments: Electroconvulsive therapy (ECT)
Used therapeutically to alleviate severe depression and bipolar disorder.
Seizures are electrically induced by applying brief electrical shocks to the head.
In contrast to the delayed therapeutic effects seen with monoamine related treatments, the
effects of other treatments (including ECT, lithium, DBS, VNS, and sleep deprivation) are
more rapid. The seizures induced by ECT often reduce symptoms within days.
-Role of Sleep
One of the most prominent symptoms of depression is disordered sleep. People with
depression often have shallow, fragmented sleep. They tend to awaken frequently, especially
toward morning. In general, they spend more time in stage 1 sleep and less time in deep,
slow-wave sleep (stages 3 and 4). They also enter REM sleep soon after falling asleep, much
earlier in the night in comparison to other people.
-Total Sleep Deprivation
One of most effective antidepressant treatments is total sleep deprivation 剥 夺 睡 眠 . Total
sleep deprivation has immediate antidepressant effects in some people. Typically, depression
is lifted by staying up overnight, but it returns after a normal night's sleep. This suggests that
a chemical builds up during waking hours that has some antidepressant effect, and it gets
cleared away during sleep. 这表明，一种具有抗抑郁作用的化学物质在醒着的时候积聚起来，在睡觉
的时候被清除掉。 REM sleep deprivation also works, although more slowly, over the course of
several weeks (similar to SSRIs).
-Anxiety disorders
Anxiety disorder: A variety of psychological disorders characterized by unrealistic and
unfounded fear and anxiety. Includes muscle tension, over activity of the autonomic nervous
system, expectation of an impending disaster, and continuous vigilance for danger.
Generalized anxiety disorder: Disorder characterized by excessive anxiety and worry serious
enough to cause disruption of their lives
Social anxiety disorder: Disorder characterized by excessive fear of being exposed to the
scrutiny of other people that leads to avoidance of social situations in which person is called
on to perform.
Panic 惊 恐 disorder: Disorder characterized by episodic periods of severe and unremitting
terror. Includes symptoms such as shortness of breath, irregularities in heartbeat, and other
autonomic symptoms, accompanied by intense fear.
Anticipatory anxiety 预见性焦虑: Fear of having a panic attack promotes anticipatory anxiety
that sometimes leads to the development of agoraphobia.
Agoraphobia 广场焦虑: Fear of being away from home or other protected places.
People often have more than one type of anxiety disorder.
Anxiety Disorder prevalence
In a given year, about 12% of people are affected by an anxiety disorder. It appears twice as
often in females as males, generally begins before the age of 25. 12% of people will develop a
specific phobia and 10% will develop social anxiety disorder at some point in their life.
Anxiety Disorder causes
The cause of anxiety disorders is a combination of genetic and environmental factors.
Environmental risk factors include a history of child abuse and poverty. Anxiety disorders
often occur with other mental disorders, particularly major depressive disorder, personality
disorder, and substance use disorder. Older people who have dementia often have problems
with anxiety.
Anxiety Disorder brain activity
Functional brain imaging studies suggest that the amygdala and prefrontal cortex are involved
in anxiety disorders. Adolescents with generalized anxiety disorder showed increased
activation of the amygdala and decreased activation of the ventrolateral 腹 外 侧 prefrontal
cortex while looking at angry faces. College students with a high level of anxiety showed
increased activation of the amygdala, which positively correlates with students’ anxiety
measures.
Anxiety Disorder treatments
Treatment options include lifestyle changes, behavioural therapy, and medications.
Lifestyle changes may include exercise, regularizing sleep patterns, and reducing caffeine
intake and smoking.
Cognitive behavioral therapy (CBT) is often effective and is a first line treatment.
When medication is called for: Benzodiazepines are sometimes used, particularly in
emergency settings because of their rapid onset, Selective serotonin reuptake inhibitors
(SSRIs) are frequently used as a first line treatment for anxiety disorders.

Lecture 23
-Obsessive-Compulsive Disorder (OCD)强迫症
OCD (less than 2% of population) is characterized by repeatedly having certain thoughts
("obsessions") and a need to repeatedly check things or repeatedly perform certain routines
("rituals“ or “compulsions”)
to an extent that it causes distress & impairs general functioning.
There are a variety of symptoms, but they often get clustered into 4 groups: symmetry,
cleaning, hoarding 囤积, and forbidden thoughts 禁忌猜想.
The "forbidden thoughts" cluster is associated with intrusive 侵入 and distressing thoughts of
a violent, religious, or sexual nature, whereas the “cleaning” cluster is associated with germs,
bodily fluids 体液, and contamination.
The compulsive behaviors are driven by intrusive thoughts, and they often involve obsessive
hand washing, cleaning, counting, or checking on things (e.g., to see if a door is locked).
Some people have difficulty throwing things out. The compulsions are often performed to
seek relief from obsession-related anxiety, driven by a fear that something bad will happen if
the ritualistic behaviour is not done properly or a belief that life cannot proceed as normal
while the imbalance remains. Most adults with OCD realize that their behaviors do not make
sense, they understand that their notions do not correspond with reality; however, they feel
that they must act as though their notions are correct, and they are typically unable to control
their obsessions or compulsions for more than a short period of time.
Incidence of OCD is less than 2 percent. Lifetime prevalence rates are slightly higher in
women than men, but diagnosis typically occurs later in women (after age 18) than men
(during adolescence). Symptoms usually start before age 25 in both sexes. The cause of OCD
is a combination of genetic and environmental factors. Genetic factors account for ~50% of
the variability. Environmental risk factors include a history of child abuse or other adverse
events. Some cases have been documented following infections.
Treatment
Treatment always involves counseling, often a version of cognitive behavioral therapy (CBT)
known as exposure and response prevention, which involves increasing exposure to what
causes the problems while not allowing the repetitive behavior to occur.
Treatment sometimes includes antidepressants such as selective serotonin reuptake inhibitors
(SSRIs)
Without treatment, the condition often lasts decades.
Sometimes OCD symptoms appear after brain damage, particularly to the basal ganglia,
cingulate gyrus 扣带回, or prefrontal cortex
Several functional imaging studies have found evidence of increased activity in the frontal
lobes and striatum in patients with OCD
Treatment for severe cases can include a brain lesion, specifically a cingulotomy 扣带切开术,
which is the cutting of a fiber bundle 纤维束 between PFC and anterior cingulate.
Deep brain stimulation within basal ganglia areas is an active area of research.
-Attention-Deficit/Hyperactivity Disorder (ADHD)注意力缺陷/多动症
ADHD is a mental disorder characterized by problems paying attention, hyperactivity, or
difficulty controlling (inhibiting) behavior in an age-appropriate manner. More than 5% of
children in North America are now being treated for ADHD. The symptoms generally appear
before a person is 12 years old, are present for more than six months, and cause problems in
school, home, or elsewhere. ADHD is usually first discovered in the classroom, where
children are expected to sit quietly and pay attention to teacher or work steadily on project.
In general, children with ADHD often: show reckless and impetuous behavior, act without
reflecting, let interfering activities intrude into ongoing tasks, have difficulty withholding a
response. Examples of symptoms of inattention: “often had difficulty sustaining attention in
work tasks or play activities” , “is often easily distracted by extraneous stimuli”.
Diagnosis can be difficult because the symptoms are not well defined. Many children with
ADHD have a good attention span for tasks they find interesting, and some hyperactivity,
inattention, and impulsivity are within the range of normative behaviors.
Prevalence rates vary widely across different communities, ranging from 1 to 10% of
children. Boys are diagnosed three times more often than girls. ADHD is often associated
with aggression, conduct disorder, learning disabilities, depression, anxiety, and low self-
esteem.
The causes of ADHD include environmental and genetic factors. Estimated heritability of
ADHD ranges from 75 to 91%. Certain cases are related to previous infection of or trauma to
the brain. Drug and alcohol use and infections during pregnancy are associated with increased
risk for the child, as is low birth weight.
Treatment
Management of ADHD typically involves counseling and medications, often stimulants that
raise dopamine levels by blocking or reversing the dopamine reuptake transporter (e.g.,
Ritalin and Adderall). Antidepressants may also be helpful.
-Stress Disorders
Stress refers to the physiological reaction caused by the perception of aversive or threatening
situations. These physiological responses prepare people for fight or flight situations and
include autonomic and endocrine responses that help to mobilize the body's energy resources
and support vigorous 剧烈 activity. Stress-related autonomic and endocrine responses 自主
和分泌反应 can cause adverse effects on health over time.
Physiology of the Stress Response
Stress activates the sympathetic branch of autonomic nervous system. Stress also activates the
adrenal glands 肾上腺 to release hormones into the blood, including epinephrine 肾上腺素,
norepinephrine 去 甲 肾 上 腺 素 , and glucocorticoids 糖 皮 质 激 素 such as cortisol. The
autonomic and hormone responses work together to increase heart rate, blood pressure, and
blood flow to muscles to make nutrients stored become available.
Glucocorticoids 糖 皮 质 激 素 : A group of hormones (corticosteroids) that are important in
protein and carbohydrate metabolism, secreted especially in times of stress.
在蛋白质和碳水化合物代谢中起重要作用的一组激素(皮质类固醇)，尤其...
Cortisol 皮 质 醇 : A specific glucocorticoid (steroid hormone) secreted by adrenal cortex in
response to stress. 肾上腺皮质在 response to stress 时分泌的一种特殊的糖皮质激素(类固醇激素)。
Secretion of glucocorticoids is controlled by the hypothalamus.
a.In response to stress, the hypothalamus starts a chain of events by releasing CRH/CRF
(corticotropin-releasing hormone/factor).
b.CRH stimulates the pituitary 垂 体 to secrete ACTH (adrenocorticotropic hormone).
c.ACTH stimulates the adrenal gland to produce glucocorticoids.
hypothalamus 释放 CRH，CRH 分泌 ACTH，ACTH 刺激肾上腺制造 glucocorticoids
Glucocorticoids
Help to break down and convert proteins into glucose, make fats available for energy, increase
blood flow, suppress secretion of sex hormones and stimulate behavioral responsiveness
Glucocorticoids have other physiological effects, too, some of which are not well understood.
Almost every cell in the body contains glucocorticoid receptors, which means that few of
them are unaffected by these hormones.
有助于分解蛋白质并将其转化为葡萄糖，使脂肪为能量，增加血液流动，抑制性激素分泌，刺激行为反应
糖皮质激素也有其他生理作用，其中一些还没有被很好地理解。几乎身体的每个细胞都含有糖皮质激素受
体，这意味着很少有细胞不受这些激素的影响。
Health Effects of Long-Term Stress
Short-term effects of glucocorticoids are essential for survival.
Long-term effects are damaging. These effects include: increased blood pressure, damage to
muscle tissue ， steroid diabetes ， infertility ， inhibition of growth ， inhibition of the
inflammatory responses, suppression of the immune system
Stress slows the healing of (flesh) wounds and predisposes people to infections.
压力会减缓(肉体)伤口的愈合，使人容易受到感染。
During three-to-five-day period just before showing symptoms of upper respiratory infection
呼吸道感染, people experienced an increased number of undesirable, stressful events.
Effects of Stress on the Brain
Monkeys near bottom of their social hierarchy are almost continuously stressed. These
monkeys seem to die more often than others from stress-related issues. Examinations post-
mortem 尸 检 found them to have signs of chronic stress, such as gastric ulcers 胃 溃 疡 ,
enlarged adrenal glands 肾上腺肿, and damaged hippocampi 海马受损.
Episodes of emotional maltreatment during childhood has been associated with a small
reduction in volume of dorsomedial prefrontal cortex. 童年时期的情感虐待事件与背内侧前额叶皮
层体积的小幅度减少有关
-Posttraumatic stress disorder(PTSD)
PTSD is a mental disorder that can develop after a person is exposed to a traumatic event,
such as sexual assault, warfare, traffic collisions, or other threats on a person's life.
Symptoms may include disturbing thoughts, feelings, or dreams related to the events, mental
or physical distress to trauma-related cues and efforts to avoid them, and an increase in the
fight-or-flight response.The symptoms can interfere with social activities, cause feeling of
hopelessness, and increase risk for suicide. It is no longer classified as an anxiety disorder
since it entails multiple emotions(e.g.guilt, shame, anger) outside the anxiety spectrum.
Some evidence suggests that PTSD is associated with abnormalities in the hypothalamic-
pituitary-adrenal (HPA) axis, which coordinates hormonal response to stress.
Several studies found evidence that increased activity in the amygdala is responsible for
emotional reactions in people with PTSD
Functional imaging studies have found that when shown pictures of faces with fearful
expressions, people with PTSD show greater activation of amygdala and smaller activation of
prefrontal cortex than people without PTSD.
Most people who have experienced a traumatic event will not develop PTSD. The likelihood
of developing PTSD increases with the number of traumatic events the person has
experienced. Approximately 30% of the variance in PTSD is caused from genetics alone.
Treatment
The main treatments for people with PTSD are cognitive behavioural therapy, group therapy,
and medication. Selective serotonin reuptake inhibitors (SSRIs) are the first-line medications
and result in benefit in about half of people.
-Addiction(Substance Abuse Disorders)
Drug addiction is an extremely serious debilitating disorder. The big players are alcohol,
opiates 鸦片, cocaine and meth 冰毒, nicotine 尼古丁, barbiturates 巴比妥酸盐 and benzos
苯类药物.
Problems with alcohol abuse: automobile accidents, fetal alcohol syndrome, cirrhosis of the
liver, Korsakoff's syndrome, increased rate of heart disease, increased rate of intracerebral
hemorrhage, pancreatitis, diabetes, etc
Heredity and Drug Abuse
Epidemiological studies estimate that genetic factors account for 40–60% of the risk factors
for alcoholism.Alcohol consumption is not distributed equally across the population; in the
United States, 10 percent of the people drink 50 percent of the alcohol. Many twin studies and
adoption studies confirm that the primary reason for this disparity is genetic.
What is Addiction?
Reinforcement: Drugs that lead to dependency must first reinforce people's behavior.
If, in a particular situation, a behavior is regularly followed by reinforcement that behavior
will become more frequent in that situation.
Effectiveness of a reinforcing stimulus is greatest if it occurs immediately after a response
occurs. If reinforcing stimulus is delayed, it becomes considerably less effective. The
consequences of the actions teach us whether to repeat that action, and events that follow a response by more than
The speed by which the brain perceives
a few minutes were probably not caused by that response.
reinforcement is thought to explain the relative addictive potential of different drugs, such as
heroin versus morphine. 大脑感知强化的速度可以解释不同药物的相对成瘾性
Neural Mechanisms
All reinforcers, natural or otherwise, elicit dopamine release in the striatum, particularly in the
nucleus accumbens 伏隔核
All addictive drugs rapidly increase dopamine levels in the nucleus accumbens.
Dopamine release in the nucleus accumbens in not as simple as it sounds, however. Aversive
stimuli can also trigger release of dopamine, and some areas of the nucleus accumbens seem
to promote avoidance behaviors. So, it’s complicated.
Negative Reinforcement
Tolerance: Fact that increasingly large doses of drugs must be taken to achieve a particular
effect.剂量越来越大才能达到效果 Caused by compensatory mechanisms that oppose the
effect of the drug. Not all addictive drugs produce tolerance and withdrawal.
Withdrawal symptoms 戒 断 反 应 : Appearance of symptoms opposite to those produced by
drug when the drug is suddenly no longer taken. Caused by presence of compensatory
mechanisms (that relate to drug tolerance)
Removal or reduction of an aversive stimulus that is contingent on a particular response, with
an attendant increase in the frequency of that response. 消除或减少某种特定反应所引起的厌恶刺
激，并随之增加这种反应的频率
(With negative reinforcement, we get the behavior to occur more by taking away something bad, by taking away
something aversive. So the idea here is when people start taking drugs, they have this fear that the withdrawal is
coming, the withdrawals aversive and they take away, they take the drugs to get rid. Of the withdrawal
symptoms. So it's maintaining the addiction is negative reinforcement to taking them to avoid the negative
feelings of withdrawal versus because people often in the throes of addiction say, I don't even enjoy this drug
anymore. I'm just scared of withdrawal at this point)
Prefrontal cortex
People with a history of drug use show the same deficits on tasks that involved the PFC as
do people with damage to this region. Addicts also show structural abnormalities in the PFC.
When addicts (who are not currently high) perform tasks that normally activate the
prefrontal cortex, their medial prefrontal cortex is less activated than that of healthy control
subjects, and they perform more poorly on the tasks
In cocaine addicts, the more cocaine they took, the less brain activity in their PFC.
comorbidity 伴随疾病
Studies have shown a high level of comorbidity of schizophrenia, ADHD, and substance
abuse. 70-90% of schizophrenics smoke cigarettes and almost half are addicted to drugs
other than nicotine.In one study from 2004 it was estimated that 7% of the population had
some form of mental illness, yet a third of all cigarettes were smoked by this group.
Abnormalities in the prefrontal cortex and its interactions with the striatum and dopamine
system may be common factor in these disorders.
Therapy for Drug Abuse:the binding site blocker approach
Naltrexone: A somewhat long-acting, slow onset opioid receptor antagonist that is prescribed
to alcoholics and opiate addicts.It reduces the high produced by opiates (because the opiates
can’t bind to the receptor), but it also tends to reduce drug, alcohol, and food cravings in
certain people.
Naloxone(Narcan): Extremely rapid (and short lived) opioid receptor antagonist that reverses
the effects of an opiate overdose. During an opiate overdose, people can lose consciousness
and stop breathing. A naloxone injection can immediately reverse these effects and even
elicit withdrawal symptoms (but naloxone is short-lived and cleared in 20-80 minutes).
Methadone maintenance: Potent opiate, similar to morphine or heroin but with a slower
onset and offset. Methadone maintenance programs administer the drug to their patients in
liquid form, which they must drink in the presence of supervising personnel. Similar
maintenance treatments are used with nicotine addiction (nicotine patches, gum, vaping, etc.)
Buprenorphine: Buprenorphine is a high affinity partial opioid receptor agonist. It strongly
binds to opioid receptors but produces only a weak effect while blocking the effect of other
opiates.It is a relatively new treatment for opiate addiction. To reduce the potential for abuse,
it is commonly mixed with a little naloxone (an opiate receptor antagonist).
Varenicline: Approved to treat nicotine addiction. It is a partial agonist at nicotinic
(acetylcholine) receptors, just as buprenorphine is a partial agonist at opioid receptors
Cocaine vaccine: Compounds have been developed that cause the person’s own immune
system to create antibodies against a drug, like cocaine.When antibodies bind to the drug, it
can no longer cross the blood brain barrier. This approach is being explored for cocaine,
heroin, meth, and nicotine.