LESSON 1.3 WORKBOOK. How can we study the behaving brain?

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1 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. What two technologies needed to be developed before we could start studying the living behaving brain/ Lesson

2 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. LESSON READING Positron emission tomography (PET) 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. Figure 13: PET scan taken from a normal brain. The areas indicated in red show high activity and the areas in blue show What does a PET scan measure and how? In a PET scan, what do the warm colors usually represent? What about cool colors? Lesson 1.3 low activity. 19

3 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. LESSON READING 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. 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 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 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. 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. 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. Why would an Alzheimer s patient have a PET scan with more areas colored in cool colors? Why would a brain tumor show up as a hot spot on a PET scan? Lesson

4 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. List three disadvantages of PET scans. What is the major difference between the PET method and MRI? Magnetic resonance imaging (MRI) 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 What does MRI measure, can you explain how? picture of an MRI scanner. Because of the extremely Lesson 1.3 high magnetic fields, it is critical that no ferrous (mag- Figure 17: MRI scanner. 21 netizable) metal is near the scanner.

5 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. LESSON READING 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. Why are MRIs not as useful to study bone as brain? What is the difference between MRI and fmri? What are is the main advantage of fmri compared to MRI? Figure 19: fmri scan. One fmri section through the brain of a person who had been Lesson 1.3 asked to read one word aloud. The regions 22 indicated in red are areas of high activity.

6 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 when researchers attempt to study how brain regions involved in complex behaviors communicate. Communication between brain regions Figure 20: MRI scan of patient with brain cancer. The light colored areas indicate the presence of a tumor. 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. How do you think MRI scans detect areas of high metabolic activity? What is fmri actually measuring? What are the implications of this for investigating complex behaviors like reading? Lesson

7 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. LESSON READING Electroencephalography (EEG) 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. 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 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 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: What does EEG measure? What are two differences between EEG and PET scans? Between EEG and MRI? Lesson

8 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. 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. What are the two characteristics of and EEG scan? What behaviors do the following EEG brain waves detect? alpha (α) beta (β) theta (θ) 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 Lesson 1.3 with drowsiness, δ waves are associated with 25 the deepest stages of sleep. delta (δ)

9 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. LESSON READING What are the benefits and drawbacks of EEG recordings? 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? If you wanted to measure H.M. s seizures using an EEG, what would you have had to do first? Lesson

10 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? 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? 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? Lesson