Download LESSON 1.3 WORKBOOK

LESSON 1.3 WORKBOOK
How can we study the behaving brain?
We are in the middle of a technological revolution when
it comes to how closely we can look at the behaving
brain. Scientists and doctors now have many different
options if they want to investigate which parts of the
brain are linked with which function – they no longer
need to wait for a Phineas Gage to show up at their
hospital with an iron spike protruding from his head! In
this lesson, we’ll take a closer look at the most common techniques used to study the behaving brain and
investigate their advantages and limitations.
How can we study the behaving brain?
Two research areas had to come together to allow this technological revolution to occur. Firstly, noninvasive methods had to be developed to visualize the behaving brain. These methods use what doctors call markers – chemicals that had some property that can be detected, either because they’re
radioactive or fluorescent or magnetic. The markers could be injected intravenously and then observed
as they enter and accumulate in, specific brain areas. The second area was computing technology. It is
only the development of computers with huge capacities for analyzing data that make it even possible
to understand what we are seeing when we use the markers to observe the brains. The combination of
these two areas into new technologies have allowed researchers to monitor brain function in a healthy
patient, as well as to study the location and extent of brain damage while a patient is still living.
Wo r k b o o k
Lesson 1.3
What two technologies needed to be developed before we could start studying the living behaving brain/
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LESSON READING
What does a PET scan measure and how?
Positron emission tomography (PET)
DEFINITIONS OF TERMS
Glucose – a simple sugar
that is an important energy
source throughout the body, but
especially in the brain
Gamma rays – form of
electromagnetic wave with
shorter wavelength than X-rays
For a complete list of defined
terms, see the Glossary.
Positron emission tomography, also called PET imaging or a PET scan, is a type of brain imaging that
uses nuclear medicine. Nuclear medicine is a branch of medicine that uses small amounts of radioactive
material to diagnose or treat a variety of diseases, including many types of cancers, heart disease and
other abnormalities. PET imaging uses a radioactive chemical called a radiotracer as the marker. It is
noninvasive, and with the exception of the intravenous injection that delivers the radiotracer to the bloodstream, is painless.
When getting a PET scan, patients first receive an intravenous injection of the radiotracer – usually radioactive glucose. After the injection, the radioactive glucose accumulates in tissues that are highly active,
like the brain. Once the radiotracer becomes concentrated in these tissues, it gives off energy in the form
of gamma rays. The assumption is that the tissues that are most active will accumulate the most tracer and
therefore will show higher levels of radioactivity. Eventually the radioactive glucose is broken down and
leaves the body. The dose of radiation given is harmless.
To detect the varying levels of radioactivity in different parts of the brain, the patient’s head is placed in
a machine that contains a camera that can detect gamma rays (otherwise known as positron emission,
hence PET scan). The camera is connected to a computer that collects information about which regions
of the brain have taken up the most radioactive glucose. As the computer accumulates the information the
camera scans different areas of the brain. Together the camera and computer produce a picture that looks
like a slice through the brain, showing the level of radioactivity that have accumulated in the brain regions
found in that slice, or section.
Figure 13 shows a PET scan of a horizontal section through
the brain of a resting 54-year-old man. The computer has
colored the image to relate color directly to the tissue concentration of radioactivity: red indicates areas of higher
concentrations, and blue indicates areas of lower concentrations. Notice that high levels of radioactivity are present in
the cortex.
Wo r k b o o k
Lesson 1.3
Figure 13: PET scan taken from a normal
brain. The areas indicated in red show
high activity and the areas in blue show
low activity.
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In a PET scan, what do the warm colors usually represent? What about cool colors?
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19
LESSON READING
DEFINITIONS OF TERMS
Figure 14 shows a PET scan of a horizontal section
through the brain of an Alzheimer’s patient. This scan
shows reduced activity in the parietal lobe compared to
either the frontal lobe or the occipital lobe. Remember that
the parietal lobe is involved in language, which suggests
that this patient will have had difficulties in language processing.
Glucose – a simple sugar
that is an important energy
source throughout the body, but
especially in the brain.
Figure 14: PET scan taken from a patient
with Alzheimer’s disease. Notice the
reduced activity in the parietal lobe (indicated with red arrow) and blue coloration.
Gamma rays – form of
electromagnetic wave with
shorter wavelength than X-rays.
Hemoglobin – protein
responsible for transporting
oxygen in the blood.
Deoxyhemoglobin –
hemoglobin once it has delivered
oxygen to body tissues.
For a complete list of defined
terms, see the Glossary.
Why would an Alzheimer’s patient have a PET
scan with more areas colored in cool colors?
Figure 15: PET scan taken from a
patient with brain cancer. Notice the
areas of heightened metabolic activity (indicated with red arrows) and
yellow/red coloration.
PET scans are good at finding areas of high metabolic activity where it does not belong, and thus have been successfully
used to detect cancer in the brain, since cancer cells, because
they are dividing rapidly are very active. The yellow/red colors
in Figure 15 indicate an area of high metabolic activity detected
by the radioactive glucose, and unfortunately for the patient, the
location of a brain tumor.
PET scans are also able to detect the origins
of seizures, which show up as areas where
metabolic activity is low. In Figure 16 there
is an area of low accumulation of radioactivity, and hence low metabolic activity, in the
parietal lobe that could be due to a seizure.
Figure 16: PET scans taken from a patient with epilepsy.
Notice the area of reduced activity in the parietal lobe
(indicated with red arrow) and blue coloration.
Wo r k b o o k
Lesson 1.3
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Why would a brain tumor show up as a hot
spot on a PET scan?
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20
LESSON READING
The major disadvantage of PET scans is what is known as spatial resolution, i.e. the ability to detect small
areas of the brain. This means that very small abnormalities – less than 1 mm in size – may be difficult to
distinguish from the blurs simply caused by the patient shifting position. As you can imagine, even 1mm
of brain may contain thousands of neurons, hence certain abnormalities, such as small areas of damage
causing seizures, can be missed. Another problem is false positives, i.e. areas that look like they have high
areas of radioactivity, but are also artifacts. Finally, the amount of radiotracer that can be safely injected
into the body is obviously limited, and this in turn can make it difficult to see different areas that have rather
low metabolic rates.
Other problems with PET scans are that they must be completed when patients are awake. The tracer
takes between 30 and 60 minutes to reach the appropriate area in the body, and the scanning process,
during which they patient has to stay still, takes an additional 45 and 60 minutes. Therefore, patients with
limited mobility or difficulty remaining still for long periods of time may find the PET scan process uncomfortable or impossible.
A final disadvantage of PET scans is their cost. For obvious reasons of safety, the radioactive tracers used
need to be able to decay and lose their radioactivity very quickly. But because the chemicals decay so
quickly, they must be produced fresh each time they are used, in an atomic particle accelerator called a
cyclotron. Therefore, the cost of the cyclotron and the salaries of the personnel who operate it must all be
added the cost of the PET scanner.
Magnetic resonance imaging (MRI)
Wo r k b o o k
Lesson 1.3
Magnetic resonance imaging, also called MRI, is another noninvasive method that is able to image internal structure in amazing detail. It is based on the principle that the body is largely composed of water
molecules. Each of these water molecules has two hydrogen nuclei or protons. When a person is put
inside a scanner with a powerful magnetic field, some of these protons align with the direction of the field.
Then a radio frequency transmitter is briefly turned on, producing a second electromagnetic field. This
radiofrequency (RF) field has just the right energy
to flip the spin of the aligned protons in the body,
so that after the RF field is turned off, those protons
that absorbed its energy and flipped revert back to
their original state by releasing a photon. The scanner detects the released photons as an electromagnetic signal, similar to radio waves. The protons in
different tissues return to their original (equilibrium)
state at different rates. These different rates can be
detected by the MRI scanner. Figure 17 shows a
picture of an MRI scanner. Because of the extremely
Figure 17: MRI scanner.
high magnetic fields, it is critical that no ferrous (magnetizable) metal is near the scanner.
List three disadvantages of PET scans.
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What is the major difference between the
PET method and MRI?
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What does MRI measure, can you explain
how?
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LESSON READING
DEFINITIONS OF TERMS
Hemoglobin – protein
responsible for transporting
oxygen in the blood.
Deoxyhemoglobin –
hemoglobin once it has delivered
oxygen to body tissues.
For a complete list of defined
terms, see the Glossary.
The computer uses the differences in when and where
photons are released as the protons flip back at different rates to create an image of different tissues. While
MRI can be used to image every part of the body, it is
particularly useful for tissues with high concentrations
of water and therefore many hydrogen nuclei, such as
the brain, muscle, connective tissue and most tumors.
These areas of low density show up as high contrast,
while areas of high density, like bone, have much lower
contrast. Because the brain in particular has a very
high water concentration and low density, MRIs reveal
brain structures at extremely high resolution. Figure
18 shows an MRI image of a sagittal section (slice)
through the brain. The corpus callosum connecting
the two hemispheres can be seen clearly.
Functional MRI (fMRI)
Figure 18: MRI scan of brain. Structural
MRI provides good contrast between the
different soft tissues of the body, making it
especially useful for brain imaging.
Functional MRI (fMRI) is a variation of the MRI principle that measures the magnetization of oxygenated hemoglobin and deoxyhemoglobin rather than
water in order to study brain activity. When brain activity increases there is an increased demand for oxygen, and the vascular system responds by increasing the
amount of oxygenated hemoglobin relative to deoxyhemoglobin. Oxygenated hemoglobin increases the MRI signal
just like magnetized water does, while deoxyhemoglobin
decreases the MRI signal relative to the oxygenized hemoglobin signal. Therefore if blood flow in a specific area
is increased the MRI signal in that area is also increased
proportionately to the neuronal activity in that area. This is
called the BOLD signal (Blood-Oxygen-Level-Dependent)
signal. To detect a BOLD signal an area of the brain is
scanned very rapidly (typically once every 2–3 seconds).
Figure 19 shows an fMRI image of a horizontal section
through the brain after a subject had been asked to read
a single word.
Wo r k b o o k
Lesson 1.3
Figure 19: fMRI scan. One fMRI section
through the brain of a person who had been
asked to read one word aloud. The regions
indicated in red are areas of high activity.
Why are MRIs not as useful to study bone
as brain?
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What is the difference between MRI and
fMRI? What are is the main advantage of
fMRI compared to MRI?
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LESSON READING
What are the benefits and drawbacks of using MRI/fMRI scans?
MRI scans are good at detecting metabolic activity where it does not belong, and thus have been successfully used to detect cancer in the brain. Figure 20 shows images of a coronal section through the back of
the brain, the light-colored regions show areas of high metabolic activity, and unfortunately for this patient,
the location of a tumor. Note that MRIs show the left hand side of the brain on the right and vice versa.
Like PET scans, MRI shows a composite picture of many thousands of neurons, and so its spatial resolution, like PET is also very low. Additionally, its temporal resolution (its resolution in time) is also slow
and this is problematic. fMRI measures brain
activity indirectly, making the assumption that
areas of highly oxygenated blood correlate with
areas where neurons are very active is reasonable. However it may be difficult to pinpoint what
those pictures of areas of high blood flow are really showing: The blood flow response to a specific area of the brain takes about two seconds
to occur, but as we know a thought can happen
in thousandths of a second. So it’s difficult to say
what a picture of a rush of blood to an area actually means.
The timing issue comes up again and again Figure 20: MRI scan of patient with brain cancer.
when researchers attempt to study how brain The light colored areas indicate the presence of a
regions involved in complex behaviors commu- tumor.
nicate. Communication between brain regions
can occur very quickly - within a hundredth of a thousandth of a second – but the increased blood flow
that this increased activity would occur far too sluggishly for MRI to detect it. So, what is the increased
blood flow actually measuring – the event itself or the brain’s slower response to communication which
happened a while ago, maybe somewhere else? The analogy that has been made is that it’s like trying
to understand the process of photosynthesis in plants by measuring how much sunlight a tree or plant is
getting. You’ll see the tree grow or plant shrink based upon sunlight, but you’re still not really much closer
to understanding how photosynthesis actually occurs.
Wo r k b o o k
Lesson 1.3
How do you think MRI scans detect areas of
high metabolic activity?
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What is fMRI actually measuring? What are
the implications of this for investigating complex behaviors like reading?
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LESSON READING
What does EEG measure?
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Electroencephalography (EEG)
DEFINITIONS OF TERMS
Glucose – a simple sugar
that is an important energy
source throughout the body, but
especially in the brain
Gamma rays – form of
electromagnetic wave with
shorter wavelength than X-rays
Electroencephalography (EEG) examines the brain much
more directly. It involves applying a set of electrodes on
the scalp and then detecting the electrical activity of brain
beneath them. In conventional EEG, the electrodes are
placed on the scalp with a conductive gel or paste that
ensures a connection that will transmit the signal. Some
systems use individual electrodes, others (Figure 21) use
caps or nets into which the electrodes have been embedded. In most clinical applications the cap consists of 19
recording electrodes placed in standard positions (Figure
22) that are distributed over specific brain regions on the
cortex such as frontal (F), parietal (P), temporal (T) and
occipital (O) (plus ground and system reference).
Brain activity between the pairs of electrodes is then detected.
Hemoglobin – protein
responsible for transporting
oxygen in the blood
Deoxyhemoglobin –
hemoglobin once it has delivered
oxygen to body tissues
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 1.3
Figure 22: Placement of EEG electrodes.
The electrodes are placed in stereotyped
positions so that the current flow between
specific regions in the cortex can be
measured.
Figure 21: EEG cap containing electrodes to record brain activity.
Each electrode is connected to one input of an amplifier that can amplify the voltage between the active electrode and the reference electrode (typically
1,000–100,000 times voltage gain). The digital EEG
signal is stored electronically and can be filtered for
display. A typical adult human EEG signal is about
10 microvolts (µV) to 100 microvolts (µV) in amplitude when measured through the scalp and this is
increased a thousand fold to about 10–20 millivolts
(mV) if a hole is drilled in the skull and the electrodes
are placed directly on the cortex (this is sometimes
necessary to detect epileptic seizures).
You can watch an EEG being done online - see this
unit on the student website or click below:
■■ Video: Measuring Brain Waves with an EEG (Electroencephalogram)
What are two differences between EEG and
PET scans? Between EEG and MRI?
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LESSON READING
What does EEG actually measure? As we know,
the brain is composed of billions of neurons that
communicate electrically (we’ll see how in more
detail later). The communication between individual neurons is called the synaptic potential. The
synaptic potentials generated by single cortical
neurons are far too small to be picked up by the
EEG. Rather the EEG reflects the sum of the communication between the thousands or millions of
neurons between each pair of electrodes. This is
why each EEG trace is reported directionally (P3 T5 [parietal 3 - temporal 5] for example). Because
each pair of electrodes samples the activity of a
population of neurons between the electrodes in
different brain regions, each of the individual EEG
traces will be different (Figure 23).
Figure 23: Normal EEG. An EEG taken from a
healthy patient. Notice how each trace (wavy
line) is coded as to what pair of electrodes it was
recorded from – we’ll talk more about that later.
Wo r k b o o k
Lesson 1.3
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What behaviors do the following EEG brain
waves detect?
alpha (α)
Scalp EEGs show waves that have characteristic frequencies that correspond to different states
of brain functioning (e.g., waking and the various
sleep stages, Figure 24). The neurons that are
communicating to cause some of these characteristic waves are well known - for example
connections from the thalamus to the cortex are
known to generate the so-called theta waves
seen during sleep. Others are not – for example
the neurons that are responsible for the so-called
occipital waves are not well understood at all.
Figure 24: Typical EEG waves. The EEG shows
typical patterns of activity that can be correlated
with various stages of sleep and wakefulness. α
waves originate from occipital cortex when the
eyes are closed, β waves are associated with
intense mental activity, θ waves are associated
with drowsiness, δ waves are associated with
the deepest stages of sleep.
What are the two characteristics of and EEG
scan?
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beta (β)
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theta (θ)
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delta (δ)
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LESSON READING
What are the benefits and drawbacks of EEG recordings?
DEFINITIONS OF TERMS
Glucose – a simple sugar
that is an important energy
source throughout the body, but
especially in the brain
Gamma rays – form of
electromagnetic wave with
shorter wavelength than X-rays
Hemoglobin – protein
responsible for transporting
oxygen in the blood
Deoxyhemoglobin –
hemoglobin once it has delivered
oxygen to body tissues
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 1.3
Clinically, EEGs are very commonly used to monitor for seizure activity, to evaluate depth of anesthesia or
coma, and to test for brain death. The major advantage of the EEG is obviously how simple it is: EEG is
totally non-invasive and unlike PET and MRI, EEG does actually directly measure the electrical behavior
of populations of neurons. Moreover, EEGs can detect changes that occur over milliseconds, which is
much closer to the time scale of actual neuronal communication and much faster than either PET or MRI.
A major disadvantage of the EEG is its poor spatial resolution, which is worse than either PET or MRI.
Placement of the electrodes means that each pair of electrodes may be measuring activity over several
centimeters – room enough for thousands if not millions of individual neurons. Another disadvantage
is that the relationship between the activity of neurons and what is depicted on the EEG trace is quite
complex: Not only does the trace between a pair of EEG electrodes represent the sum of the activities
of thousands of neurons, but those electrodes will only detect neurons that are all communicating at the
same time (synchronously) because it can’t detect individual neurons. In order to communicate (fire)
synchronously these neurons need to be to be aligned in the same direction, i.e. to have similar spatial
orientation. If the neurons don’t line up they won’t create the waves of electrical activity that the EEC electrodes detect. Neurons connecting the thalamus and the cortex (thalamocortical neurons) have these
characteristics, as do neurons extending from the cortex to the spinal cord, but many other neurons do
not, and so they will never be detected by EEG.
Another problem with EEG is that activity from deep within the brain is more difficult to detect than currents near the skull. This is because of the simple electrical principle of the square rule – that voltage
fields decline with the square of the distance. So in cases where activity deeper in the brain needs to be
measured, a hole must be drilled in the skull, which is very invasive
Could you measure the behavior of the basal
ganglia with an EEG?
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If you wanted to measure H.M.’s seizures using an EEG, what would you have had to do
first?
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26
STUDENT RESPONSES
Which of the described imaging techniques (PET, MRI/fMRI, EEG) would you choose if you had to examine a new-born baby
who you suspected had been born with structural abnormalities in their cerebellum? _________________________________
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Remember to identify your
sources
Which of the described imaging techniques (PET, MRI/fMRI, EEG) would you choose if a patient came to your surgery with a
bad headache, and you suspected they might have brain cancer? ________________________________________________
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Which of the described imaging techniques (PET, MRI/fMRI, EEG) would you choose if a patient came to your research lab with a
severe case of anterograde amnesia and you wanted to diagnose where the deficits originated from. What tests would you do?
Would you completely trust the results?
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Wo r k b o o k
Lesson 1.3
27