research methods to study the brain

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3.3 Psychologists Study the Brain Using Many Different Methods

Learning objective.

Compare and contrast the techniques that scientists use to view and understand brain structures and functions.

Perhaps the most immediate approach to visualizing and understanding the structure of the brain is to directly analyze the brains of human cadavers. When Albert Einstein died in 1955, his brain was removed and stored for later analysis. Researcher Marian Diamond (1999) later analyzed a section of the Einstein’s cortex to investigate its characteristics. Diamond was interested in the role of glia, and she hypothesized that the ratio of glial cells to neurons was an important determinant of intelligence. To test this hypothesis, she compared the ratio of glia to neurons in Einstein’s brain with the ratio in the preserved brains of 11 other more “ordinary” men. However, Diamond was able to find support for only part of her research hypothesis. Although she found that Einstein’s brain had relatively more glia in all the areas that she studied than did the control group, the difference was only statistically significant in one of the areas she tested. Diamond admits a limitation in her study is that she had only one Einstein to compare with 11 ordinary men.

Lesions Provide a Picture of What Is Missing

Lesions allow the scientist to observe any loss of brain function that may occur. For instance, when an individual suffers a stroke, a blood clot deprives part of the brain of oxygen, killing the neurons in the area and rendering that area unable to process information. In some cases, the result of the stroke is a specific lack of ability. For instance, if the stroke influences the occipital lobe, then vision may suffer, and if the stroke influences the areas associated with language or speech, these functions will suffer. In fact, our earliest understanding of the specific areas involved in speech and language were gained by studying patients who had experienced strokes.

Figure 3.13

Areas in the frontal lobe of Phineas Gage were damaged when a metal rod blasted through it. Although Gage lived through the accident, his personality, emotions, and moral reasoning were influenced. The accident helped scientists understand the role of the frontal lobe in these processes.

It is now known that a good part of our moral reasoning abilities are located in the frontal lobe, and at least some of this understanding comes from lesion studies. For instance, consider the well-known case of Phineas Gage, a 25-year-old railroad worker who, as a result of an explosion, had an iron rod driven into his cheek and out through the top of his skull, causing major damage to his frontal lobe (Macmillan, 2000). Although remarkably Gage was able to return to work after the wounds healed, he no longer seemed to be the same person to those who knew him. The amiable, soft-spoken Gage had become irritable, rude, irresponsible, and dishonest. Although there are questions about the interpretation of this case study (Kotowicz, 2007), it did provide early evidence that the frontal lobe is involved in emotion and morality (Damasio et al., 2005).

More recent and more controlled research has also used patients with lesions to investigate the source of moral reasoning. Michael Koenigs and his colleagues (Koenigs et al., 2007) asked groups of normal persons, individuals with lesions in the frontal lobes, and individuals with lesions in other places in the brain to respond to scenarios that involved doing harm to a person, even though the harm ultimately saved the lives of other people (Miller, 2008).

In one of the scenarios the participants were asked if they would be willing to kill one person in order to prevent five other people from being killed. As you can see in Figure 3.14 “The Frontal Lobe and Moral Judgment” , they found that the individuals with lesions in the frontal lobe were significantly more likely to agree to do the harm than were individuals from the two other groups.

Figure 3.14 The Frontal Lobe and Moral Judgment

Control participants and participants with lesions in areas other than the frontal lobes have much lower engagements in harm and participants with lesions in the frontal lobes have engage much higher in harm.

Koenigs and his colleagues (2007) found that the frontal lobe is important in moral judgment. Persons with lesions in the frontal lobe were more likely to be willing to harm one person in order to save the lives of five others than were control participants or those with lesions in other parts of the brain.

Recording Electrical Activity in the Brain

In addition to lesion approaches, it is also possible to learn about the brain by studying the electrical activity created by the firing of its neurons. One approach, primarily used with animals, is to place detectors in the brain to study the responses of specific neurons. Research using these techniques has found, for instance, that there are specific neurons, known as feature detectors , in the visual cortex that detect movement, lines and edges, and even faces (Kanwisher, 2000).

Figure 3.15

A participant in an EEG study has a number of electrodes placed around the head, which allows the researcher to study the activity of the person’s brain. The patterns of electrical activity vary depending on the participant’s current state (e.g., whether he or she is sleeping or awake) and on the tasks the person is engaging in.

A less invasive approach, and one that can be used on living humans, is electroencephalography (EEG) . The EEG is a technique that records the electrical activity produced by the brain’s neurons through the use of electrodes that are placed around the research participant’s head. An EEG can show if a person is asleep, awake, or anesthetized because the brain wave patterns are known to differ during each state. EEGs can also track the waves that are produced when a person is reading, writing, and speaking, and are useful for understanding brain abnormalities, such as epilepsy. A particular advantage of EEG is that the participant can move around while the recordings are being taken, which is useful when measuring brain activity in children who often have difficulty keeping still. Furthermore, by following electrical impulses across the surface of the brain, researchers can observe changes over very fast time periods.

Peeking Inside the Brain: Neuroimaging

But techniques exist to provide more specific brain images. Functional magnetic resonance imaging (fMRI) is a type of brain scan that uses a magnetic field to create images of brain activity in each brain area . The patient lies on a bed within a large cylindrical structure containing a very strong magnet. Neurons that are firing use more oxygen, and the need for oxygen increases blood flow to the area. The fMRI detects the amount of blood flow in each brain region, and thus is an indicator of neural activity.

Very clear and detailed pictures of brain structures (see, e.g., Figure 3.16 “fMRI Image” ) can be produced via fMRI. Often, the images take the form of cross-sectional “slices” that are obtained as the magnetic field is passed across the brain. The images of these slices are taken repeatedly and are superimposed on images of the brain structure itself to show how activity changes in different brain structures over time. When the research participant is asked to engage in tasks while in the scanner (e.g., by playing a game with another person), the images can show which parts of the brain are associated with which types of tasks. Another advantage of the fMRI is that is it noninvasive. The research participant simply enters the machine and the scans begin.

Although the scanners themselves are expensive, the advantages of fMRIs are substantial, and they are now available in many university and hospital settings. fMRI is now the most commonly used method of learning about brain structure.

Figure 3.16 fMRI Image

The fMRI creates brain images of brain structure and activity. In this image the red and yellow areas represent increased blood flow and thus increased activity. From your knowledge of brain structure, can you guess what this person is doing?

Photo courtesy of the National Institutes of Health, Wikimedia Commons – public domain.

The primary advantage of TMS is that it allows the researcher to draw causal conclusions about the influence of brain structures on thoughts, feelings, and behaviors. When the TMS pulses are applied, the brain region becomes less active, and this deactivation is expected to influence the research participant’s responses. Current research has used TMS to study the brain areas responsible for emotion and cognition and their roles in how people perceive intention and approach moral reasoning (Kalbe et al., 2010; Van den Eynde et al., 2010; Young, Camprodon, Hauser, Pascual-Leone, & Saxe, 2010). TMS is also used as a treatment for a variety of psychological conditions, including migraine, Parkinson’s disease, and major depressive disorder.

Research Focus: Cyberostracism

Neuroimaging techniques have important implications for understanding our behavior, including our responses to those around us. Naomi Eisenberger and her colleagues (2003) tested the hypothesis that people who were excluded by others would report emotional distress and that images of their brains would show that they experienced pain in the same part of the brain where physical pain is normally experienced. In the experiment, 13 participants were each placed into an fMRI brain-imaging machine. The participants were told that they would be playing a computer “Cyberball” game with two other players who were also in fMRI machines (the two opponents did not actually exist, and their responses were controlled by the computer).

Each of the participants was measured under three different conditions. In the first part of the experiment, the participants were told that as a result of technical difficulties, the link to the other two scanners could not yet be made, and thus at first they could not engage in, but only watch, the game play. This allowed the researchers to take a baseline fMRI reading. Then, during a second inclusion scan, the participants played the game, supposedly with the two other players. During this time, the other players threw the ball to the participants. In the third, exclusion, scan, however, the participants initially received seven throws from the other two players but were then excluded from the game because the two players stopped throwing the ball to the participants for the remainder of the scan (45 throws).

The results of the analyses showed that activity in two areas of the frontal lobe was significantly greater during the exclusion scan than during the inclusion scan. Because these brain regions are known from prior research to be active for individuals who are experiencing physical pain, the authors concluded that these results show that the physiological brain responses associated with being socially excluded by others are similar to brain responses experienced upon physical injury.

Further research (Chen, Williams, Fitness, & Newton, 2008; Wesselmann, Bagg, & Williams, 2009) has documented that people react to being excluded in a variety of situations with a variety of emotions and behaviors. People who feel that they are excluded, or even those who observe other people being excluded, not only experience pain, but feel worse about themselves and their relationships with people more generally, and they may work harder to try to restore their connections with others.

Key Takeaways

Studying the brains of cadavers can lead to discoveries about brain structure, but these studies are limited due to the fact that the brain is no longer active.
Lesion studies are informative about the effects of lesions on different brain regions.
Electrophysiological recording may be used in animals to directly measure brain activity.
Measures of electrical activity in the brain, such as electroencephalography (EEG), are used to assess brain-wave patterns and activity.
Functional magnetic resonance imaging (fMRI) measures blood flow in the brain during different activities, providing information about the activity of neurons and thus the functions of brain regions.
Transcranial magnetic stimulation (TMS) is used to temporarily and safely deactivate a small brain region, with the goal of testing the causal effects of the deactivation on behavior.

Exercise and Critical Thinking

Consider the different ways that psychologists study the brain, and think of a psychological characteristic or behavior that could be studied using each of the different techniques.

Chen, Z., Williams, K. D., Fitness, J., & Newton, N. C. (2008). When hurt will not heal: Exploring the capacity to relive social and physical pain. Psychological Science, 19 (8), 789–795.

Damasio, H., Grabowski, T., Frank, R., Galaburda, A. M., Damasio, A. R., Cacioppo, J. T., & Berntson, G. G. (2005). The return of Phineas Gage: Clues about the brain from the skull of a famous patient. In Social neuroscience: Key readings (pp. 21–28). New York, NY: Psychology Press.

Diamond, M. C. (1999). Why Einstein’s brain? New Horizons for Learning . http://www.newhorizons.org/neuro/diamond_einstein.htm -->

Eisenberger, N. I., Lieberman, M. D., & Williams, K. D. (2003). Does rejection hurt? An fMRI study of social exclusion. Science, 302 (5643), 290–292.

Kalbe, E., Schlegel, M., Sack, A. T., Nowak, D. A., Dafotakis, M., Bangard, C.,…Kessler, J. (2010). Dissociating cognitive from affective theory of mind: A TMS study. Cortex: A Journal Devoted to the Study of the Nervous System and Behavior, 46 (6), 769–780.

Kanwisher, N. (2000). Domain specificity in face perception. Nature Neuroscience, 3 (8), 759–763.

Koenigs, M., Young, L., Adolphs, R., Tranel, D., Cushman, F., Hauser, M., & Damasio, A. (2007). Damage to the prefontal cortex increases utilitarian moral judgments. Nature, 446 (7138), 908–911.

Kotowicz, Z. (2007). The strange case of Phineas Gage. History of the Human Sciences, 20 (1), 115–131.

Macmillan, M. (2000). An odd kind of fame: Stories of Phineas Gage . Cambridge, MA: MIT Press.

Miller, G. (2008). The roots of morality. Science, 320 , 734–737.

Van den Eynde, F., Claudino, A. M., Mogg, A., Horrell, L., Stahl, D.,…Schmidt, U. (2010). Repetitive transcranial magnetic stimulation reduces cue-induced food craving in bulimic disorders. Biological Psychiatry, 67 (8), 793–795.

Wesselmann, E. D., Bagg, D., & Williams, K. D. (2009). “I feel your pain”: The effects of observing ostracism on the ostracism detection system. Journal of Experimental Social Psychology, 45 (6), 1308–1311.

Introduction to Psychology Copyright © 2015 by University of Minnesota is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License , except where otherwise noted.

Incorporate STEM journalism in your classroom

Exercise type: Discussion
Topic: Neuroscience

Studying the brain 101

Download Student Worksheet

Directions for teachers:

Before students answer the first question, have them read “ Scientists have mapped an insect brain in greater detail than ever before ” from Science News online and watch the video “See all of the nerve cells in a larval fruit fly’s brain” linked in the article. A version of the article, “The fruit fly brain in exquisite detail,” appears in the April 22, 2023 issue of Science News .

Next, ask students to read the Science News Explores article “ Explainer: What is a neuron? ” and answer the first section’s remaining questions. Use the second section’s last question to lead a class discussion about techniques for studying the brain. Reading “ Scientists Say: Neurotransmitters ” from Science News Explores will help students with question 5 in the first section.

Thinking about nerve parts

1. After watching the video “See all of the nerve cells in a larval fruit fly’s brain,” discuss what you noticed with a partner. What did you observe? What was interesting or surprising?

Student answers will vary. Some possible answers could include that the nerve cells look like balloons with strings. The colors seem to indicate that there are many different types of nerve cells that appear to have no regular distribution around the brain. The overall shape of the brain with its two distinct sides is surprising.

2. Read “ Explainer: What is a neuron? ” and re-watch the video. Use the information from the article to explain what you see in the video. Use correct vocabulary.

The fruit fly brain is made up of many different types of neurons that appear to be randomly distributed among two spherical structures, one on the left side of the brain and one on the right. The round objects represent cell bodies, which means the strings probably represent axons and dendrites. From the video, it is hard to tell where the connections (synapses) are between the various parts of the nerves.

3. What questions do you still have about what you’re seeing in the video?

Why are the tails attached to the cell bodies so long in the larval fruit fly’s brain? Where are the synapses? How many cross-sections of the brain did it take to create this image? What do each of the colors represent? What’s in the fluid in synapses? 4. What is neuroscience? Explain why neurons are the foundation of neuroscientists’ work.

Neuroscience is the study of the nervous system, including its development and structures. Neurons are nerve cells found in the brain, spinal cord and other parts of the body. The job of neurons is to relay information and give directions to the rest of the body. To understand the nervous system, neuroscientists work to understand neurons and how they function.

5. Based on what you have read, consider how neurons help you sense, respond and learn. Describe a behavior and give a simple explanation of what neurons do.

If I smell toast burning, I hurry to the toaster and pull the toast out. The next time I make toast, I will lower the toasting setting. Neurons in my nose helped me sense the smoke and told my brain I had to do something. My brain signaled nerves in my arms and legs to move those body parts, and my brain learned what to do to prevent my toast from smoking in the future.

Neurons sense all kinds of information around us and send signals to the brain. The body uses chemicals called neurotransmitters to signal nerves that they must act. The neurotransmitters go across a space called a synapse. Dendrites, which are part of a nerve cell, pick up the signal and send it to a cell body, another part of a nerve cell. The cell body sends the message to the axon, and the message then goes to the end of the axon, which is the axon terminal.

Studying brains

1. How could studying a larval fruit fly’s brain lead to better understanding of the human brain?

Larval fruit flies share a wide range of behaviors with humans. Fruit flies take in sensory information and learn. Findings from fruit fly studies might help scientists identify patterns in brain function and behaviors that are shared by many species, including humans. Methods of investigating larval fruit fly brains also might be useful in studying human brains.

2. What tools did scientists featured in the Science News article use to study the fruit fly’s brain?

To create a 3-D model of the larval fruit fly brain, the scientists used an electron microscope to take cross-sectional images of the fly’s brain and then used a computer to combine the images.

3. Search the Science News or Science News Explores archives for articles about brain studies. Pick one article and explain what tools or methods scientists used in their brain research. An example of a tool is a PET scan; an example of a method might be a behavioral evaluation. More tools are listed in Explainer: How to read brain activity from Science News Explores .

Students’ selected articles will vary. In “ Brain scans suggest the pandemic prematurely aged teens’ brains ” from Science News online, the scientists used MRI scans to study teen brains. In “ Cell phones on the brain ” from Science News Explores , the researchers used PET scans for their imaging work.

4. Is the method described in the article used to study human brains, animal brains or both? Research your chosen method and describe what you can learn about the brain using this method. Cite your sources.

Student answers will vary. For example, one method of brain imaging uses a PET scan, which can be used on both human and animal brains. With this method, you can measure activity in different parts of the brain. This can tell you which parts of the brain and its tissues are functioning normally and where there might be a problem. “ Cell phones on the brain ” from Science News Explores highlights a study that used PET scans.

5. Share the method you researched with your class. As a class, discuss the different methods of studying the brain and the advantages and disadvantages of each. In what situation would researchers choose to use one method over another?

Student answers will vary.

The Emerging Field of Human Neural Organoids, Transplants, and Chimeras: Science, Ethics, and Governance

Each year, tens of millions of individuals in the U.S. suffer from neurological and psychiatric disorders including neurodegenerative diseases such as Alzheimer's Disease and Parkinson's Disease, and psychiatric disorders such as autism spectrum disorder, depression and schizophrenia. Treatments for these diseases are often completely lacking or only partially effective, due in large part to the difficulty of conducting brain research and the complexity of the brain itself.

Researchers in recent years have developed new models to better represent and study the human brain. The three models considered in this report, all of which generate and use pluripotent stem cells from healthy individuals and patients, are human neural organoids, human neural transplants, and human-animal neural chimeras. The Emerging Field of Human Neural Organoids, Transplants, and Chimeras: Science, Ethics, and Governance reviews the status of research, considers its benefits and risks, discusses associated ethical issues, and considers governance mechanisms for this type of research.

Read Full Description

Report Highlights
Interactive Overview
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All Recent News

Review Examines COVID-19 Vaccination and Adverse Events

Science Academies Issue Statements to Inform G7 Talks

Supporting Family Caregivers in STEMM

A Vision for High-Quality Preschool for All

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Chapter 4. Brains, Bodies, and Behaviour

4.3 Psychologists Study the Brain Using Many Different Methods

Learning objective.

Compare and contrast the techniques that scientists use to view and understand brain structures and functions.

One problem in understanding the brain is that it is difficult to get a good picture of what is going on inside it. But there are a variety of empirical methods that allow scientists to look at brains in action, and the number of possibilities has increased dramatically in recent years with the introduction of new neuroimaging techniques. In this section we will consider the various techniques that psychologists use to learn about the brain. Each of the different techniques has some advantages, and when we put them together, we begin to get a relatively good picture of how the brain functions and which brain structures control which activities. Perhaps the most immediate approach to visualizing and understanding the structure of the brain is to directly analyze the brains of human cadavers. When Albert Einstein died in 1955, his brain was removed and stored for later analysis. Researcher Marian Diamond (1999) later analyzed a section of Einstein’s cortex to investigate its characteristics. Diamond was interested in the role of glia, and she hypothesized that the ratio of glial cells to neurons was an important determinant of intelligence. To test this hypothesis, she compared the ratio of glia to neurons in Einstein’s brain with the ratio in the preserved brains of 11 other more “ordinary” men. However, Diamond was able to find support for only part of her research hypothesis. Although she found that Einstein’s brain had relatively more glia in all the areas that she studied than did the control group, the difference was only statistically significant in one of the areas she tested. Diamond admits a limitation in her study is that she had only one Einstein to compare with 11 ordinary men.

Lesions Provide a Picture of What Is Missing

An advantage of the cadaver approach is that the brains can be fully studied, but an obvious disadvantage is that the brains are no longer active. In other cases, however, we can study living brains. The brains of living human beings may be damaged — as a result of strokes, falls, automobile accidents, gunshots, or tumours, for instance. These damages are called lesions . In rare occasions, brain lesions may be created intentionally through surgery, such as that designed to remove brain tumours or (as in split-brain patients) reduce the effects of epilepsy. Psychologists also sometimes intentionally create lesions in animals to study the effects on their behaviour. In so doing, they hope to be able to draw inferences about the likely functions of human brains from the effects of the lesions in animals. Lesions allow the scientist to observe any loss of brain function that may occur. For instance, when an individual suffers a stroke, a blood clot deprives part of the brain of oxygen, killing the neurons in the area and rendering that area unable to process information. In some cases, the result of the stroke is a specific lack of ability. For instance, if the stroke influences the occipital lobe, then vision may suffer, and if the stroke influences the areas associated with language or speech, these functions will suffer. In fact, our earliest understanding of the specific areas involved in speech and language were gained by studying patients who had experienced strokes.

A skull with a bar piercing down through the top of the head and through the jaw.

It is now known that a good part of our moral reasoning abilities is located in the frontal lobe, and at least some of this understanding comes from lesion studies. For instance, consider the well-known case of Phineas Gage (Figure 4.12) , a 25-year-old railroad worker who, as a result of an explosion, had an iron rod driven into his cheek and out through the top of his skull, causing major damage to his frontal lobe (Macmillan, 2000). Although, remarkably, Gage was able to return to work after the wounds healed, he no longer seemed to be the same person to those who knew him. The amiable, soft-spoken Gage had become irritable, rude, irresponsible, and dishonest. Although there are questions about the interpretation of this case study (Kotowicz, 2007), it did provide early evidence that the frontal lobe is involved in emotion and morality (Damasio et al., 2005). More recent and more controlled research has also used patients with lesions to investigate the source of moral reasoning. Michael Koenigs and his colleagues (Koenigs et al., 2007) asked groups of normal persons, individuals with lesions in the frontal lobes, and individuals with lesions in other places in the brain to respond to scenarios that involved doing harm to a person, even though the harm ultimately saved the lives of other people (Miller, 2008). In one of the scenarios the participants were asked if they would be willing to kill one person in order to prevent five other people from being killed. As you can see in Figure 4.13, “The Frontal Lobe and Moral Judgment,” they found that the individuals with lesions in the frontal lobe were significantly more likely to agree to do the harm than were individuals from the two other groups.

Recording Electrical Activity in the Brain

In addition to lesion approaches, it is also possible to learn about the brain by studying the electrical activity created by the firing of its neurons. One approach, primarily used with animals, is to place detectors in the brain to study the responses of specific neurons. Research using these techniques has found, for instance, that there are specific neurons , known as feature detectors , in the visual cortex that detect movement, lines and edges, and even face s (Kanwisher, 2000).

A less invasive approach, and one that can be used on living humans, is electroencephalography (EEG), as shown in Figure 4.14. The EEG is a technique that records the electrical activity produced by the brain’s neurons through the use of electrodes that are placed around the research participant’s head. An EEG can show if a person is asleep, awake, or anesthetized because the brainwave patterns are known to differ during each state. EEGs can also track the waves that are produced when a person is reading, writing, and speaking, and are useful for understanding brain abnormalities, such as epilepsy. A particular advantage of EEG is that the participant can move around while the recordings are being taken, which is useful when measuring brain activity in children, who often have difficulty keeping still. Furthermore, by following electrical impulses across the surface of the brain, researchers can observe changes over very fast time periods.

Peeking inside the Brain: Neuroimaging

Although the EEG can provide information about the general patterns of electrical activity within the brain, and although the EEG allows the researcher to see these changes quickly as they occur in real time, the electrodes must be placed on the surface of the skull, and each electrode measures brainwaves from large areas of the brain. As a result, EEGs do not provide a very clear picture of the structure of the brain. But techniques exist to provide more specific brain images. Functional magnetic resonance imaging (fMRI) is a type of brain scan that uses a magnetic field to create images of brain activity in each brain area . The patient lies on a bed within a large cylindrical structure containing a very strong magnet. Neurons that are firing use more oxygen, and the need for oxygen increases blood flow to the area. The fMRI detects the amount of blood flow in each brain region, and thus is an indicator of neural activity. Very clear and detailed pictures of brain structures can be produced via fMRI (see Figure 4.15, “fMRI Image”). Often, the images take the form of cross-sectional “slices” that are obtained as the magnetic field is passed across the brain. The images of these slices are taken repeatedly and are superimposed on images of the brain structure itself to show how activity changes in different brain structures over time. When the research participant is asked to engage in tasks while in the scanner (e.g., by playing a game with another person), the images can show which parts of the brain are associated with which types of tasks. Another advantage of the fMRI is that it is noninvasive. The research participant simply enters the machine and the scans begin. Although the scanners themselves are expensive, the advantages of fMRIs are substantial, and they are now available in many university and hospital settings. The fMRI is now the most commonly used method of learning about brain structure.

There is still one more approach that is being more frequently implemented to understand brain function, and although it is new, it may turn out to be the most useful of all. Transcranial magnetic stimulation (TMS) is a procedure in which magnetic pulses are applied to the brain of a living person with the goal of temporarily and safely deactivating a small brain region . In TMS studies the research participant is first scanned in an fMRI machine to determine the exact location of the brain area to be tested. Then the electrical stimulation is provided to the brain before or while the participant is working on a cognitive task, and the effects of the stimulation on performance are assessed. If the participant’s ability to perform the task is influenced by the presence of the stimulation, the researchers can conclude that this particular area of the brain is important to carrying out the task. The primary advantage of TMS is that it allows the researcher to draw causal conclusions about the influence of brain structures on thoughts, feelings, and behaviours. When the TMS pulses are applied, the brain region becomes less active, and this deactivation is expected to influence the research participant’s responses. Current research has used TMS to study the brain areas responsible for emotion and cognition and their roles in how people perceive intention and approach moral reasoning (Kalbe et al., 2010; Van den Eynde et al., 2010; Young, Camprodon, Hauser, Pascual-Leone, & Saxe, 2010). TMS is also used as a treatment for a variety of psychological conditions, including migraine, Parkinson’s disease, and major depressive disorder.

Research Focus: Cyberostracism

Neuroimaging techniques have important implications for understanding our behaviour, including our responses to those around us. Naomi Eisenberger and her colleagues (2003) tested the hypothesis that people who were excluded by others would report emotional distress and that images of their brains would show that they experienced pain in the same part of the brain where physical pain is normally experienced. In the experiment, 13 participants were each placed into an fMRI brain-imaging machine. The participants were told that they would be playing a computer “Cyberball” game with two other players who were also in fMRI machines (the two opponents did not actually exist, and their responses were controlled by the computer). Each of the participants was measured under three different conditions. In the first part of the experiment, the participants were told that as a result of technical difficulties, the link to the other two scanners could not yet be made, and thus at first they could not engage in, but only watch, the game play. This allowed the researchers to take a baseline fMRI reading. Then, during a second, inclusion, scan, the participants played the game, supposedly with the two other players. During this time, the other players threw the ball to the participants. In the third, exclusion, scan, however, the participants initially received seven throws from the other two players but were then excluded from the game because the two players stopped throwing the ball to the participants for the remainder of the scan (45 throws). The results of the analyses showed that activity in two areas of the frontal lobe was significantly greater during the exclusion scan than during the inclusion scan. Because these brain regions are known from prior research to be active for individuals who are experiencing physical pain, the authors concluded that these results show that the physiological brain responses associated with being socially excluded by others are similar to brain responses experienced upon physical injury. Further research (Chen, Williams, Fitness, & Newton, 2008; Wesselmann, Bagg, & Williams, 2009) has documented that people react to being excluded in a variety of situations with a variety of emotions and behaviours. People who feel that they are excluded, or even those who observe other people being excluded, not only experience pain, but feel worse about themselves and their relationships with people more generally, and they may work harder to try to restore their connections with others.

Key Takeaways

Studying the brains of cadavers can lead to discoveries about brain structure, but these studies are limited because the brain is no longer active.
Lesion studies are informative about the effects of lesions on different brain regions.
Electrophysiological recording may be used in animals to directly measure brain activity.
Measures of electrical activity in the brain, such as electroencephalography (EEG), are used to assess brainwave patterns and activity.
Functional magnetic resonance imaging (fMRI) measures blood flow in the brain during different activities, providing information about the activity of neurons and thus the functions of brain regions.
Transcranial magnetic stimulation (TMS) is used to temporarily and safely deactivate a small brain region, with the goal of testing the causal effects of the deactivation on behaviour.

Exercise and Critical Thinking

Consider the different ways that psychologists study the brain, and think of a psychological characteristic or behaviour that could be studied using each of the different techniques.

Chen, Z., Williams, K. D., Fitness, J., & Newton, N. C. (2008). When hurt will not heal: Exploring the capacity to relive social and physical pain. Psychological Science, 19 (8), 789–795.

Diamond, M. C. (1999). Why Einstein’s brain? New Horizons for Learning . Retrieved from https://web.archive.org/web/20111007191916/http://education.jhu.edu/newhorizons/Neurosciences/articles/einstein/

Eisenberger, N. I., Lieberman, M. D., & Williams, K. D. (2003). Does rejection hurt? An fMRI study of social exclusion. Science, 302 (5643), 290–292.

Kalbe, E., Schlegel, M., Sack, A. T., Nowak, D. A., Dafotakis, M., Bangard, C., & Kessler, J. (2010). Dissociating cognitive from affective theory of mind: A TMS study. Cortex: A Journal Devoted to the Study of the Nervous System and Behavior, 46 (6), 769–780.

Kanwisher, N. (2000). Domain specificity in face perception. Nature Neuroscience, 3 (8), 759–763.

Koenigs, M., Young, L., Adolphs, R., Tranel, D., Cushman, F., Hauser, M., & Damasio, A. (2007). Damage to the prefontal cortex increases utilitarian moral judgments. Nature, 446 (7138), 908–911.

Kotowicz, Z. (2007). The strange case of Phineas Gage. History of the Human Sciences, 20 (1), 115–131.

Macmillan, M. (2000). An odd kind of fame: Stories of Phineas Gage . Cambridge, MA: MIT Press.

Miller, G. (2008). The roots of morality. Science, 320 , 734–737.

Van den Eynde, F., Claudino, A. M., Mogg, A., Horrell, L., Stahl, D., & Schmidt, U. (2010). Repetitive transcranial magnetic stimulation reduces cue-induced food craving in bulimic disorders. Biological Psychiatry, 67 (8), 793–795.

Young, L., Camprodon, J. A., Hauser, M., Pascual-Leone, A., & Saxe, R. (2010). Disruption of the right temporoparietal junction with transcranial magnetic stimulation reduces the role of beliefs in moral judgments. PNAS Proceedings of the National Academy of Sciences of the United States of America, 107 (15), 6753–6758.

Image Attributions

Figure 4.12: “ Phineas gage – 1868 skull diagram ” by John M. Harlow, M.D. (http://it.wikipedia.org/wiki/File:Phineas_gage_-_1868_skull_diagram.jpg) is in the public domain.

Figure 4.14: “ EEG cap ” by Thuglas (http://commons.wikimedia.org/wiki/File:EEG_cap.jpg) is in the public domain .

Figure 4.15: Face recognition by National Institutes of Health (http://commons.wikimedia.org/wiki/File:Face_recognition.jpg) is in public domain.

Long Descriptions

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Introduction to Psychology - 1st Canadian Edition Copyright © 2014 by Jennifer Walinga and Charles Stangor is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License , except where otherwise noted.

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Providing a study guide and revision resources for students and psychology teaching resources for teachers.

Ways of Studying the Brain: Scanning Techniques, including Functional Magnetic Resonance Imaging (fMRI); Electroencephalogram (EEGs) and Event-Related Potentials (ERPs); Post-Mortem Examinations

March 16, 2021 - paper 2 psychology in context | biopsychology.

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AO1: Ways of Studying the Brain

The brain is the main focus of neuroscience. Studying the brain gives us important insights into the underlying foundations of our behaviour and mental processes. A variety of methods are used by scientists in order to study the different areas and functions of the brain. Some involve scanning the living brain, looking for patterns of electrical activity associated with performance of particular tasks. Other methods involve studying sections of a deceased brain to investigate anatomical reasons for behaviour observed when the patient was alive.

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Unit 3: Current Methods in Neuroscience

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Unit 3 Introduction

This unit introduces some of the major techniques with which scientists gain understanding of the structure and function of the human brain. What kinds of experimentation help us better understand how neurons communicate and how different parts of the brain work together? Some methods can be used to directly alter brain activity in a living person, while others merely record the brain’s activity or create a map of where that activity is located. Students will learn which methods can be used without damaging or permanently impacting the subjects, and which are best for clinical uses. Students will also discuss ethical concerns that exist surrounding the development and use of these technologies. Lastly, this unit covers current methods in animal systems that are revealing new insights into the human brain.

What's In This Unit?

Lesson 1: Non-Invasive Methods in Humans
Lesson 2: Invasive Methods in Humans
Lesson 3: Ethical Issues with Neuroscience Methods
Lesson 4: Methods in Animal Research
MRI/fMRI – Magnetic Resonance Imaging (MRI) uses magnetic fields and radio waves to obtain a picture of the brain (or other organs/tissue) inside the body. Functional Magnetic Resonance Imaging (fMRI) uses this same technology, with some additional adjustments, to look at blood flow in the brain over time, which indicates real-time brain activity, often while the subject is engaged in a cognitive task.
PET – Positron Emission Tomography (PET) uses a radioactive tracer (which is injected or swallowed) to measure brain function.
CT – Computed Tomography (CT) is a type of 3-D X-ray that can be used to image the brain.
EEG – An Electroencephalogram (EEG) uses multiple electrodes placed on the surface of the skull to measure the electrical activity in the brain.
Temporal resolution - How fast a brain imaging method can gather data of the brain’s activity. Methods with high temporal resolution can give detailed information about rapidly changing patterns of activity in the brain.
Spatial resolution - How small an area of the brain an imaging method can gather data from. Methods with high spatial resolution can give detailed information about the structure of the brain or where in the brain certain activity is. Much like the number of pixels on a screen, the more chunks the brain is divided into, the sharper and crisper the image will be.

Lesson 1: Non-Invasive Neuroscience Methods Objective: Students will be able to explain the advantages and disadvantages of the most common non-invasive methods currently used in neuroscience and their potential for treating brain disorders and mental health conditions.

In order to activate students’ observational skills, ask them to analyze the images below of different technical brain imaging methods.

Explain that there are many different ways to get a visual representation of what is going on inside the head. Each method has strengths and weaknesses, and because of this, certain methods are typically used in certain settings.

All images show a horizontal cross section of a brain. The CT image appears fuzzy and gray, with poor definition between different brain structures. The MRI image is black and white with clear sharp distinction between gray and white matter. The PET image is very colorful, with every aspect of the brain appearing on a spectrum from red to blue. The fMRI image is similar to the MRI image but with added sections of red or blue over top of the gray structures.

Which images are the sharpest? Which are the fuzziest?
Which images have intensity or color scales? What do you think the colors or intensities might signify in each image?
Compare the CT/MRI images with the PET/fMRI. What differences and similarities do they see between these groups?

Things to note that will help you during student discussion:

If students point out that MRI and fMRI look sharper than CT and PET, explain that the date of development of each technology correlates with the increasing image resolution. CT was introduced in the early 1970s, PET and MRI in the 1980s, and fMRI in the 1990s. Most present-day research in cognitive neuroscience uses fMRI when looking at brain activity for this very reason.
If students point out that CT doesn’t show the difference between the white matter and gray matter within the brain, you can explain that this is why CT is not commonly used for neuroscience experiments but is often used by doctors and hospitals to see the location of tumors or areas of damage within the brain. Refer to Unit 1 , Lesson 5 for more on gray and white matter.

Use the Mapping the Brain interactive activity from NOVA scienceNOW to help students explore several non-invasive imaging techniques. Guide them through the activity using the steps below.

Provide students with the Mapping the Brain worksheet .
Coronal cross sections divide the front of the head from the back.
Sagittal cross sections divide the left side of the head from the right.
Axial cross sections divide the top of the head from the bottom.
The slider at the bottom allows you to scroll through the brain. Notice the yellow-green line through the head on the left side of your screen moves along with you as you scroll, showing you where you are within the head.
The menu on the right shows all the different brain regions that you can select.
The slider at the right changes the color transparency of the selected brain region.
Students will select one of the brain regions in the menu on the right-hand side of the screen and answer questions 1-3 in the worksheet. If time allows, you can have students choose a second brain region and answer questions 1-3 again.
How does imaging technology help scientists research the brain?
Why might scientists use more than one imaging technique when conducting their research?

The following information is teacher-facing and can be utilized to teach students new information in whatever format works best for you and your students.

Key points:

Non-invasive methods can be used to study the structure and function of the brain, as well as to modify brain activity.
Different methods measure different indicators of brain activity, such as electrical signals (EEG), blood oxygen levels (fMRI), or radioactive tracers (PET).
The accuracy and resolution of timing and spatial location of brain activity are two major characteristics to consider when comparing the benefits and disadvantages of different methods.

In Unit 1 , Lesson 4, we saw how lesion studies were used historically to learn about the roles and functions of specific brain regions. However, the accident or event that caused the lesion in question may have other impacts in other regions of the brain, so it is hard to be certain that a particular symptom is purely due to a particular lesion or brain region. Modern techniques offer a more sophisticated way to look at healthy brains, to see what their structure looks like and which regions are active during particular tasks or events.

Techniques for Studying Brain Structure

The most common techniques for getting highly detailed images of the brain are computed tomography (CT) and magnetic resonance imaging (MRI) . A CT scan combines X-ray technology with computer processing to create detailed cross-sectional images of the body. MRI uses a strong magnetic field and radio waves to generate detailed images of the body's internal structures. MRI provides valuable information about soft tissues, organs, and structures that may not be as clearly visible with other imaging methods. CT scans, however, are much faster than MRIs (10 minutes vs. up to an hour) and are preferred for emergency situations requiring immediate treatment, like a stroke.

Individual strands of white matter are visible, with all the gray matter removed. Strings of white matter are color coded such that sections running top to bottom (ie: down the spinal cord) are blue, sections going from one hemisphere to the other are red, and other sections are green.

DTI imaging creates detailed and beautiful color coded images of white matter bundles. Image credit: NICHD/P. Basser

Techniques for Studying Brain Activity or Function Other types of non-invasive techniques can measure neural activity and other kinds of brain changes at the very same time that people are performing mental tasks or psychology experiments. These methods allow us to pinpoint which areas of the brain seem to be involved in specific thought processes.

A human head wearing an EEG cap covered in electrodes is shown, hooked up to a computer. The computer screen is zoomed in so that the electrical activity from each electrode is visible on screen.

EEG directly records the electrical activity of neurons at the surface of the brain. Data from each electrode in the EEG cap is plotted on a graph in order to track brain waves relating to sleep patterns, seizures, or other changes in electrical activity. Image credit: BioRender.com

Functional Magnetic Resonance Imaging (fMRI) relies on the fact that when a particular region of the brain becomes more active, there is an increase in blood flow and oxygenation to that specific area. By comparing the images taken during different tasks or conditions, we can identify which regions of the brain are activated or deactivated. However, fMRI is a slow technique. This means that it has high spatial resolution and takes crisp detailed pictures of the brain structure but since it has low temporal resolution, it can only take a new picture of the brain’s activity every 2 seconds (during which time the brain can do many different things!). It is also important to remember that there are many inferential and statistical steps in between the raw fMRI data and a pretty picture of a region that “lights up” with neural activity during a task! Many types of computer processing are required to create the final image.
Positron Emission Tomography (PET) is used to study brain function by measuring the metabolic activity and blood flow in different regions of the brain. After a person is injected with a radioactively labeled tracer molecule similar to glucose, oxygen, or a neurotransmitter, a PET scan can follow the uptake and use of the tracer by different brain regions. PET scans have high accuracy in measuring biological function, but their spatial and temporal resolution are limited by the properties of the detector.

A human head is shown with individual MEG magnetometers around it. The back of the brain appears red and yellow, indicating higher activity, while the side of the front of the brain appears blue, indicating lower activity.

MEG imaging can be used to create a heatmap of where brain activity is occurring. Image credit: Flickr/Los Alamos National Laboratory

Modifying Brain Activity Beyond characterizing brain structure and function, newer non-invasive technologies such as transcranial magnetic stimulation (TMS) or transcranial direct current stimulation (tDCS) allow researchers to alter neural activity in a region of the brain by applying electrical or magnetic stimulation. This can increase or decrease activity in neural circuits in the region where the instrument is applied. These techniques are often compared to electroconvulsive therapy (ECT) because they change brain activity, but they do so in a more specific and more targeted fashion. These techniques are being studied for both therapeutic and enhancement purposes; they are addressed in more detail in Unit 7 , Lesson 1.

This website gives a nice overview of various methods of neuroimaging , with links to other sources. (McGill University)
The image galleries on this site include collections of images from brain researchers that show different techniques used in current research and their applications to understanding the brain and brain health. (The Franklin Institute)
This interview with neuroscientist Wei-Chung Allen Lee describes why and how researchers aim to understand the connectivity of the brain . (Harvard Medical School)
EEG: This video gives a good overview of electroencephalography technique s. (2-Minute Neuroscience)
fMRI: This video with Alan Alda is engaging and very simply explains how functional magnetic resonance imaging works and what it’s like to be in the scanner. (PBS/Brains On Trial)
MRI: A brief video on how general magnetic resonance imaging works . (National Institute of Biomedical Imaging and Bioengineering)
PET: A brief video on the methods of positron emission tomography . (National Institute of Biomedical Imaging and Bioengineering)
MEG: This video gives a good overview of current magnetoencephalography methods and how it is used in conjunction with other technologies. (Alt Shift X/ARC Centre of Excellence in Cognition and its Disorders)
This article compares the differences between CT and MRI . (Healthline)
This neuroscience blog post directly compares the strengths and weaknesses of PET and fMRI . (Brainy Behavior)
This article is a helpful summary of how fMRI data can be misinterpreted and how other complementary techniques can offer a more reliable understanding of the brain. (Vox)

Have students complete the following activity considering when different types of imaging techniques are appropriate. Students can refer to the Non-Invasive Imaging Methods student guide for reference.

Scenario #1 : A baseball pitcher gets hit in the head by a line drive. Which method(s) would you use to determine what injuries he may have sustained? (CT for rapid screening for fractures, MRI to assess soft tissue damage)
Scenario #2: You want to characterize brain health during aging by measuring sleep quality and performance on memory tasks. Which method(s) would you use to predict brain health using these measures? (EEG for sleep quality, fMRI for cognitive function, MRI for brain structure analysis)
Scenario #3: You want to determine how fast dopamine is produced and neurons are activated after a person with Parkinson’s disease receives a new medication. Which method(s) would you use to look at the brain’s response? (PET for dopamine production, fMRI for neuronal activity)
Scenario #4: You want to study how brain activity across a network of brain regions differs between veterans who developed post-traumatic stress disorder (PTSD) and those who did not, following a brain injury in combat. Which method(s) would you use to look at brain network activity? (MEG or EEG for brain activity, MRI for identifying brain regions)
Ask students to consider what type of imaging method is best for each different situation. Students may use this reference sheet to recall the different imaging techniques.
What type of imaging technique to use. Include multiple methods if appropriate.
Information about how the methodologies work and why they are best suited to this scenario.

Lesson 2: Invasive Methods Objective: Students will be able to explain the value and applications of invasive neurosurgical techniques in learning about the brain and in treating brain disorders.

To introduce the idea of invasive methods guide students through the following intro activity:

Show students this video of a deep brain stimulation surgery performed at the Northwestern University Department of Neurosurgery. Note that the video shows footage of live surgery, but is not particularly graphic.
Why do you think the patient and her medical team opted to try this surgery?
What non-invasive methods were used as part of the surgery prep? What information did they provide for the surgery team?
How was the patient monitored during the surgery?
How do you think they determined the surgery was successful?

Explain the background information below to students to frame the following activity: Wilder Penfield (1891-1976) was a Canadian neurosurgeon and pioneering researcher in the field of epilepsy and neurology. Penfield’s work using invasive neurosurgical techniques had a major impact on our modern understanding of the brain. He developed a surgical procedure called the "Montreal Procedure" for the treatment of epilepsy. During this procedure, he could electrically stimulate specific areas of the brain in conscious patients undergoing neurosurgery. This allowed him to create detailed maps of the brain and identify functional areas responsible for various sensory, motor, and cognitive functions.

Have students read this short article from Youngzine about Wilder Penfield and his work .

A cross section of the brain is shown, on which the map of the body is displayed, showing which parts of this section of cerebral cortex get input from which parts of the body. The hands, fingers, lips, and tongue, are overrepresented and appear overly large compared to other body parts.

Many regions of the cerebral cortex, including the part responsible for processing touch and body sensation, contain a spatial map of the sensory environment (in this case, the skin). Image credit: OpenStax , licensed under the Creative Commons Attribution 3.0 Unported license.

What does the sensory homunculus diagram represent?
What is the “Montreal Procedure,” and how did the technique allow Wilder Penfield to create the diagram?
How were Penfield’s techniques similar or different to what you observed in the video of modern deep brain stimulation surgery?

The following information is teacher-facing and can be utilized to teach students new information in whatever format works best for you and your students.

Key Points:

Invasive techniques of studying the brain yield more precise information about the stimuli, timing, and location of brain activity than non-invasive techniques.
Devices implanted directly into the brain can modulate the brain’s electrical activity to treat some brain disorders.
Signals recorded from the brain can be interpreted by computers to control external devices or prosthetics.

In order to gain insight into how the brain works, scientists from long ago used to need direct access to the brain so they could record the activity from neurons or stimulate those cells with electricity—like Penfield’s experiments. As described in Lesson 1, new technologies have made it possible to both record from neurons and stimulate without drilling a hole in the skull, but invasive methods can still be helpful, especially for direct medical intervention.

Treating Brain Disorders Deep Brain Stimulation (DBS) involves the implantation of a device that can deliver electrical impulses to these targeted areas to modulate and regulate the electrical activity in the brain, especially for managing symptoms of movement disorders such as Parkinson’s disease, tremor, and epilepsy. Electrodes are surgically inserted through holes in the skull into the targeted brain regions. The electrodes are then connected to the stimulator, which is implanted in the body. After surgery, the device is programmed for optimal electrical stimulation to manage the patient’s symptoms.

Connecting to External Devices A Brain-Computer Interface (BCI) is a technology that allows direct communication between the human brain and an external computer or prosthetic device without having to be relayed through the muscles or limbs. In general, a BCI records brain activity signals, then interprets and translates them into commands or actions that can be used to control the external device. Surgically implanted BCIs are typically used for users with serious disorders or injuries. There are also non-invasive wearable BCIs, but these are more commonly used for nonmedical purposes. Most BCIs are currently limited to experimental applications. Reference Unit 7 , Lesson 2 to see more on these state-of-the-art methodologies.

Direct Measurement of Brain Activity Intracranial recording is a technique used to directly measure electrical activity within the brain. It involves placing electrodes directly onto or inside the brain tissue to record and analyze neural signals. Intracranial recording provides powerful data because of its precision and high spatial and temporal resolution. For medical purposes, this technique is typically used in patients with epilepsy or other conditions that require precise mapping of brain activity. However, once the electrodes have been placed they can also be used for nonmedical research purposes—importantly, with the patient’s consent—to record other types of information that are processed in those brain areas.

This website gives a good overview of Deep Brain Stimulation and the surgical process. (Johns Hopkins Medicine)
This video shows how a woman with tetraplegia (paralyzed from the neck down) was able to learn to control a robotic arm using a brain-computer interface . (Brown University)
This 2022 report reviews the current technology of brain-computer interfaces as well as their opportunities and challenges. (U.S. Government Accountability Office)
This 2022 article describes the process of intracranial recording and ethical issues around informed consent. ( Science Magazine)
In a 2022 study, scientists performed intracranial recording on epilepsy patients with electrodes placed in their auditory cortex and had them listen to different types of sounds. After analyzing brain activity, the scientists discovered a population of neurons that responds specifically to song! (MIT Technology Review)

Explain the background information below to students to frame the following activity: In this lesson we have seen how invasive techniques of studying the brain can provide critical insights into how, where, and when the brain processes different types of information, and how these insights can be used for new types of therapy for brain disorders and injuries. Now try mapping your own brain! We will model the results of using invasive measurement technologies by using a technique called the two-point discrimination task.

Have students create their own sensory homunculus using this Brain Maps handout from BrainFacts.org as a guide. The basic steps are broken down below:

Provide students with a brief background lecture using points from the Brain Maps handout (pgs 1-3). These slides may also help. Introduce the activity to students: “Today you will explore brain mapping in a very personal way. Each of you will create your own individual homunculus.”
Students create the two-point discrimination tool. Directions are on pages 3-4 of the handout.
Students measure the two-point discrimination threshold at various places on the body and record results.

Image shows two examples of small squares of paper. On each side of the square, there are 2 toothpicks sticking out the same distance from the paper (where they are secured with glue or tape), but each set of 2 toothpicks have a different length of space between them, from 0.38 mm up to 6 cm).

Students will create small two-point discrimination tools with classroom items such as toothpicks, tape, glue, and thick paper. Image credit: BrainFacts.org

Lesson 3: Ethical Issues with Neuroscience Methods Objective: Students will be able to explain a few common ethical concerns relating to the most common methods of cognitive neuroscience.

Introduce the lesson by explaining the background information below and guiding them through the following activity: This lesson will touch on topics of diversity, inclusion, and other ethical considerations in the field of neuroscience.

If the brain is the same organ, why does diversity in neuroscience subjects matter?
Diversity in sex and gender?
Diversity in genetic ancestry?
Diversity in geographic location?
Why are the researchers using a simple EEG device?
What are some of the technical challenges faced by the researcher?
What are some of the values and concerns expressed by people in the village?
If students are familiar with examples of historical discrimination and abuse in biomedical research of African American communities in the U.S. (e.g., the cases of Henrietta Lacks and the Tuskegee Syphilis Study), extend the discussion to connect with the impacts of this cultural distrust. This NPR article discusses an example of research initiatives aiming to overcome that troubling legac y (not specific to neuroscience).

Guide students through the analysis of the following case study about a patient with chronic migraines who was almost denied a medically necessary EEG due to her hair texture and style.

Have students read this article from KFF Health News about the patient’s challenges with getting an EEG .
What were the instructions given to Sadé by the medical facility? Why are these instructions “anti-Black”?
How do you think these instructions made Sadé, and other Black and Brown patients feel?
Does the article mention any methods that get around these hair restrictions? What are they?
If a facility does not have ways around the restrictions, how could they more inclusively communicate these barriers to patients with thick hair, braids, or extensions/wigs?
Lead a whole class discussion after students have had a chance to independently reflect.
Like any rapidly evolving technology, brain imaging raises several important ethical considerations.
Brain imaging devices should be designed to make sure everyone has equal access to these techniques and research data are more representative of the population.
Even scientists can fall victim to logical fallacies in interpreting brain imaging data based on their own preconceptions.
The use of AI for analyzing fMRI data to decode the specific meaning of neural activity patterns is raising new concerns about privacy and consent.

Implicit Bias in EEG Research If you, personally, haven’t encountered a particular issue before, then you may not factor in that issue when designing new technology. One example is that electrodes for EEG technology were primarily designed by people of Caucasian descent who tended to have thin, often straight, hair. As a result, existing EEG electrodes can be difficult to apply to people with curlier, thicker, and more highly textured hair including many Black and multiracial people. These barriers have produced an overrepresentation of people of Caucasian descent in EEG research data, skewing research findings. Today, scientists are redesigning EEG electrodes to work well with thick textured hair and can be tucked under braids to fit snugly against the scalp. This work is being led by many scientists and engineers who themselves are Black and have hair of this type, in order to correct the problems in the field. Similar biases are embedded in other methods as well, affecting not just inclusion in research but also the accuracy of medical diagnostics.

Drawing the Wrong Conclusions Many neuroscience research studies are designed to assign the subject a certain task or stimulus and then observe imaging data of the resulting brain activation. However, sometimes studies start by looking at brain imaging data and work backwards to draw conclusions about how someone is feeling or what they are experiencing based solely upon their brain activity or structure. The problem with this is that each region of the brain can be involved in many different tasks and it is impossible to know exactly what a particular activity pattern means from imaging alone, but scientists and journalists can often make this mistake due to preconceived expectations.

Decoding Your Thoughts With artificial intelligence and machine learning, more sophisticated analysis of fMRI imaging data is making it possible to decode what someone is thinking. An AI decoder can be trained to process a person’s brain activity patterns that are associated with known mental states or thoughts. When the trained decoder is applied to new fMRI data, it maps the new data to the training patterns to predict what the person is thinking. Such neural decoding experiments raise ethical concerns about consent and how to protect the privacy of your thoughts—especially when it comes to issues of personal identity such as health, gender, or sexuality—as technology continues to advance. (See more details on AI and future technologies in Unit 7 , Lesson 4.)

This article describes the research into developing EEG electrodes that work with more types of hair and includes interviews with young Black scientists. (Massive Science)
This article explains the implicit biases in various neuroimaging technologies and methods of analysis. (Nautilus)
Students may be familiar with similar technical issues that came to light during the Covid-19 pandemic with pulse oximeters that didn’t work as well on people with darker skin. This article highlights researchers trying to fix the problem . (STAT News)
This interview with fMRI expert Russ Poldrack highlights fallacies common in interpreting neuroimaging research and the idea that scientists and companies are trying to improve brain imaging so as to be able to “read our minds.” (The Verge)
This blog post written by graduate students in neuroscience explains the idea of “reverse inference,” with some key examples. (Knowing Neurons)
This article discusses how artificial intelligence can be used to analyze fMRI to try to predict behavior or “read minds,” and what ethical problems may result. (CNN)
This article from NPR describes a recent study from the University of Texas at Austin where scientists used fMRI and AI to detect stories in people’s minds by decoding language patterns. (NPR)

Explain the background information below to students to frame the following activity. Although it is currently not possible to use any method of brain imaging to truly “read your mind” with reliable accuracy, this may become possible in the future. As discussed earlier in the lesson, we can record from human brains well enough to control a robotic arm, given enough training, but the same technology is not advanced enough to be able to decode or predict what a person is thinking. If brain imaging improves to the point that it IS possible to know what someone is thinking without them having to say or do anything, what are the ethical implications? One concern is about issues of privacy and how to keep one’s thoughts private. Another concern is how this information would be used—who would have access to the resources to read your mind without your permission?

Guide students through the following analysis using the steps below:

Pose this question to students to get them thinking aloud: Should neural decoding technology be used to read the minds of unconscious patients?
Have students read about this case study of a person who suffered damage to the cerebral cortex and was not visibly responsive, but could perform basic communication using a simple code.
Give students this ethical decision making framework from the Northwest Association for Biomedical Research ( teacher background guide ) and research the facts and ethical issues associated with brain decoding in order to answer the question posed in #1.

Optional Example: This article (and linked podcast) from NPR describes Martin Pistorius, a man from South Africa who developed locked-in syndrome . He had gone into a vegetative state at age 12 and remained so for years. When he started waking up, he was unable to move or communicate so none of his family members realized he had returned. Eventually he was able to use computer technology to communicate using his eyes.

Lesson 4: Methods in Animal Research Objective: Students will be able to describe some common techniques used in animal experimental models that allow studies of the brain in cellular-level detail and with precise control of function.

Introduce the lesson by explaining the background information below and guiding them through the following activity: To begin thinking about animal methods in neuroscience we will analyze a study performed at Northwestern University that uses a recently developed technology in animal systems called optogenetics. This method allows researchers to turn on and off a targeted set of neurons using light to understand their function. (An article accompanying the video provides more background information on optogenetics and describes the details of the study.)

Show students this video of research to study the brain circuits underlying social bonding .
How did the scientists program the mice’s behavior?
What parts of the brain do you think the devices were connected to?
What behaviors did you observe in the video when the devices were synchronized? Desynchronized?
This experiment was the first time researchers used wireless devices for optogenetic control. Why was that advance important for investigating this particular research question?
How do you think the results of this study might help us understand the human brain and behavior?
Do you think this technology could be used in humans? Why or why not?

Explain the background information below to students to frame the following activity. Sometimes the study of certain brain activity is not physically or ethically possible in a human brain, and this is where animal methods come in!

Guide student groups through the following discussion in small groups:

Ask small groups to list out the invasive and non-invasive neurological methods of study discussed in Lessons 1 and 2.
Using what you know about the methods listed, what kind of experiments are possible to do in living humans and which are not?
What kind of experiments might be easier or more ethical to conduct on animals instead of humans?
Could you manipulate a person’s thoughts or behaviors and observe resulting changes in brain activity. Answer: Yes. Intracranial recording allows us to do this in humans at a limited scale.
Could you manipulate cellular activity and observe the changes in thoughts or behaviors in humans? Answer: No. Our current technologies don’t allow us to control the activity of individual cells in living humans.
Could you study the effects of a new drug that has only been tested in cell culture (cells growing in a dish in a lab) on human brain activity? Answer: No. Drugs must be tested in animals before they can move to human trials.
Reflect on how our current methods for human research limit our understanding of brain activity and ethical considerations of studying human brains.
Ask groups to share out their answers and find common themes in their responses.
Experimental research on animals is a difficult ethical issue for some people, but many medical breakthroughs we enjoy today are due to well-designed and ethical animal research.
Specific techniques in animals, such as Brainbow and optogenetics, are allowing scientists to map brain circuits and functions in unprecedented detail.
Humanized animal models are laboratory animals that express human genes in order to learn more about human diseases and to test possible treatments.

Ethics of Animal Research Going even further than the invasive methods used in humans, techniques developed for animal systems in recent years have given scientists the tools to map brain structure and manipulate function with unprecedented precision. These new methods are yielding new insight into human brain function and disorders. However, the use of animals in research is a controversial ethical issue. It is important to note that experiments using living animals are not performed lightly and go through a rigorous approval process. These experiments must be approved by a committee designed to minimize the number of animals used and the discomfort that these animals must experience. Veterinarians and animal care staff work to keep animals comfortable and happy, and scientists are required to be trained in animal handling and care. Many medical advances in neuroscience and beyond, including vaccines for polio and rabies, the development of some antibiotics, cancer treatments, and organ transplantation, have been developed thanks to the use of animals in research. These new treatments are not only used to improve human lives, but can be used in a veterinary setting to improve the health of animals as well.

Visualizing Connections “Brainbow” is a technique used to visualize the complex connections within the brain. It uses a combination of genetic engineering and fluorescent proteins to color code individual cells in the brain. Researchers can then use advanced microscopy techniques to track and distinguish cells in regions of the brain, allowing them to study how neurons connect and interact with each other and change over time. It is most commonly used in mice, fruit flies, and zebrafish.

Three images at different magnifications show that each neuron and its axons are color coded a different and vibrant fluorescent color, making the identification of each neuron in a circuit possible.

Brainbow images showing labeling of individual cells. Image credit: Lichtman & Sanes, 2008; licensed under the Creative Commons Attribution 3.0 Unported license.

Manipulating Function at a Cellular Level Optogenetics combines genetic engineering and optics to control and manipulate the activity of specific neurons in living organisms, typically mice or other animals. It allows researchers to selectively activate or inhibit the activity of particular neurons with precise timing and spatial resolution, providing insights into the function and connectivity of neural circuits. Light-sensitive proteins are genetically introduced into target neurons to act like a switch—scientists can then use light to turn those neurons “on” and “off,” as shown in the illustration. By activating or inhibiting specific groups of neurons, scientists can observe the resulting changes in behavior, cognition, sensory processing, or other brain functions. This is similar to earlier studies on individuals with brain lesions, but more powerful as the precise regions of the brain turned off or on can be controlled at will by the experimenters.

A rat is shown, its head translucent to show the brain within. A fiber optic is shining yellow light into the brain, which is zoomed in to show it impacting certain neurons but not others.

Optogenetics uses fiber optics implanted in to the head of the animal expressing light-sensitive proteins to turn the neurons containing those proteins on or off by changing their activity. Image credit: BioRender.com

Increasing Human Relevance As discussed in Unit 1 , Lesson 6, there is much we can learn from the brain structure and function of experimental animal models, but they’re still not human. How can scientists maintain the practical benefits of animal research while getting closer to understanding what actually happens in humans? “Humanized” animal models use genetic engineering and transplantation techniques to introduce human genes or cells into an animal model to mimic specific human traits or diseases for research purposes. For brain research, scientists create animals with human genes or cells to better model human development, physiology, and neurological disorders, or to get more informative data on the safety and efficacy of drugs and therapies in development before human testing.

This 15 min podcast from the National Science Teachers Association was made specifically for K-12 teachers interested in helping their students understand the benefits of animal research and its ethical considerations .
This article is a good overview of the protections in place to make scientific animal research as safe and ethical as possible . (The Conversation)
This video provides good visual analogies of how the Brainbow technique works and what information it reveals. (BrainFacts.org)
This article includes examples of the beauty of Brainbow images . ( Scientific American )
This article discusses how Brainbow complements other non-invasive techniques in humans in efforts to map the entire “connectome,” or a full circuit diagram, of the brain. (BrainFacts.org)
This video gives a good overview of the development of optogenetics and what it could be used for. (SciShow)
This video interview with Ed Boyden at MIT, one of the pioneers of optogenetics, conveys his hopes of what the technology might be able to accomplish in humans someday. Note that in the nine years since this video was produced, gene therapy technology in humans has significantly advanced (using CRISPR gene editing, for example), removing one of the potential technical hurdles—though many more remain.
This article describes a study in which mice were genetically modified to express a human gene involved with Alzheimer’s disease to examine age-related changes in the brain and behavior . (National Institutes of Health)
This article describes a study where Stanford researchers transplanted human neural cells into rat brains to investigate how the human cells could grow and function in the hybrid brain. More about experiments with brain organoids and their ethical considerations is covered in Unit 7 , Lesson 3 . (Fierce Biotech)

Explain the background information below to students to frame the following activity: As we have learned from the technologies introduced in this lesson, technical advances in genetic engineering, electronics, and transplantation have opened up new avenues in animal research to understand the brain. However, these new techniques also raise many questions as to when and how they should be used. Communicating the potential benefits, challenges, and ethical issues to the public, and understanding public questions and concerns, is an essential part of responsible scientific research and innovation.

Ask students to script a short news segment about research on humanized animals in small groups using the steps below. Scripts should follow the “3 Cs of news writing”: be clear, concise, and correct.

Break students into groups of 4
Supporting sources:
Precision gene editing paves way for transgenic monkeys (Scientific American)
Bioethical considerations for transgenic nonhuman primate models in neuroscience research (National Academies)
Human brain cells transplanted into rat brains hold promise for neuropsychiatric research (Stanford University)
Are rats with human brain cells still just rats? (MIT Technology Review)
Scientific expert
Member of the public
Anchor: Introduce the segment (~45 words)
Scientific expert: Why was this research valuable? What was learned? (~200 words)
Ethicist: What are some of the ethical concerns with this type of research? (~200 words)
Member of the public: Do you think more research like this should be done? Why or why not? You may be creative about this person’s motivations and interest in the topic. (~150 words)
Anchor: Closing/conclusion (~45 words)

Optional: Encourage students to film their script if time and resources allow. Optional: Students can be asked to evaluate another group’s presentation for accuracy and helpful depiction of the ethical concerns.

For more information about the Neuroscience & Society Curriculum, please contact [email protected] .

Neuroscience & Society Curriculum

Launch Lesson • Unit 1: Neurons and Anatomy • Unit 2: Education and Development • Unit 3: Current Methods in Neuroscience • Unit 4: Mental Health and Mental Health Conditions • Unit 5: Drugs and Addiction • Unit 6: Law and Criminology • Unit 7: Future Technologies

This project was supported by funding from the National Institutes of Health Blueprint for Neuroscience Research under grant #R25DA033023 and additional funding from the Dana Foundation. Its content is solely the responsibility of the authors and does not necessarily represent the official views of NIH or the Dana Foundation.

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Decoding the brain...

Decoding the brain through research—the future of brain health

Read our brain health collection.

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Peer review
David Z Wang , professor 1 ,
Lee H Schwamm , professor 2 ,
Tianyi Qian , professor 3 4 ,
Qionghai Dai , professor 4
1 Neurovascular Division, Department of Neurology, Barrow Neurological Institute, St Joseph Hospital and Medical Center, Phoenix, AZ, USA
2 Comprehensive Stroke Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
3 Department of Public Health, School of Medicine, Tsinghua University, Beijing
4 Tencent Healthcare, Tencent AIMIS, Shenzhen, China
5 Department of Automation and Institute for Brain and Cognitive Science, Tsinghua University, Beijing, China
Correspondence to: David Wang david.wang{at}dignityhealth.org

David Z Wang and colleagues look at the latest advances in brain research and how they might affect treatment of brain disorders

The world has come a long way in solving the mystery of the brain, understanding its fundamental role in human consciousness and discovering methods to treat its disorders. In The Sacred Disease in ~430 BC, Hippocrates wrote that the brain served to house the ventricles, whose main purpose was to be a container and transit point for the breath or air (pneuma) from outside the body—the force that brought to life our joys, pleasures, laughter, and grief. Thus, the brain was a reservoir for an animated substance that produced the human experience of consciousness and personality rather than the source of that activity itself. 1 Our knowledge of the brain and its functional complexity remained at the level of three ventricles where our soul lies (Nemesius, da Vinci) for hundreds of years until modern neuroscience began to uncover the fine network of neuronal circuits that made up the solid substance of the brain.

With the advent of modern neuroimaging, the complex structure of the brain has been brilliantly revealed, and this has helped greatly in the treatment of many brain related disorders. Other articles in this series have provided updates on a wide range of topics, including neurodegenerative diseases, mental disorders, cerebrovascular diseases, epilepsy, monogenic neurological diseases, and in vivo brain function testing. 2 3 4 5 6 With help from gross anatomy to electronic microscopy, tissue staining to profiling, cell physiology, and synaptic chemistry, neuroscientists have elucidated the mechanisms and pathophysiology of many common brain diseases. For example, trinucleotide repeat expansion is now known to be responsible for many genetically inherited degenerative diseases such as Huntington’s disease, and amyloid precursor gene or presenilin gene mutations can cause Alzheimer’s disease.

On the other hand, despite centuries of discovery on mechanisms of brain disease, treatment options remain limited. Most treatments still provide only alleviation of symptoms, though recent breakthroughs in gene therapy such as onasemnogene abeparvovec-xioi to treat children with spinal muscular atrophy 7 and reperfusion therapy for acute ischaemic stroke hold the promise to truly revolutionise treatment for neurological disease. While options are available to modify disease expression with medications—such as in the treatment of Parkinson’s disease, multiple sclerosis, and epilepsy—we are far from curing them.

Entering the 21st century, perhaps we now have better ways to understand the mechanism of those brain disorders that are still a mystery and find the precise treatment. The key will likely be interdisciplinary research. Many ongoing brain health research programmes have already been multidimensional, combining neurobiology, physics, engineering, big data science, and artificial intelligence.

Imaging advances

In the future, it is likely that humans will be able to live longer, and do so with augmented capabilities supported by machine-human interactions. One exciting advance is new ways of observing in vivo brain-wide activities at the cellular level. A real time, ultra-large scale, high resolution (RUSH) macroscope has recently been developed that can provide video-rate gigapixel imaging of biological dynamics at centimetre scale and micrometre resolution, with a data throughput of up to 5.1 gigapixels a second. 8 RUSH has enabled in vivo functional imaging of neural networks across the whole mouse brain at single dendrite resolution and brain-wide tracking of leucocytes during pathological processes, and the technology opens up a new horizon for large scale brain imaging to study various brain diseases at a systematic level. 8

Another example is the better understanding of the precise number of brain cells needed to complete a particular task. By constructing an explicit model of face selective cells that could decode an arbitrary realistic face from face cell responses and predict the firing of cells in response to an arbitrary realistic face, Chao and colleagues identified that macaques require only 200 cells to remember a face. 9 These findings have far reaching significance. For the first time, a specialised task of the brain can be attributed to a specific number and type of brain cells in a specific circuit. This may allow scientists to build artificial models of explicit brain functions and experiment with mechanisms of injury and repair at a cellular or molecular level. Such mapping may aid our understanding of brain function and recovery and guide the rebuilding of brain circuits or resection of dysfunctional brain cells rather than whole tissues. It may also help us pinpoint the cells and circuits that are responsible for addictive behaviours, from smoking to substance use disorders to gambling.

Resilience and plasticity of brain cells

The common belief is that when a brain has been removed, brain death is imminent. However, such belief has recently been shattered. Sestan and colleagues collected brains of 6-8 month old pigs four hours after death and bathed them in specialised perfusate solutions. They found that brain cells and synapses of certain areas of brain began to recover and show signs of cellular activities. 10 Their finding suggests that there may be a late window of treatment after onset of brain anoxia when brain tissue can recover, analogous to the benefit of late window thrombectomy. This discovery has taught us that brain cells can survive and recover after loss of circulation, and that favourable conditions may preserve a reservoir of resilient brain cells that are slow progressors to ischaemic necrosis.

Evidence is also emerging on how brain cells can adapt. A recent report of functional neuronal connectivity in adults without apparent loss of function after brain hemispherectomy sheds new light on brain plasticity. The study provides the first comprehensive analysis of whole brain functional connectivity across the full repertoire of resting state networks after hemispherectomy and shows preservation of resting state networks but an increase in internetwork connectivity with other functional brain networks. When hemispheric resection occurred in patients younger than 11, the retained hemisphere was able to protect the jeopardised functions by enhancing cellular interaction and synaptic activity. 11

Harnessing the power of big data

Artificial intelligence (AI) has been widely applied in clinical diagnosis and patient monitoring. Recent studies have attempted to classify or detect Alzheimer’s disease and other cognitive impairment, 12 13 acute neurological events, 14 15 16 17 18 focus of epilepsy, autism spectrum disorder, and attention deficit/hyperactivity disorder by using deep learning based algorithms. The data in these AI models include not only medical images but also clinical scores, in vitro diagnostic test results, and other functional and structure information. 19 20 21 22 23 24 25 These studies showed high sensitivity and specificity from their test set, and work is ongoing on how to incorporate the routine use of these AI systems into a clinical setting.

The lack of a large dataset from multiple centres, the limited coverage of a disease spectrum, and unclear risk of using AI are major limitations of these blackbox systems. In contrast, Wang and colleagues have recently proposed a “vascular aware” unsupervised learning technique, VasNet, 26 which provides the end users with explainable images, including both vascular structures and multidimensional features such as anatomical, physiological, biochemical, and cellular details. The enriched outputs could augment human decision making on treating vascular diseases and contribute to the emergence of the next generation of healthcare engineering.

The US Food and Drug Administration has already approved several automatic quantitative measurement software systems for disease classification (eg, NeuroQuant, Quantib, RAPID). Brain morphometry analysis software can automatically examine segments of brain tissue and detect minute changes. This technology can help early detection of degenerative brain diseases by comparing the results from individuals with a large dataset and images of healthy people. To take racial differences in the brain into account, some Asian companies have developed software based on datasets acquired from Asian populations ( http://quant-health.com ). Use of a deep learning based segmentation algorithm could improve the accuracy and test-retest stability in segmenting and measuring the volume of brain structure, abnormal lesions, perfusion deficit area, and other characteristics. The resulting quantified values could be used to assign a clinical score automatically, avoiding the variation arising from subjective measurement and interobserver inconsistency.

AI algorithms can also objectively analyse the data collected from a depth camera or wearable devices, assess behaviour, and evaluate facial expressions. 27 28 29 The quantified values produced would not be affected by the physicians’ experiences, and errors can be avoided since the spatial-temporal resolution of the hardware is much smaller than visual evaluation by humans. Such early detection may allow treatment of a disease before a person shows clinical signs of brain dysfunction. Quantified measurements can be used as biomarkers to monitor the progress of the disease and help evaluate the efficacy of precision therapy.

Prospect of cure

One of the potential ways of curing a brain disorder is to correct its diseased protein structure. Many neurological diseases are caused by misfolded proteins, including Huntington’s, Parkinson’s, and Alzheimer’s disease. AlphaFold, a Google company, has successfully predicted a protein structure by using large genomic data. The 3D models of proteins that AlphaFold generates are far more accurate than any that have come before—making significant progress on one of the core challenges in biology. The ability to predict a protein’s shape from its DNA sequence is useful to scientists because it is fundamental to understanding its role within the body, as well as diagnosing and treating diseases believed to be caused by protein misfolding. 30

We have entered into an exciting new era of brain science research and discovery. With the advent of AI, advanced imaging, genomics, psychosocial analytics, and protein engineering we may be closer than ever to new precision medicine approaches to treat many brain disorders.

Key messages

In the past decade, neuroscience and brain research have entered into a new era

It is now possible to understand brain physiology and pathophysiology better through direct and in vivo observation of live brain

In the coming years, artificial intelligence will likely be part of brain science and assist or replace certain brain function

Genetic or protein alterations may provide a cure for many brain disorders in the near future

Contributors and sources: DZW drafted the first manuscript. LHS, TYQ, and QHD critically reviewed and revised the manuscript. DZW is an expert in stroke clinical research. LHS is an expert in neuroscience research and stroke care quality improvement. TYQ is an expert in big data and artificial intelligence. QHD is an expert in brain research and artificial intelligence.

Competing interests: We have read and understood BMJ policy on declaration of interests and declare that we have no competing interest.

Provenance and peer review: Commissioned; externally peer reviewed.

This article is part of a series launched at the Chinese Stroke Association annual conference on 10 October 2020, Beijing, China. Open access fees were funded by the National Science and Technology Major Project. The BMJ peer reviewed, edited, and made the decision to publish these articles .

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ .

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↵ FDA approves innovative gene therapy to treat pediatric patients with spinal muscular atrophy, a rare disease and leading genetic cause of infant mortality. Press release, 24 May 2019. https://www.fda.gov/news-events/press-announcements/fda-approves-innovative-gene-therapy-treat-pediatric-patients-spinal-muscular-atrophy-rare-disease#:~:text=The%20U.S.%20Food%20and%20Drug,genetic%20cause%20of%20infant%20mortality
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↵ Saplakoglu Y. How the brain still works when half of it is missing. Live Science, 22 Nov 2019. https://www.livescience.com/hemisphere-removed-brain-plasticity.html
↵ Payan A, Montana G. Predicting Alzheimer’s disease: a neuroimaging study with 3D convolutional neural networks. arXiv 2015:1502.02506. [Preprint.] https://arxiv.org/abs/1502.02506 .
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↵ Liu S, Liu S, Cai W, Pujol S, Kikinis R, Feng D. Early diagnosis of Alzheimer’s disease with deep learning. 2014 IEEE 11th international symposium on biomedical imaging. 29 Apr-2 May, 2014:1015-8. https://ieeexplore.ieee.org/document/6868045 .
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↵ Sarraf S, Tofighi G. Classification of Alzheimer’s disease using fMRI data and deep learning convolutional neural networks. 2016. https://arxiv.org/abs/1603.08631 .
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↵ Evans R, Jumper J, Kirkpatrick J, et al. De novo structure prediction with deep-learning based scoring. In: Thirteenth critical assessment of techniques for protein structure prediction. Abstracts, 1-4 December 2018.

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Researchers Develop Method to Study Brain Connectivity, Functionality

Research method integrates human cortical organoids into developing rat brains, allowing for study of brain processes associated with disease

October 13, 2022 • Press Release

Scientists have developed a research method that allows for a much more detailed examination of the brain processes involved in some neurological and mental disorders. This is achieved by growing human cortical organoids in culture and inserting them into developing rodent brains to see how they integrate and function over time. The study, funded by the National Institute of Mental Health (NIMH), part of the National Institutes of Health, appears in the journal Nature .

“This work provides a significant advance in the ability of scientists to study the cellular and circuit underpinnings of complex human brain disorders. It allows organoids to get ‘wired’ in a more biologically relevant context and function in ways they can’t do in a petri dish,” said David Panchision, Ph.D., chief of the Developmental and Genomic Neuroscience Research Branch in the Division of Neuroscience and Basic Behavioral Science at NIMH.

Example of a transplanted human cortical organoid (t-hCO) in the rat cortex.

Researcher Sergiu Pasca, M.D. , and colleagues at Stanford University, Stanford, California, demonstrated that a cortical organoid cultured from human stem cells can be transplanted onto—and integrated into—the developing rat brain to study certain developmental and functional processes. The findings suggest that transplanted organoids may offer a powerful tool for investigating the processes associated with disease development.

Researchers sometimes use cortical organoids—three-dimensional cultures of human stem cells that can mirror some of the developmental processes seen in typical brains—as a model for investigating how some aspects of the human brain develops and functions. However, cortical organoids lack the connectivity seen in typical human brains, limiting their usefulness for understanding complex brain processes. Researchers have been trying to overcome some of these limitations by transplanting individual human neurons into adult rodent brains. While these transplanted neurons connect with rodent brain cells, they do not become fully integrated due to the developmental limitations of the adult rat brain.

In this study, the team of researchers advanced the use of brain organoids for research by transplanting an intact human cortical organoid into a developing rat brain. This technique creates a unit of human tissue that can be examined and manipulated. The researchers used methods previously pioneered in the Pasca lab to create cortical organoids using human-induced pluripotent stem cells—cells derived from adult skin cells that have been reprogrammed into an immature stem-cell-like state. They then implanted these organoids onto the rat primary somatosensory cortex, a part of the brain involved in processing sensation.

The researchers did not detect any motor or memory abnormalities or abnormalities in brain activity in the rats that received the transplanted organoid. Blood vessels from the rat brain successfully supported the implanted tissue, which grew over time.

To understand the extent to which the organoids could integrate into the rat somatosensory cortex, the researchers infected a cortical organoid with a viral tracer that spreads through brain cells as an indicator of functional connections. After transplanting the marked organoid onto the rat’s primary somatosensory cortex, researchers detected the viral tracer in multiple brain areas, such as the ventrobasal nucleus and the somatosensory cortex. In addition, the researchers observed new connections between the thalamus and the transplanted area. These connections were activated using electrical stimulation and stimulation of the rat’s whiskers, indicating that they were receiving meaningful sensory input. Moreover, the researchers were able to activate human neurons in the transplanted organoid to modulate the rat’s reward-seeking behavior. The findings suggest functional integration of the transplanted organoid into specific brain pathways.

Structurally and functionally, after seven to eight months of growth, the transplanted brain organoid resembled neurons from human brain tissue more than human organoids maintained in cell culture. The fact that the transplanted organoids mirrored the structural and functional features of human cortical neurons led the researchers to wonder if they could use transplanted organoids to examine aspects of human disease processes.

“The promise of this platform is not only in identifying what molecular processes underlie the advanced maturation of human neurons in living circuits and leveraging it to improve conventional in vitro models, but also in providing behavioral readouts for human neurons,” said Dr. Pasca.

To examine this, the researchers generated cortical organoids with cells from three participants with a rare genetic disorder associated with autism and epilepsy called Timothy syndrome and three participants without any known diseases and implanted them onto the rat brain. Both types of organoids integrated into the rat somatosensory cortex, but organoids derived from Timothy Syndrome patients displayed structural differences. These structural differences did not appear in organoids that were created from the cells of patients with Timothy Syndrome and maintained in cell culture.

“These experiments suggest that this novel approach can capture processes that go beyond what we can detect with current in vitro models,” said Dr. Pasca. “This is important because many of the changes that cause psychiatric disease are likely subtle differences at the circuit level.”

Revah, O., Gore, F., Kelley, K. W., Andersen, J., Sakai, N., Chen, X., Li, M., Birey, F., Yang, X., Saw, N. L., Baker, S. W., Amin, N. D., Kulkarni, S., Mudipalli, R., Cui, B., Nishino, S., Grant, G. A., Knowles, J. K., Shamloo, M. … Pașca S. P. (2022). Maturation and circuit integration of transplanted human cortical organoids. Nature https://doi.org/10.1038/s41586-022-05277-w

MH115012 , DA050662 , RR026917 , OD030452

About the National Institute of Mental Health (NIMH): The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website .

About the National Institutes of Health (NIH) : NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website .

NIH…Turning Discovery Into Health ®

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3.3: Psychologists Study the Brain Using Many Different Methods

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Learning Objectives

Compare and contrast the techniques that scientists use to view and understand brain structures and functions.

Lesions Provide a Picture of What Is Missing

Figure $\PageIndex{13}$

In one of the scenarios the participants were asked if they would be willing to kill one person in order to prevent five other people from being killed. As you can see in Figure $\PageIndex{14}$, they found that the individuals with lesions in the frontal lobe were significantly more likely to agree to do the harm than were individuals from the two other groups.

Figure $\PageIndex{14}$ The Frontal Lobe and Moral Judgment

Recording Electrical Activity in the Brain

Figure $\PageIndex{15}$

A less invasive approach, and one that can be used on living humans, is electroencephalography (EEG). The EEG is a technique that records the electrical activity produced by the brain’s neurons through the use of electrodes that are placed around the research participant’s head. An EEG can show if a person is asleep, awake, or anesthetized because the brain wave patterns are known to differ during each state. EEGs can also track the waves that are produced when a person is reading, writing, and speaking, and are useful for understanding brain abnormalities, such as epilepsy. A particular advantage of EEG is that the participant can move around while the recordings are being taken, which is useful when measuring brain activity in children who often have difficulty keeping still. Furthermore, by following electrical impulses across the surface of the brain, researchers can observe changes over very fast time periods.

Peeking Inside the Brain: Neuroimaging

Very clear and detailed pictures of brain structures (see, e.g., Figure $\PageIndex{16}$) can be produced via fMRI. Often, the images take the form of cross-sectional “slices” that are obtained as the magnetic field is passed across the brain. The images of these slices are taken repeatedly and are superimposed on images of the brain structure itself to show how activity changes in different brain structures over time. When the research participant is asked to engage in tasks while in the scanner (e.g., by playing a game with another person), the images can show which parts of the brain are associated with which types of tasks. Another advantage of the fMRI is that is it noninvasive. The research participant simply enters the machine and the scans begin.

Figure $\PageIndex{16}$ fMRI Image

Photo courtesy of the National Institutes of Health, Wikimedia Commons – public domain.

Research Focus: Cyberostracism

Key Takeaways

Studying the brains of cadavers can lead to discoveries about brain structure, but these studies are limited due to the fact that the brain is no longer active.
Lesion studies are informative about the effects of lesions on different brain regions.
Electrophysiological recording may be used in animals to directly measure brain activity.
Measures of electrical activity in the brain, such as electroencephalography (EEG), are used to assess brain-wave patterns and activity.
Functional magnetic resonance imaging (fMRI) measures blood flow in the brain during different activities, providing information about the activity of neurons and thus the functions of brain regions.
Transcranial magnetic stimulation (TMS) is used to temporarily and safely deactivate a small brain region, with the goal of testing the causal effects of the deactivation on behavior.

Exercise and Critical Thinking

Consider the different ways that psychologists study the brain, and think of a psychological characteristic or behavior that could be studied using each of the different techniques.

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Diamond, M. C. (1999). Why Einstein’s brain? New Horizons for Learning . Retrieved from http://www.newhorizons.org/neuro/diamond_einstein.htm

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Introduction to psychology, methods of studying the human brain.

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New state of mind: rethinking how researchers understand brain activity.

Understanding the link between brain activity and behavior is among the core interests of neuroscience. Having a better grasp of this relationship will both help scientists understand how the brain works on a basic level and uncover what specifically goes awry in cases of neurological and psychological disease.

One way that researchers study this connection is through what are known as “brain states,” patterns of neural activity or connectivity that emerge during specific cognitive tasks and are common enough in all individuals that they become predictable. Another, newer, approach is the study of brain waves, rhythmic, repetitive patterns of brain cell activity caused by synchronization across cells.

In a new paper, two Yale researchers propose that these two ways of thinking about brain activity may not represent separate events but two aspects of the same occurrence. Essentially, they suggest that though brain states are traditionally thought of as a snapshot of brain activity while waves are more like a movie, they’re capturing parts of the same story.

Reconsidering these two approaches in this context, the researchers say, could help both fields benefit from the methods and knowledge of the other and advance our understanding of the brain.

Inspired by ecological, conservation, and Indigenous philosophies, Maya Foster, a third-year Ph.D. student in the Department of Biomedical Engineering, began pursuing this idea once she joined the lab of Dustin Scheinost , an associate professor in the Department of Radiology and Biomedical Imaging at Yale School of Medicine.

They are co-authors of the new paper , published April 5 in the journal Trends in Cognitive Sciences.

“ We’re arguing that rather than a brain state being one single thing, it’s a collection of things, a collection of discrete patterns that emerge in time in a predictable way,” she said.

In an interview with Yale News, Foster and Scheinost describe their proposal, and discuss how they might help researchers better understand the mysteries of the brain. This interview has been edited and condensed.

When did you start to consider these might be two aspects of the same occurrence?

Maya Foster: This has been on my mind even before I came to this lab. I was reading a book — “Erosion: Essays of Undoing” by Terry Tempest Williams — and she talks about how human-made machinery like helicopters cause vibrations that interrupt the natural pulse of things and cause things like rock formations to fall apart. Relatedly, there are a lot of Indigenous populations that believe everything has a pulse. And that got me thinking of the brain and whether we have some type of resonance or vibration that can be disrupted.

Then I joined this lab and Dustin let me experiment with a lot of different things. During one of those experiments, I input some data into a particular analysis and the outputs looked wave-like, and patterns emerged and then repeated. That took me down a whole rabbit hole of research literature and there was a lot of evidence for this idea of wave-like patterns in brain states.

What are the benefits of considering brain states as wave-like?

Foster: I think it creates a synergy where both sides — the brain state folks and the brain wave folks — benefit by learning from each other. And maybe the gaps in knowledge we have now when it comes to how brain activity relates to behavior might be filled by both groups working together.

Dustin Scheinost: Brain waves are newer in this field and they’re complex. And any time you can take something new and relate it to something old — brain states in this case — it gives you a natural jumping off point. You can bring along everything you’ve learned so far. It’s kind of like not throwing the baby out with the bath water. We don’t need to drop brain states. They’ve informed us, but we can go in a different direction with them too.

How are you proposing researchers consider brain states and brain waves now?

Foster: Borrowing from physics, when you analyze light, it can be a discrete point — a photon — or it can be wave-like. And that’s one way we’re thinking about this. Similarly, depending on how you analyze brain states you can get static patterns, much like a photon, or you if you look at activity more dynamically, certain patterns start to occur more than once over time, kind of like a wave.

So we’re arguing that rather than a brain state being one single thing, it’s a collection of things, a collection of discrete patterns that emerge in time in a predictable way.

For example, if we measured four distinct patterns in brain activity as someone completed a cognitive task, a brain state could be that pattern one emerges, then pattern three, then two, then four, and that series might repeat over time. And when that repetition stops, that would be the end of that particular brain state.

You also draw comparisons to the musical technique known as “fugue.” How does that fit with how you’re visualizing these phenomena?

Foster: I’m a music person, so that’s where this came from. In a fugue, you have a basic melody and then that melody emerges later in the music in different forms and formats. For instance, the melody will play, then some other music comes in, then the melody returns with the same rhythm and time sequence but maybe it’s in a different key.

Fugues are cyclical and wave-like, they have distinct groups of notes, and there’s a systematic repetition and sometimes layering of the main melody. We’re arguing that brain states are also wave-like, have distinct patterns of brain activity, and display systematic repetition and layering of sequential patterns.

How are you hoping other researchers respond to your argument?

Foster: I would love feedback, honestly. There is evidence for what we’re proposing but when it comes to implementing these ideas going forward, it would be helpful to have a conversation about how that might work. There are a lot of different strategies and I’m interested in a broader conversation about how we as researchers might go about studying this.

What’s it like as someone who has been in this field for a while to have a student come in with a new idea like this?

Scheinost: You can get set in your ways as a researcher and you need new ideas, new creativity. Sometimes they may sound outlandish when you first hear them. But then you ruminate, and they start to take form. And it’s fun. That’s really where the fun of this job is, to hear new ideas and see how people discuss and debate them.

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Lesion studies in contemporary neuroscience

Avinash r. vaidya.

1 Department of Cognitive, Linguistic, and Psychological Sciences, Carney Institute for Brain Sciences, Brown University, Providence, RI, USA

Maia S. Pujara

2 Section on the Neurobiology of Learning and Memory, Laboratory of Neuropsychology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA

Michael Petrides

3 Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada

Elisabeth A. Murray

Lesley k. fellows.

Studies of humans with focal brain damage and non-human animals with experimentally induced brain lesions have provided pivotal insights into the neural basis of behavior. As the repertoire of neural manipulation and recording techniques expands, the utility of studying permanent brain lesions bears re-examination. Studies on the effects of permanent lesions provide vital data about brain function that are distinct from those of reversible manipulations. Focusing on work carried out in humans and nonhuman primates, we address the inferential strengths and limitations of lesion studies, recent methodological developments, the integration of this approach with other methods, and the clinical and ecological relevance of this research. We argue that lesion studies are essential to the rigorous assessment of neuroscience theories.

Lesion studies: A mainstay of neuroscience

Studying the effects of brain lesions on behavior and cognition is one of the most established and influential methods in neuroscience. In the 19 th century, case studies of patients with focal brain damage provided the first evidence that complex cognitive processes, such as those underlying language, have dissociable components that depend on different regions of the brain [ 1 , 2 ]. Brain lesion studies constituted the foundation of cognitive neuroscience that emerged in the mid to late 20 th century. This included seminal work such as Brenda Milner’s demonstration that memory, like language, involves distinct component processes with their own neural substrates [ 3 , 4 ], as well as the work of Mortimer Mishkin and Leslie Ungerleider on the dissociable contributions of the dorsal and ventral visual pathways in nonhuman primates (NHPs; see Glossary) [ 5 , 6 ]. These investigations helped to inspire decades of influential new ideas: cognitive theories, intrepid studies of neural activity, and new models of brain function (e.g., [ 7 , 8 , 9 , 10 ]). Studies of subjects with focal lesions have since continued to provide fundamental insights in the fields of learning [ 11 , 12 ], cognitive control [ 13 , 14 , 15 , 16 ], social behavior [ 17 , 18 ], memory [ 19 , 20 , 21 , 22 ], and more.

The advent of new neural manipulation methods, both invasive (e.g., optogenetics, chemogenetics) and noninvasive (e.g., transcranial magnetic stimulation, TMS; transcranial focal ultrasound), and the explosion of increasingly sophisticated functional neuroimaging methods, such as positron emission tomography (PET), functional magnetic resonance imaging (fMRI), and electrophysiological measures of neural activity, calls for a critical re-examination of the strengths and limitations of chronic, focal lesion studies. The purpose of this article is to evaluate the role of lesion methods as they relate to other causal and correlative methods in the toolkit of contemporary cognitive and systems neuroscience. Specifically, we discuss four topics: (i) inferences that can be made from lesion studies compared to other methods, (ii) combining lesion studies with correlative methods, (iii) recent advances in lesion methods, and (iv) lesion studies outside the laboratory. Although many of the points raised here may apply to other animal models, we focus on evidence from humans and NHP lesion studies given the similarities between the neuroanatomy of NHPs and humans in terms of cortical expansion [ 23 , 24 ] and topographical connections (e.g., corticocortical [ 24 , 25 ] and corticobasal ganglia pathways [ 26 ]). Our goal in focusing on humans and NHPs is to highlight the similarities of lesion findings in these models and to emphasize how invasive lesion studies in NHPs have been essential in filling inferential gaps in this work. We conclude that (i) chronic lesion studies provide unique, vital insights into brain function that cannot be achieved via temporary inactivation methods or correlational studies of brain activity, and (ii) integrating insights gleaned from lesion studies with results from other methods is crucial for advancing neuroscience.

What inferences can lesion studies support?

Studies of brain activity, either through electrophysiology, fMRI, PET, or other methods, test whether cognitive processes are associated with activity in neurons, brain regions, or networks. These techniques comprise a powerful set of investigative tools but cannot differentiate the regions that are involved during some cognitive process from those that are necessary for that process. This limitation cannot be addressed by further methodological refinement [ 27 ]. In contrast, lesion studies can demonstrate the necessity of a region for a particular cognitive process, not just its mere association with that process. In well-designed studies, null results can be equally informative for constraining neuroscientific theories, particularly when data from other methods (e.g., correlations between a behavioral task condition and neural activity) suggest that a lesion in a specific region should impair an associated behavior. Recent examples of informative null findings include demonstrations that excitotoxic lesions of orbitofrontal cortex (OFC) do not affect stimulus reversal and probabilistic reinforcement learning in NHPs [ 28 , 29 ], that dorsal anterior cingulate cortex (ACC) damage in humans does not affect behavioral indices of response conflict [ 13 , 30 , 31 ], that humans with ventromedial prefrontal cortex (vmPFC) damage can make choices consistent with their subjective preferences [ 32 , 33 ], and that non-navigational spatial memory is unaffected by hippocampal damage in NHPs [ 34 ]. These findings challenge current models of brain–behavior relationships and push the field towards more refined hypotheses and better behavioral indicators of the processes in question. In the following section we describe key considerations in making inferences from lesion studies, the strengths and limitations of this approach, and how this method differs from others.

Methodological considerations for studies of focal lesions

In human subjects, lesions to a circumscribed brain area can occur following disease, injury, or neurosurgical treatment. Although the lesions are not under experimental control and can vary with regard to etiology, size, laterality, and age of onset, the selection of participants is. Anatomical specificity is determined by the inclusion and exclusion criteria for a given study, a balance between the anatomical region of interest (ROI), the natural patterns of common lesion causes, and pragmatic considerations of sample size and study duration. In NHPs, a focal lesion can be induced via surgical intervention by targeting a region within a predefined anatomical boundary, which affords greater experimental control. The accuracy of the lesion depends on the method used to create it and on experimenter skill. We elaborate on some of the key design considerations for lesion studies in Box 1 .

How to judge the inferential strength of a lesion study

A full description of best practices and available methods for designing a lesion study is beyond the scope of the present manuscript. Such resources can be found in the following references: [ 176 – 179 ]). Here, we briefly describe some of the key features to be considered:

Premorbid functioning

In humans, brain lesions are usually caused by a neurological event, such that data are rarely available about premorbid cognitive function (although see [ 180 , 181 ]). Clinical interviews, level of education, crystallized IQ, and questionnaires on pre- and postmorbid function can help to fill these gaps [ 182 , 183 ]. In NHPs, subjects with lesions may be compared to subjects with sham surgery, subjects with surgery in another location, or to their own presurgical performance when within-subject comparisons are possible. This latter form of control may also be possible in some rare cases in humans, such as when lesions are made as a planned course of treatment in psychiatric populations (e.g., [ 13 ] or in epilepsy). However, the patients undergoing these procedures are not neurologically healthy, which complicates inferences about ‘premorbid’ function.

Control groups

Comparing subjects with lesions to matched controls is critical for establishing the effects of these lesions. This control group should be demographically matched to the lesion group and recruited from the same population. However, there are other factors that accompany brain damage (e.g., use of psychoactive medication) that are not controlled for in these comparisons. Inclusion of a control group comprised of subjects with brain damage sparing the ROI can help account for these factors. In human subjects, lesions are often not constrained to the ROI, and a control group that shares damage outside the ROI can provide greater assurance that behavioral changes in the ROI group are anatomically specific.

Lesions in human patients are frequently confounded by features related to the source of damage. For example, ischemic stroke patients are more likely to have cerebrovascular disease and small, “silent” infarcts that may be associated with deficits unrelated to the lesion under study [ 184 ], while treatment for brain tumors may have additional neurological consequences (e.g. radiation therapy). The etiology of a lesion is also usually associated with the pattern of damage (e.g., strokes follow vascular branches). Including patients with diverse etiologies can mitigate these problems by reducing lesion covariance and decoupling deficits from a specific neurological disease.

Neuropsychological screening

Experimental tasks are never truly process-pure. For example, a “simple” reinforcement-learning task may depend on working memory, sustained attention, and reading comprehension. Neuropsychological screening tests that tap a wide range of functions can control for potential explanations and provide insight into the latent factors that underlie deficits.

Statistical power

As with many neuroscience methods, sample sizes tend to be low in neuropsychological studies of patients [ 185 ]. In studies of brain lesions in human patients, sample size is generally constrained by the difficulty of recruiting, screening and testing a special population of subjects. Dedicated registries of such patients can be one solution, but this requires on-going investment to recruit, assess and maintain such listings of potential research participants, much as centers must invest in supporting other methodological platforms (imaging, etc.) so that individual experiments can be carried out in a timely fashion [ 186 ]. Sample sizes are also small in studies of NHPs, mostly due to the costs of studying these animals. Given these constraints, statistical power in studies of human subjects can be most readily improved by testing a large sample of healthy control subjects, who are easier to recruit.

In both cases, destruction of brain tissue causes permanent loss of neurons and, therefore, termination of function in the affected region. Evidence that a lesion reliably alters a behavior (e.g., performance on a task where items must be retained in memory over a delay) can then be used to test a causal link between the brain region and the cognitive process underlying the behavior (e.g., memory). Demonstrating a link between a lesion and a behavioral process, however, is not trivial. A cognitive or behavioral change associated with a lesion must be disentangled from nonspecific symptoms that may accompany brain damage, and other potential sources of between-subject variance. Drawing conclusions from lesion studies depends on evaluating the functional and anatomical selectivity of behavioral changes (i.e., Does a lesion affect related behaviors? Are the effects specific to a certain region?). Dissociation logic, which we discuss in Box 2 , has been vital in this effort, not only in lesion studies, but in neuroscience more broadly.

Dissociation logic in lesion studies

In neuroscience, dissociation logic has played a central role in testing the specificity of region-function relationships. Testing whether a brain region is involved in function X but not function Y is helpful in that it provides stronger evidence for functional specificity than the demonstration of an association (i.e., showing that region A is involved in function X, without testing other functions). However, a single dissociation is still a relatively weak form of inference when these functions can be accounted for by a single process (e.g., if function X is simply a more demanding form of function Y). A crossover double dissociation can be used to make a stronger claim by demonstrating that region A is involved in function X but not Y, whereas region B is involved in Y but not X ( Figure I ) [ 187 ]. Even this case is not impervious to potential alternative single-process explanations [ 188 ].

In practice, true dissociations can be challenging to test and require careful consideration of control conditions to ensure that two processes are really independent. One criticism of this approach is that each task might engage the brain in a different way and hence potentially rely on a different set of regions, yielding increasingly granular task dissociations – and ultimately less meaningful distinctions [ 189 ]. This problem is not unique to lesion studies but speaks to a broader issue in neuroscience regarding whether theory should lump or split functions. Similar issues were raised regarding fMRI research that appeared to uncover an unending number of functional associations (i.e., Is there a specific brain network for playing board games? What about a network specific for playing checkers?). There is no easy solution to this problem. In any model-fitting exercise, adding parameters may explain more variance but will eventually hamper the generalizability of the model to new data. Similarly, there is an important trade-off in the number of functional dissociations a neuroscientific theory might make and its generalizability outside the experimental settings within which it was developed. That is to say, some dissociations may reveal more significant information about the specialization of brain regions and may also be more likely to stand the test of time than others. The choice of experimental question remains the most vital factor in determining whether an experiment is likely to uncover a crucial new functional dissociation with broader significance, or simply explain noise.

Figure I (Box 2):

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Y-axes indicate to performance in tasks measuring performance in Functions X and Y. Bars represent performance of control group and groups with lesions in regions A and B.

Compensatory processes in lesion studies

Brain damage causes immediate cognitive and behavioral changes, followed by a dynamic period of functional reorganization before subjects reach a chronic state where changes stabilize. In the hyperacute period immediately following injury, both humans and NHPs briefly suffer from the effects of brain edema and inflammation, which cause transient, diffuse brain dysfunction. In the subsequent weeks and months, during the acute phase of a lesion, functional recovery takes place through cellular- and systems-level processes that reorganize circuits at the site of the lesion [ 35 ], recruit redundant or alternative pathways, and modify an individual’s behavioral repertoire. While these compensatory processes are sometimes considered uninteresting as they may ‘mask’ deficits observed in the acute phase, they can also provide valuable information about the capacities and limitations of intact neural systems. For example, lesions to striate cortex cause major visual field impairments, but research over several decades has revealed that some basic visual processing is preserved (i.e., “blind-sight”) due to intact processing in separate pathways [ 36 ]. A lesion is considered chronic months or years after injury, when the effects of damage on brain function have stabilized. Critically, patients and NHPs tested years, or even decades, from the time of injury will show persistent behavioral deficits in specific tasks, such as the profound lifelong memory impairments caused by bilateral medial temporal lobectomy in patient H.M. [ 37 – 41 ]. Measuring behavior and neural activity at multiple time points in the course of recovery can help distinguish between behavioral and neural changes caused by acute chronic effects of a lesion [ 42 – 47 ].

The etiology of a lesion may also affect how the brain adapts to damage. For example, functional changes following brain damage as a result of stroke are most severe immediately after the event, with some recovery of function occurring rapidly, then reaching a plateau within about 6 months [ 48 , 49 ]. In contrast, brain tumors cause damage over a long period of time, through compression, distortion, or infiltration of tissue, as well as through edema, microcirculatory effects, and local electrolyte abnormalities [ 50 ], followed by the effects of surgical resection of the tumor. Whether the cognitive effects of brain tumors are comparable to those of stroke, particularly when the tumors are slow-growing and allow more time for plasticity to occur, has been a subject of debate [ 51 , 52 , 53 , 54 ], and comparison of single- and multistage lesions in animal models suggests that the rate of damage may affect outcome [ 55 ]. A recent study compared a large sample of frontal lobe-damaged patients with different lesion etiologies (stroke, fast and slow-growing tumors) in several executive function tests. Etiology was not a strong predictor of patients’ deficits in this sample [ 56 ]. Behavioral effects in the chronic phase of focal lesions thus may relate more closely to the region of damage than to etiology in human patients.

The rate at which brain development occurs varies across different brain regions or networks [ 57 ]. Cross-sectional and longitudinal developmental lesion studies provide essential information about how lesioning brain regions affects behavior during the course of brain maturation. For example, whereas amygdala damage acquired in infancy in NHPs permanently disrupts normative affective responses to stimuli with either positive and negative valence [ 58 ], it only mildly disrupts social cognition in the long term [ 59 ]. These results suggest that intact amygdala function across development is necessary for normal emotional, but not social, cognition throughout the lifespan. Adults who incurred vmPFC damage as infants show more exaggerated personality changes (e.g., increased impulsivity, insensitivity to punishment) compared to patients with adult-onset lesions to the same region, who show relatively milder and more subtle personality changes [ 60 ]. This work reveals the critical role of these regions for normal developmental trajectories of these complex traits and may provide insight into the processes that occur in developmental psychopathologies such as autism or oppositional defiant disorder.

Comparing chronic lesion methods and temporary manipulations of neural activity

Like lesion studies, manipulation methods (e.g., TMS, pharmacological agents, optogenetics, and chemogenetics) allow researchers to draw causal links between behavior and brain function. However, unlike lesion studies, manipulations of neural activity are temporary and reversible, providing temporal specificity and amenability to within-subject experimental designs. Manipulation methods can also be used to up- and down-regulate activity within a brain region to study how changing neural dynamics affects behavior. Advances in genetic tools have allowed neural manipulations of brain circuits to reach unprecedented levels of detail in rodents (e.g., optogenetics, chemogenetics). Application of genetic targeting technologies in NHPs are comparatively in their infancy but are advancing rapidly [ 61 , 62 ]. Applications of optogenetics in NHPs have so far been shown to produce transient or weak effects on behavior following perturbation of neuronal targets, findings that are in conflict with lesion or micro-stimulation results within the same regions [ 63 , 64 ]. Although the source of these differences remains unclear, these techniques hold great promise for advancing our understanding of the functional relevance of separable neural circuits.

Temporary manipulation methods are often assumed to recapitulate what is observed following chronic lesions. However, in practice these methods have fundamentally different effects on brain function that should be considered when drawing interpretations about causal brain-behavior relationships. A recent study in zebra finches elegantly demonstrated that these methods can potentially reach fundamentally different conclusions about the necessity of a region ( Figure 1 ) [ 65 ]. Temporary inactivation of a region of the zebra finch brain caused dramatic degradation of birdsong. However, birdsong recovered within days of a permanent lesion to the same region, with major impairments only observed briefly in the hours following damage. Behavioral recovery was associated with the rapid return of spontaneous activity in a region downstream of the lesion, which prior lesion work had established as necessary for normal behavior [ 66 ]. These data argue that temporary inactivation may mimic behavioral effects in the acute phase of a lesion, with potentially wide-ranging effects on activity and neural dynamics in distant regions.

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This schematic is based on the results of [ 65 ]. (1) In this hypothetical example, performance in a task is directly related to the function of region B, which processes crucial information from inputs coming from region A. Region B also receives inputs from region C that are not crucial to the process region B completes for task performance, but exert a separate, secondary influence on the homeostatic activity of this region. (2) Temporary inactivation of region C causes a perturbation of region B, which leads to a disruption of performance. (3) By contrast, permanently lesioning region C does not affect performance because of compensation in region B for the loss of this input. (4) However, a permanent lesion of region B causes a performance deficit that cannot be compensated for.

This example illustrates a key distinction between reversible manipulation and lesion methods that has become increasingly clear in recent years. Chronic lesions can reveal the necessary contributions of damaged brain regions that are not recovered by reorganization and plasticity [ 67 ]. Although temporary manipulations also reveal necessary functions of a region in the moment of a perturbance, these “off-target” effects disrupt homeostatic activity within the network of the affected region [ 68 – 71 ], and even coupling across multiple brain systems [ 72 ], placing the brain in a previously unencountered physiological state [ 73 ]. This is not to say that permanent lesions do not affect activity in regions distant from the site of damage, but instead, that these regions have had time to compensate to the effects of a lesion and reach a new homeostatic state of function. These approaches therefore provide complementary information about the necessity of a region for a given behavior, making them non-interchangeable, mutually informative tools in the neuroscience toolkit.

Converging evidence: Combining lesion studies with other methods

Since different methods provide unique information about the brain, combining methodological approaches yield critical new insights. In the following section, we discuss how combining lesion studies with recordings of neural activity uncovers the necessary contributions of the damaged region to function in distant parts of the brain, and how findings from lesion studies can be used to test hypotheses with other methods.

Combining lesion studies with measurements of brain activity

Methods for studying brain activity (e.g., fMRI, electrophysiology, and PET imaging) have grown tremendously in the past few decades and have benefitted from application of more sophisticated analytic approaches (e.g., multivariate pattern analysis, functional connectivity, model-based analyses) [ 74 , 75 , 76 , 77 ]. These studies have provided insight into the information represented by brain activity in different regions, and the time-course over which these representations interact and are maintained. These methods also demonstrate how this information is represented – that is, the code used by neurons for aspects of cognitive processing (e.g., the grid-like coding of space in the entorhinal cortex [ 78 ]). However, these methods cannot test the necessity or sufficiency of this activity for the cognitive processes under investigation. For example, the activity of neurons that discriminate expectancy of reward versus punishment does not necessarily indicate that these neurons have any direct bearing on making predictions about outcome value. Such an observation could, in principle, be made with high reliability over many studies, but these data would still not provide evidence that this pattern of activity is causally involved in value prediction per se . Methods that measure correlation between brain activity and behavior provide important information but, alone, they have unavoidable inferential limits.

Studying the effects of lesions on brain activity provides causal evidence for the contribution of a damaged brain region to functional processes measured in connected regions. For example, fMRI studies comparing vmPFC lesion patients to healthy controls demonstrated that vmPFC lesions result in decreased ventral striatum activity during monetary reward anticipation [ 79 ] and increased amygdala activity in response to aversive images [ 80 ]. A recent EEG investigation of patients with lateral PFC damage showed that the impairments of these subjects in switching between internally and externally directed attention was related to altered theta power during these attentional states [ 81 ]. In NHPs, functional recording techniques such as fMRI [ 82 , 83 , 84 ], PET imaging [ 85 ], and electrophysiology [ 86 , 87 , 88 ] have been used in conjunction with lesions to characterize causal functional interactions between brain regions. This direction of research promises to provide a better understanding of the causal roles that different brain regions play in the neural dynamics underlying cognitive processes.

Applications of lesion findings in other methodological approaches

Lesion evidence are fertile ground for new hypotheses about neural function that may be tested with other methods. Lesion studies in NHPs that demonstrated a double dissociation for the functions of mid- and posterior dorsolateral prefrontal cortex generated testable predictions about the function of homologous regions. Subsequent human functional imaging experiments confirmed the association of these regions with monitoring information in working memory and conditional selection between competing responses, respectively [ 89 – 92 ]. Similarly, studies of the contributions of perirhinal cortex to memory in macaques [ 93 , 94 ] led to a series of neuropsychological and fMRI studies in humans that continue to elucidate perirhinal cortex function today [ 95 , 96 ].

Building converging evidence depends on objective reference points that translate between methods and models. For example, lesion studies have long been used to direct neurophysiological recording studies, when a focal recording site must be chosen prior to chamber and electrode implantation. They can serve a similar role in functional imaging studies by motivating localization of function through ROI analyses [ 97 ], especially where statistical thresholding in a whole-brain analyses might obscure effects in smaller regions such as the amygdala or striatum. Coordinates for maximum density of lesion overlap, or results from voxel-based lesion-behavior mapping (described further in the following section), can also be used to define ROIs for functional imaging studies or targets for temporary manipulation studies. Unfortunately, these data are currently dispersed and hard to compare across studies. Collating these data in a meta-analytic platform similar to NeuroSynth ( http://neurosynth.org/ ), and hosting lesion masks and behavioral data in online repositories could help construct a bridge between lesion studies and these other methods. We discuss further applications for data sharing and open science in lesion studies in Box 3 .

The critical role of lesion studies in open science

As the scientific community embraces open science applications to make data and analytical tools accessible, researchers working with lesioned subjects should consider ways to collaborate and make provisions for data sharing. Here we outline the advantages of, and practical guidelines for, pursuing collaborative and open scientific methods in lesion work.

Given the rarity of subjects with brain lesions in both human and NHP studies, respectively, the long-term advantages of aggregate or cumulative data in a large database are three-fold: (1) Collaboration and open science can help overcome the oft-cited limitation of small, heterogeneous samples in lesion studies. (2) Repeated measures from the same subject over time can unearth insights on longitudinal changes in behavior from the time of damage onset and resolve unanswered questions regarding plasticity. (3) A larger sample of subjects will make it possible to clarify the effects of individual differences in lesion etiology, psychoactive medication, and other factors that can vary from study to study.

The primary goal is to create an online repository which only vetted researchers can access, to be able to pool data across multiple research sites. Practical guidelines for meeting this goal can be borrowed from the neuroimaging community. There are many databases for fMRI data, such as NeuroVault, OpenfMRI.org, LORIS, COINS, XNAT, NITRC, SciTran, PRIME-DE (exclusively for NHPs), and others, that accept and export their datasets organized according to a data organization standard called ‘brain imaging data structure’ (BIDS; http://bids.neuroimaging.io ) [ 190 , 191 , 192 , 193 , 194 , 195 , 196 ]. The BIDS standard is designed specifically for fMRI, but a similar standard could be created to organize essential data and metadata for lesion datasets, including lesion masks, VLBM coordinates, self-report measures, neuropsychological data from standard testing batteries, and experimental test results.

In practice, this will take concerted effort and collaboration from laboratories with access to lesion patients and NHPs with focal brain damage. There are several special ethical considerations in sharing these sensitive data from clinical populations, the main ones being the higher likelihood of subject identification given the rare nature of these cases, as well as subjects consenting to having their data being included in a larger database. Access control of such data, similar to that implemented for sensitive genomic information, could also limit risks to patient confidentiality. A resource of this nature, however, could accelerate the rate of discoveries that have yet to be made with existing datasets from lesion samples and provide powerful tools that the broader neuroscience community can use to focus their analyses.

Recent advances in lesion methods

Historically, lesion studies, particularly in humans, have been most closely associated with localizationist approaches to understanding behavioral and cognitive processes. However, no process can occur in a single region without relevant inputs and outputs. A complementary perspective emphasizes how these processes arise from interactions within networks of connected brain regions [ 98 ]. Methodological developments are allowing investigators to interrogate information from lesion studies in new ways — particularly in testing both network and regional hypotheses for brain functions. In the following section, we will describe some of the methodological advances that are opening up these lines of inquiry in humans, as well as complementary approaches that can be used in NHPs.

Lesion behavior mapping approaches in humans

Conventionally, chronic lesions are studied to test the role a region plays in a particular function, usually by comparing the effects of damage to one region against a control group of healthy subjects or subjects with damage to a different region ( Figure 2a ). In investigations of humans, variability in lesion size and extent is unavoidable, and subjects are typically classified into groups based on some a priori anatomical criteria, limiting the spatial resolution of these studies. Voxel-based lesion-behavior mapping (VLBM), or lesion-symptom mapping, takes advantage of the variability of lesions in human patients to make associations between lesions and behavioral performance without the constraint of an ROI ([ 99 – 102 ]; Figure 2b ). In its most common application, VLBM uses massive univariate statistics to compare the behavior of patients with damage in each voxel against all other patients in a dataset. This method can thus reveal where damage was most strongly associated with a change in behavior at a more granular level than is possible with group comparisons.

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In this network, each circular node represents, solid lines represent connections between these regions and dashed lines indicate broken connections between regions caused by a lesion. Nodes are mirrored on the left and right side, representing homologous regions in the right and left ‘hemispheres’ (LH/RH). a . Comparisons between groups with damage to different regions (red and blue nodes) can be used to infer the necessity of these regions for cognitive functions. b. Rather than rely on a priori groups, univariate lesion-behavior mapping (LBM) tests the association of damage with a function across a set of regions, yielding a continuous statistical map for the effect of damage at each location (i.e., the graded colored nodes) c. Multivariate LBM tests the association between a pattern of damage in multiple regions and an observed deficit rather than just any particular region. This method is thus more sensitive to distributed regions that may contribute to some function (i.e., multiple dark red nodes). d. Tract, or connection-based LBM instead tests how damage to specific connections within this network (i.e., red dashed lines) affect function. e . In NHPs, crossed unilateral lesions may be used to ensure that specific regions cannot interact within a hemisphere, allowing inferences about the necessity of this interaction for function.

Recently, several groups have developed multivariate VLBM methods that take a different approach to assessing the localization of function. Although the specific approaches differ, these methods generally test whether there is a consistent relationship between damage in some set of voxels, which may be close together or far apart, and a specific behavior ( Figure 2c [ 99 , 103 , 104 ]). Thus, while univariate VLBM tests for the strongest associations between a behavioral change and damage, multivariate approaches test which patterns of damage cause similar changes in behavior. Simulations have shown that this multivariate approach may be particularly useful in cases where damage in multiple regions causes behavior to change in a similar direction (e.g, if damage to the amygdala and OFC caused similar learning deficits). However, more work is needed to directly test how the distinct assumptions of these approaches impact the conclusions they may draw about brain-behavior relationships.

Lesion methods for testing network hypotheses

Many lesion studies aim to test whether damage to a specific gray matter region disrupts a particular behavior. In such cases, white matter damage is frequently treated as a nuisance variable that needs to be controlled for, or a limitation on the interpretation of the data. In contrast, other work has explicitly studied disconnection syndromes—that is, how damage to connections between two or more brain regions affects behavior [ 98 ]. In some cases, lesions may primarily affect white matter bundles, disrupting networks while leaving cortical and subcortical gray matter mostly intact. Although VLBM can test associations between white matter damage and behavior in principle, this method does not explicitly test the relationship between disruption of specific tracts, or region-to-region connections and behavior. Recently developed approaches have taken advantage of variability in white matter damage across human patients, and the development of diffusion-tensor imaging tools, to test specific causal relationships between disrupted connections and behavior specifically, using analyses akin to VLBM ( Figure 2d ). Tract-based lesion-behavior mapping uses white matter atlases in a standard brain space to test if behavioral changes are associated with lesions that interrupt major white matter bundles [ 105 ]. Connectome-based lesion-behavior mapping offers a somewhat different approach, using diffusion imaging from subjects with lesions to examine how deficits correlate with metrics of connectivity (e.g., probabilistic tractography) between pre-defined cortical ROIs [ 106 ]. However, these methods rely on certain assumptions in reconstructing white matter tracts (e.g., anisotropy of water diffusion, accurate registration of lesions to white matter atlases based on healthy controls), which impose limitations. Diffusion imaging methods can only provide best guesses for the structural connections between regions, and are affected by abnormalities and distortions of brain tissue, potentially affecting interpretation of these data in subjects with brain lesions [ 106 , 107 ]. Comparison of these estimates against post-mortem histological data may identify long-distance pathways that are difficult to identify with in vivo tractography alone and pathways where these tools are prone to errors [ 108 , 109 ].

Other work has focused on relating changes in functional connectivity after lesions to changes in behavior. These studies have taken two general approaches: either (1) examining how lesions affect functional connectivity in patients and relating these changes to behavior [e.g. 110 ], or (2) using information about functional connectivity in healthy subjects to predict the remote effects of brain lesions and testing the relationship between these predicted remote effects and behavior [ 111 , 112 ]. These tools yield additional insights into the role that network dynamics may play in behavior, beyond testing the contributions of any particular brain region. However, these functional connectivity measures have major limitations. As these measures are correlative, the direction of activity in both healthy and damaged brains is difficult to interpret. For example, changes in connectivity between regions A and B after a lesion to area C could result from either loss of common input from C to both A and B, loss of an input from C to just A or B, or loss of an input from C to an intermediary area D that connects with both A and B. Careful control measures of potential confounds and testing model assumptions also need to be taken into account in interpreting these data – for example, hemodynamic signal in fMRI studies might also be affected cerebrovascular disease [ 113 , 114 ].

Overall, these new tools are allowing investigators to advance the types of questions that can be asked about the relationships between lesions, brain networks, and behavior. However, parsing whether the behavioral effects of a lesion in a patient are due to loss of function within a damaged region, or depend on critical lines of communication between multiple regions in a network, remains a central challenge in this research. Unfortunately, available analysis tools do not allow these potential sources of variance to compete with each other in the same statistical model to explain the observed behavioral changes in lesion patients. For now, the focus on relating behavior to either network or regional effects of damage depends on the hypothesis tested in individual studies. Lesion-behavior mapping methods also require relatively large samples for sufficient regional coverage and statistical power, which can act as a practical limitation in their use given the challenges of recruiting participants with focal lesions.

Complementary approaches in NHPs for testing regional and network roles

Complementary studies in NHPs can rule out separate contributions of white matter and grey matter to cognitive functions [ 115 ]. In recent decades this work has been crucial for refining our understanding of the functions of several brain regions. Two major surgical techniques have been used in NHP work to create focal lesions: aspiration and excitotoxic approaches. Aspiration lesions employ subpial suction and cauterization of tissue, typically under visual guidance with the aid of an operating microscope. In some cases, aspiration lesions affect not only cortex (grey matter) but also axons coursing nearby or through that region (fibers of passage). The extent of this injury depends on the location of the aspirated region and geometry of the underlying white matter tracts. By comparison, excitotoxic lesions induced by local injection of neurotoxins are more selective than aspiration lesions, destroying cell bodies while sparing the underlying fibers of passage. These distinctions, that are practically testable only in animal models, are important for providing evidence about the causal roles of cortical regions in the observed deficits (via excitotoxic damage) versus their connections and interactions (via aspiration damage).

Investigations in NHPs also yield information about regional specializations at a higher resolution than is possible in studies of human patients. Fine-grained targeting of smaller brain regions in NHPs is especially useful for investigating functions of subregions within larger cortical structures (e.g., the orbital and ventromedial regions of prefrontal cortex) that tend to be damaged together in human lesion studies and are known to differ in cytoarchitecture and connectivity to other regions [ 116 ]. For example, studies of working memory in patients with frontal lobe damage encompassing several cytoarchitectonic areas revealed impairments in both monitoring within working memory and making conditional selections between competing stimuli [ 117 , 118 ]. However, experiments with more selective lesions in NHPs were able to show that these functional contributions depended on distinct subregions within the dorsolateral prefrontal cortex [ 89 , 90 ]. Researchers have similarly used lesions in NHPs to dissociate contributions of sub-regions of PFC in value-based decision-making [ 42 , 119 , 120 ], regulating defensive responses to threatening stimuli [ 121 , 122 ], and social cognition [ 123 , 124 ]. These studies in NHPs are highly valuable for constraining search spaces in whole-brain neural recording methods or suggesting target sites for clinical treatments (e.g., as in [ 125 ]).

In animal models, the necessity of interactions between different regions can be tested directly through surgically severing specific white matter tracts in some cases (e.g., the corpus callosum or the fornix) or through crossed unilateral lesions in the two hemispheres. Crossed-surgical disconnection lesions leave a single brain region in both hemispheres intact but prevent these regions from interacting within the same hemisphere (e.g., [ 43 ]). This technique can answer questions about functional interactions between two, or more [ 126 ], brain regions ( Figure 2e ). Investigations employing crossed-surgical disconnection methods have been informative in supporting circuit interaction models for processes such as value-based decision-making [ 43 , 126 – 128 ], discrimination learning [ 129 – 131 ], and memory [ 132 ].

Lesion studies outside the laboratory

Applying neuroscientific research findings for diagnosis and treatment of many neurological and psychiatric disorders is complicated by the radical complexity of behavior outside of the laboratory and the challenge of relating these behaviors to operationalizable cognitive processes. In the following section, we describe how lesion studies can connect basic and clinical neuroscience and provide important insights into real-world behaviors.

The role of lesion studies in the clinic

Lesion studies form a unique bridge between basic and clinical neuroscience. Although we have primarily focused on lesion studies in basic science, these findings may also translate into improvements in patient care. Lesion studies directly relate brain dysfunction — in the form of a lesion — to behavioral deficits. Similarly, manipulations of brain activity in NHPs or humans can be used to test causal predictions about relationships between brain activity and behavioral and cognitive symptoms in psychiatric populations [ 133 , 134 ]. Most immediately, these studies inform neuropsychologists and physicians about likely cognitive impairments in neurological disease, guiding prognosis and treatment [ 135 ]. Information gleaned from lesion studies in NHPs can identify potential loci for neurosurgical interventions (e.g., deep brain stimulation), noninvasive manipulations (e.g., TMS) to treat neurological and psychiatric diseases [ 136 , 137 ], and follow-up studies to reveal the pharmacological, physiological and molecular mechanisms underlying a behavior.

Lesion studies also provide a vital bridge in the other direction: linking behavioral deficits to neurobiology. Importantly, brain lesions are not a model of ‘induced’ psychiatric diseases. Although neurological lesion patients and psychiatric patients may have overlapping symptomatology, the correspondence of symptoms is not complete, the etiologies are very different, and there is far less regional specificity underlying dysfunction in psychiatric disorders [ 138 – 140 ]. However, principled identification of common and distinct deficits in psychiatric and neurological patients could be a promising route for better understanding the neurobiological origins of psychiatric symptoms. Uncovering common deficits in focal brain lesions and psychiatric disorders is in keeping with the goal of symptomatic and neurobiological classifications for psychiatric disease [ 141 ]. For example, parallels between the specific social deficits in humans and NHPs with amygdala lesions and people with autism spectrum disorders have provided clues about the neurobiological basis of the latter [ 142 – 144 ]. Finding common cognitive tests or computational principles that link behavioral deficits in lesion patients and psychiatric populations may establish vital connections between neurobiology, cognition, and behavior [ 145 , 146 ].

Studying real and realistic behavior in lesion studies

The ecological validity of experimental tasks designed to investigate specific constructs in neuroscience is sometimes called into question (e.g., [ 147 ]). Lesion studies can uniquely shed light on how specific brain regions support complex cognitive constructs such as personality, morality, aesthetic valuation, and insight, by examining the behavior of subjects with lesions in naturalistic and semi-naturalistic contexts. Verbal, written, and pictorial responses by subjects with brain damage have a long history in neuropsychological research and have revealed the effects of damage on memory [ 148 ], perception [ 149 ], problem solving [ 150 ], and scene construction [ 151 , 152 ]. Such data shed light on cognitive impairments that simpler behavioral readouts (e.g. binary choices, reaction times) cannot easily access. Although the topic of ecologically valid methods in human neuropsychology has been discussed in depth [ 153 ], here we highlight work that involves individual case studies and semi-naturalistic experiments to expand on information gathered from empirically-driven studies of these processes.

Simulating real-world semi-naturalistic contexts allows the effects of lesions to be studied closely in a setting that is perhaps more ecologically meaningful than structured laboratory tasks. For example, the “Multiple Errands Test” (MET) was designed to mimic various “real world” demands on planning, such as shopping for various objects (e.g., a cookie, a candle) under specific efficiency constraints (e.g., spending as little money and time as possible) — behaviors which were thought to be affected by frontal lobe damage [ 154 ]. Patients with vmPFC damage showed more errors on the MET and fewer overall completions of the task compared to healthy controls [ 155 ]. Likewise, Patient S.M., who had exclusive, bilateral damage to her amygdalae as a result of a congenital condition, had shown impairments on several laboratory tests of fear expression [ 156 ]. Based on this evidence, S.M. was taken through several real-world settings known to induce fear in normal subjects, such as a haunted house and a pet shop to handle live snakes and spiders [ 157 ]. As predicted, though S.M. expressed feelings of arousal, she did not display the typical ‘fear’ or defensive responses characteristic of normal individuals. These experiments allow a greater appreciation of the function of brain regions in the real world that cannot be easily captured in laboratory settings, and help refine an understanding of what parameters are essential to include in structured experimental tasks.

Tests using naturalistic stimuli or settings have also been developed to characterize deficits in higher-order processes following lesions in NHPs. While a manual test apparatus found no deficit in spatial memory in macaques with hippocampal lesions [ 158 ], an analagous foraging task involving navigation revealed this region was essential for memory of spatial [ 159 ]. Similar to the test of S.M., unconditioned behavioral responses to common predators such snakes and spiders have been tested in NHPs reared in the laboratory [ 160 ]. Remarkably, amygdalectomized NHPs show a fascination with snake stimuli that is reminiscent of the behaviors observed in patient S.M. [ 161 ]. In an yet more dramatic demonstration of the essential role of the amydala for survival, an early study released six NHPs with amygdala lesions that into the wild. Four of these animals failed to show appropriate social behaviors, were rejected from social groups, and eventually died as a result [ 162 ]. Less constrained tests in such cases may be more sensitive in detecting behavioral deficits and uncovering brain-behavior relationships than more structured tasks.

New and emerging technologies hold promise for advancing naturalistic experiments and generating rich behavioral data both inside and outside the laboratory. Virtual reality (VR) systems can be used to parametrize semi-naturalistic experiments by simulating real-world settings [ 163 , 164 ]. For example, the MET task described above was recently adapted for a VR environment [ 165 ] and has been used to test stroke patients [ 166 ], patients with Parkinson’s Disease [ 167 ], and patients with obsessive-compulsive disorder [ 168 ] and could therefore be used to replicate and build on the findings previously described in vmPFC lesion patients and other lesion groups. Researchers have already started employing VR tasks in studies of NHPs to study spatial memory and navigation, specifically as it relates to foraging behaviors [ 169 ]. In addition to VR, smartphones and wearable biosensors (and implantable biosensors, in the case of NHPs) are providing new means of studying behavior, either through experience sampling [ 170 ] or measuring movement and physiology [ 171 – 173 ]. These technologies have been used minimally in NHPs and have not yet been applied to test human patients [ 133 , 137 ] but may be especially useful for studies of mind-wandering, mood, sleep, memory, and decision-making.

Concluding Remarks

In this review, we have described the inferential strengths and weaknesses of the lesion method and contextualized this approach in the larger methodological toolkit available to neuroscience researchers. As with all neuroscientific methods, lesion studies have certain limitations and opportunities for improvement (see “ Outstanding Questions ” box). As neuroscientists, our primary goal remains building and testing useful models of function that can account for what we can learn through all available methods. We believe that this goal is better served by triangulating evidence from termination, manipulation, and correlational methods to provide convergent, complementary, or divergent evidence for theories of brain function ( Figure 3 ) [ 174 ]. Models that can accommodate data from diverse methods should be preferred, as they are robust to different forms of evidence and supported by multiple lines of inquiry [ 175 ]. Any model that is based on data solely from one method, even across multiple experiments, is less likely to capture the contributions of a region or network given the complicated spatiotemporal dynamics of brain function and the inferential limitations of each approach. The future challenges of neuroscience will demand a “divide and conquer” solution where models are tested with multiple approaches simultaneously. Successfully implementing this goal will depend on researchers who are focused on different methods and model systems working together towards convergent hypothesis testing. We anticipate that this review will facilitate that exchange by providing a contemporary guide on what lesion studies contribute to neuroscience research.

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Popular neuroscientific methods are sorted by the type of information they provide about brain function. Termination methods involve irreversible changes in brain function through the destruction of some brain region or pathway (via a lesion), neurons with particular characteristics (via a neurotoxin such as MPTP), or vulnerable systems (in neurodegenerative diseases such as Huntington’s disease). Manipulation methods include perturbation techniques that reversibly change brain activity (e.g., optogenetics). Correlation methods include techniques for measuring brain activity and testing the association between this activity and different behaviors and task performance (e.g., task-related fMRI). Triangulating evidence from each of these methods can build a better understanding of brain functions. Abbreviations: DREADD, designer receptor exclusively activated by designer drugs; M/EEG, magnetoencephalography/electroencephalography; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; (f)MRI, (functional) magnetic resonance imaging; PET, positron emission tomography; tDCS, transcranial direct current stimulation; TMS, transcranial magnetic stimulation.

Outstanding questions for future research

What is the extent of neuronal plasticity after damage? Is plasticity equivalent between brain areas or are some fundamentally more ‘plastic’ than others?
Genetic techniques have predominantly been used to create tools that can manipulate neuronal function. How might these tools also be used to test the effects of termination of function within specific cell types or selectively lesion circuits with greater specificity than currently available methods?
How might we use emerging models of brain networks to generate hypotheses for lesion results and test cognitive neuroscience models?
Lesions in human subjects typically affect both gray and white matter; however, the effects of this damage are usually examined separately depending on the study question. How can we best test the effects of a lesion on behavior within a single statistical model that appropriately attributes variance to damage within regions or their connections?
How can we better compare experiments across laboratories? How can we achieve a stronger track record of replicating work across multiple research groups working with different sets of subjects?
What kind of meta-analytic tools can we use to synthesize published data across lesion studies in humans and NHP? For example, could comparative anatomy be used to place these data into a common framework that would allow more direct comparison of findings?
In most cases, the judgment of a single rater remains the gold standard in registering lesions to a common brain space. Automated tools for lesion analysis have been showing more promise but remain impractical in many cases (e.g., when research-grade MRI scans or images without major distortions or artifacts are not available). Therefore, can we develop better tools for segmenting and registering the extent of lesion damage in humans and NHP?
How can we better study the rich behavior of lesion subjects outside of constrained laboratory settings? How might these data be used to inform development of neuropsychological tests or be used in conjunction with these tests in clinical assessments?

Highlights/Trends Box

Lesion studies have been fundamental to many core theories in cognitive and behavioral neuroscience.
Lesion work in human and nonhuman primate lesion studies has unique inferential strengths that are distinct from temporary manipulations or correlative measures of neural activity.
New methodological developments are underway that are expanding the range of questions that can be tested in studies of subjects with brain lesions.
Lesion studies form a critical bridge between basic science and behavior in the clinic and real-world settings.
Testing theories with multiple lines of evidence using different approaches, including lesion studies, manipulations of neural activity, and correlations with neural activity, will be essential to the future of neuroscience.

Acknowledgements

We thank Dr Sébastien Tremblay for providing the original impetus for this review and for helpful insights and comments. We also thank Drs Vincent Costa and Linda Yu for constructive comments and suggestions on drafts of this manuscript. This work was supported by funding from the National Institute for Mental Health (NIMH, grants ZIA MH00288712 and F32 MH116592-01A1), the Canadian Institutes of Health Research (CIHR, grants FDN-143212 and PJT 159554), the Natural Sciences and Engineering Research Council of Canada (NSERC, RGPIN 06-066, RGPIN-2019-05176), and the Canada First Research Excellence Fund (Healthy Brains for Healthy Lives).

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How Our Brains Work: Connecting Lab-Grown Brain Cells Yields New Insights

By Institute of Industrial Science, The University of Tokyo April 11, 2024

Researchers from the Institute of Industrial Science, The University of Tokyo, find that providing lab-grown ‘cerebral organoids’ with connections similar to those in real brains enhances their development and activity. Credit: Institute of Industrial Science, The University of Tokyo

A collaborative research team has developed a method to connect lab-grown brain tissues, enhancing the understanding of brain development and functions, and paving the way for potential advancements in treating neurological conditions.

The idea of growing a functioning human brain-like tissues in a dish has always sounded pretty far-fetched, even to researchers in the field. Towards the future goal, a Japanese and French research team has developed a technique for connecting lab-grown brain-mimicking tissue in a way that resembles circuits in our brain.

Advancements in Neural Studies

It is challenging to study exact mechanisms of the brain development and functions. Animal studies are limited by differences between species in brain structure and function, and brain cells grown in the lab tend to lack the characteristic connections of cells in the human brain. What’s more, researchers are increasingly realizing that these interregional connections, and the circuits that they create, are important for many of the brain functions that define us as humans.

Previous studies have tried to create brain circuits under laboratory conditions, which have been advancing the field. Researchers from The University of Tokyo have recently found a way to create more physiological connections between lab-grown “neural organoids,” an experimental model tissue in which human stem cells are grown into three-dimensional developmental brain-mimicking structures. The team did this by linking the organoids via axonal bundles, which is similar to how regions are connected in the living human brain.

Enhanced Understanding Through Innovation

“In single-neural organoids grown under laboratory conditions, the cells start to display relatively simple electrical activity,” says co-lead author of the study Tomoya Duenki. “when we connected two neural organoids with axonal bundles, we were able to see how these bidirectional connections contributed to generating and synchronizing activity patterns between the organoids, showing some similarity to connections between two regions within the brain.”

The cerebral organoids that were connected with axonal bundles showed more complex activity than single organoids or those connected using previous techniques. In addition, when the research team stimulated the axonal bundles using a technique known as optogenetics, the organoid activity was altered accordingly and the organoids were affected by these changes for some time, in a process known as plasticity.

“These findings suggest that axonal bundle connections are important for developing complex networks,” explains Yoshiho Ikeuchi, senior author of the study. “Notably, complex brain networks are responsible for many profound functions, such as language, attention, and emotion.”

Given that alterations in brain networks have been associated with various neurological and psychiatric conditions, a better understanding of brain networks is important. The ability to study lab-grown human neural circuits will improve our knowledge of how these networks form and change over time in different situations, and may lead to improved treatments for these conditions.

Reference: “Complex activity and short-term plasticity of human cerebral organoids reciprocally connected with axons” by Tatsuya Osaki, Tomoya Duenki, Siu Yu A. Chow, Yasuhiro Ikegami, Romain Beaubois, Timothée Levi, Nao Nakagawa-Tamagawa, Yoji Hirano and Yoshiho Ikeuchi, 10 April 2024, Nature Communications . DOI: 10.1038/s41467-024-46787-7

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1 comment on "how our brains work: connecting lab-grown brain cells yields new insights".

Consider finding relationships defining the evolution of flux lines in terms of Hebbian-type (“wire together if firing together”) learning rules. A recent article on the strong force over extended distances reminded me of this idea. As a strong force coupling remains constant over increasing distances it could be concluded that a conserved (wired-together”) entanglement-based flux line effect is demonstrated. Seems with gravity the same effect, suggestive of slowly-growing DM filaments, could be shown best with two separated spinning masses sharing the same spin axis over sufficient time scales.

FWIW, there’s never a shortage of dubious people who prefer to see gravity as non-quantizable. Most are apparently on a low-quality zero-information political mission to point people away from simple obvious things such as Newton’s inverse-square rule being a flux rule, or the lack of logic in applying an energy balance over a system with multiple simultaneous rates of time, just as they simply are too embarrassed to admit gravity bends light by changing its velocity.

5.4 Psychologists Study the Brain Using Many Different Methods

Charles Stangor and Jennifer Walinga

Learning Objective

Compare and contrast the techniques that scientists use to view and understand brain structures and functions.

Lesions Provide a Picture of What Is Missing

It is now known that a good part of our moral reasoning abilities is located in the frontal lobe, and at least some of this understanding comes from lesion studies. For instance, consider the well-known case of Phineas Gage (Figure 5.16) , a 25-year-old railroad worker who, as a result of an explosion, had an iron rod driven into his cheek and out through the top of his skull, causing major damage to his frontal lobe (Macmillan, 2000). Although, remarkably, Gage was able to return to work after the wounds healed, he no longer seemed to be the same person to those who knew him. The amiable, soft-spoken Gage had become irritable, rude, irresponsible, and dishonest. Although there are questions about the interpretation of this case study (Kotowicz, 2007), it did provide early evidence that the frontal lobe is involved in emotion and morality (Damasio et al., 2005). More recent and more controlled research has also used patients with lesions to investigate the source of moral reasoning. Michael Koenigs and his colleagues (Koenigs et al., 2007) asked groups of normal persons, individuals with lesions in the frontal lobes, and individuals with lesions in other places in the brain to respond to scenarios that involved doing harm to a person, even though the harm ultimately saved the lives of other people (Miller, 2008). In one of the scenarios the participants were asked if they would be willing to kill one person in order to prevent five other people from being killed. As you can see in Figure 5.17, “The Frontal Lobe and Moral Judgment,” they found that the individuals with lesions in the frontal lobe were significantly more likely to agree to do the harm than were individuals from the two other groups.

Frontal Lobe and Moral Judgment graph. Long description available.

Recording Electrical Activity in the Brain

In addition to lesion approaches, it is also possible to learn about the brain by studying the electrical activity created by the firing of its neurons. One approach, primarily used with animals, is to place detectors in the brain to study the responses of specific neurons. Research using these techniques has found, for instance, that there are specific neurons , known as feature detectors , in the visual cortex that detect movement, lines and edges, and even face s (Kanwisher, 2000).

A less invasive approach, and one that can be used on living humans, is electroencephalography (EEG), as shown in Figure 5.18. The EEG is a technique that records the electrical activity produced by the brain’s neurons through the use of electrodes that are placed around the research participant’s head. An EEG can show if a person is asleep, awake, or anesthetized because the brainwave patterns are known to differ during each state. EEGs can also track the waves that are produced when a person is reading, writing, and speaking, and are useful for understanding brain abnormalities, such as epilepsy. A particular advantage of EEG is that the participant can move around while the recordings are being taken, which is useful when measuring brain activity in children, who often have difficulty keeping still. Furthermore, by following electrical impulses across the surface of the brain, researchers can observe changes over very fast time periods.

Peeking inside the Brain: Neuroimaging

Although the EEG can provide information about the general patterns of electrical activity within the brain, and although the EEG allows the researcher to see these changes quickly as they occur in real time, the electrodes must be placed on the surface of the skull, and each electrode measures brainwaves from large areas of the brain. As a result, EEGs do not provide a very clear picture of the structure of the brain. But techniques exist to provide more specific brain images. Functional magnetic resonance imaging (fMRI) is a type of brain scan that uses a magnetic field to create images of brain activity in each brain area . The patient lies on a bed within a large cylindrical structure containing a very strong magnet. Neurons that are firing use more oxygen, and the need for oxygen increases blood flow to the area. The fMRI detects the amount of blood flow in each brain region, and thus is an indicator of neural activity. Very clear and detailed pictures of brain structures can be produced via fMRI (see Figure 5.19, “fMRI Image”). Often, the images take the form of cross-sectional “slices” that are obtained as the magnetic field is passed across the brain. The images of these slices are taken repeatedly and are superimposed on images of the brain structure itself to show how activity changes in different brain structures over time. When the research participant is asked to engage in tasks while in the scanner (e.g., by playing a game with another person), the images can show which parts of the brain are associated with which types of tasks. Another advantage of the fMRI is that it is noninvasive. The research participant simply enters the machine and the scans begin. Although the scanners themselves are expensive, the advantages of fMRIs are substantial, and they are now available in many university and hospital settings. The fMRI is now the most commonly used method of learning about brain structure.

Research Focus: Cyberostracism

Key Takeaways

Studying the brains of cadavers can lead to discoveries about brain structure, but these studies are limited because the brain is no longer active.
Lesion studies are informative about the effects of lesions on different brain regions.
Electrophysiological recording may be used in animals to directly measure brain activity.
Measures of electrical activity in the brain, such as electroencephalography (EEG), are used to assess brainwave patterns and activity.
Functional magnetic resonance imaging (fMRI) measures blood flow in the brain during different activities, providing information about the activity of neurons and thus the functions of brain regions.
Transcranial magnetic stimulation (TMS) is used to temporarily and safely deactivate a small brain region, with the goal of testing the causal effects of the deactivation on behaviour.

Exercise and Critical Thinking

Consider the different ways that psychologists study the brain, and think of a psychological characteristic or behaviour that could be studied using each of the different techniques.

Image Attributions

Figure 5.16: “ Phineas gage – 1868 skull diagram ” by John M. Harlow, M.D. (http://it.wikipedia.org/wiki/File:Phineas_gage_-_1868_skull_diagram.jpg) is in the public domain.

Figure 5.18: “ EEG cap ” by Thuglas (http://commons.wikimedia.org/wiki/File:EEG_cap.jpg) is in the public domain .

Figure 5.19: Face recognition by National Institutes of Health (http://commons.wikimedia.org/wiki/File:Face_recognition.jpg) is in public domain.