Chapter 7

Why are resting-state measurements useful to researchers?

Resting-state images in PET and rs-fMRI can identify abnormalities in brain function. rs-fMRI can also identify functional connections in the resting brain.

Resting-state MRI (rs-MRI)

The living brain is always active. rs-MR is used to infer brain function and connectivity by studying fMRI signals when participants are "resting" (i.e., not engaged in any specific task).

Compensation

The neuroplastic ability to modify behavior from that used prior to the damage

Ethology

The objective study of animal behavior, especially under natural conditions

Stereotaxic apparatus

This instrument allows the precise positioning of all brain regions relative to each other and to landmarks on the skull.

Optogenetics

Transgenic technique that combines genetics and light to control targeted cells in living tissue Based discovery that light can activate proteins

chemogenetics

Transgenic technique that combines genetics and synthetic drugs to activate targeted cells in living tissue.

Using Animals in Brain-Behavior Research

Two important issues Do animals actually contract the same neurological diseases as humans? How ethical is it to use animals in research?

Brain lesions

Used by Karl Lashley (1920s) to find location of memory in the brain Ablation: removal or destruction of tissue Scoville removed the hippocampus from H. M. to treat epilepsy (produced amnesia). Substantia nigra ablated to study Parkinson disease.

Laboratory animals can model some disorders, such as stroke, but are less useful for modeling most ____ disorders, such as ADHD, because it is difficult to re-create the human-specific conditions for these disorders.

behavioral

Concentrations of different chemicals in the brain can be measured in postmortem tissue using a(n) ____ or in vivo using ____ or ____.

biochemical; in either order: microdialysis; voltammetry

In addition to imaging the density of different brain regions, CT and MRI can be used to assess ____.

brain injury or brain damage

Guidelines of the Canadian Council on Animal Care

1. The use of animals in research, teaching, and testing is acceptable only if it promises to contribute to the understanding of environmental principles or issues, fundamental biological principles, or development of knowledge that can reasonably be expected to benefit humans, animals, or the environment 2. Optimal standards for animal health and care can result in enhanced credibility and reproducibility of experimental results. 3.Acceptance of animal use in science critically depends on maintaining public confidence in the mechanisms and processes used to ensure necessary, human, and justified animal use. 4. Animals are used only if the researcher's best efforts to find an alternative have failed. Researchers who use animals employ the most humane methods on the smallest number of appropriate animals required to obtain valid information. Legislation concerning the care and use of laboratory animals in the United States is set forth in the Animal Welfare Act. In addition, the NIH administers the Health Research Extension Act. All accredited North American universities that receive government grant support are required to provide adequate treatment for all vertebrate animals.

Cerebral voltammetry

A small carbon fiber electrode and a metal electrode are implanted in the brain. Small current is passed through the metal electrode. Current causes electrons to be added to or removed from the surrounding chemicals. Changes can be translated into a measure of extracellular levels of specific neurotransmitters that are measured as they occur

Legislation governing the care and use of laboratory animals used in the United States was set forth in the ________.

A.Animal Welfare Act (correct) b. Institutional Review Board (IRB) c. National Institutes of Health (NIH) d. Laboratory Animal Care International

Legislation governing the care and use of laboratory animals used in the United States was set forth in the ____.

Animal Welfare Act

List some of the reasons for conducting scientific research in animals.

Animal experimentation can help researchers better understand the functions of human and nonhuman body, brain, and behavior, as well as develop medicines and treatments for humans and other animals.

Catherine is interested in the relationship between dopamine levels in the nucleus accumbens and drug taking. What method(s) could she use to determine this relationship?

Answers will vary but should touch on one or more of the methods described in Table 7-2. For example, cerebral voltammetry can be used to measure the change in dopamine concentration in the nucleus accumbens following the introduction of corticosterone, as was done by Wheeler and his colleagues.

Drug Manipulations

Brain activity can be stimulated. Administration of drugs can pass into the bloodstream and enter the brain through an indwelling cannula that allows direct application of drugs to specific brain structures. Drugs can influence the activity of specific neurons in specific brain regions. Because drug effects wear off over time, it is possible to study drug effects on learned behaviors, such as skilled reaching.

Outline the various brain-stimulation methods that either activate or inhibit neural activity.

Brain-stimulation methods include using electrical pulses, as in DBS; magnetic fields, such as in TMS; ultrasonic beams, as in HIFU; chemicals, by administering drugs; or in the transgenic techniques of optogenetics (which employs light), chemogenetics (which employs synthetic drugs to interact exclusively with designer receptors), or genetic engineering, in the case of CRISPR-Cas9 techniques.

To avoid compensation following permanent lesions, temporary and reversible lesion techniques are used.

Regional cooling prevents synaptic transmission. Local administration of a GABA agonist increases local inhibition.

Explain briefly the computed tomography (CT) method of brain imaging.

CT produces X-ray images of one object from many angles and then uses scanning software to combine them into a three-dimensional image of the brain.

fMRI and optical imaging measure changes in ____.

Cerebral blood flow

event-related potential (ERP)

Complex electroencephalographic waveform related in time to a specific sensory event.

Anatomical Imaging Techniques

Computed Tomography (CT scan) X-ray beams are passed through the brain at many different angles, creating many different images. Images are combined with the use of computing and mathematical techniques to create a three-dimensional image of the brain. MRI & MRS

EEG: Recording Graded Potentials from Thousands of Cells

EEG measures the summed graded potentials from many thousands of neurons. Reveals features of the brain's electrical activity. The EEG changes as behavior changes. An EEG recorded from the cortex displays an array of patterns, some of which are rhythmical. The living brain's electrical activity is never silent, even when the person is asleep or comatose.

Anatomical studies rely on techniques such as ____ tissue postmortem or visualizing living tissue using ____.

sectioning and staining; multiphoton imaging

The study of genes and behavior focuses on individual differences in _____, whereas the study of epigenetics and behavior examines differences in ____.

DNA; gene expression

CT Scan and Brain Reconstruction

Dense skull forms a white border. Gray matter density does not differ from white matter density enough for a CT scan to distinguish between the two. Cortex and its underlying white matter show up as homogeneous gray. Ventricles can be visualized because the fluid in them is far less dense. Some major fissures in the cortex are rendered darker.

Diffusion Tensor Imaging (DTI)

Detects the directional movements of water molecules to image nerve fiber pathways in the brain Used to delineate abnormalities in neural pathways

What is the advantage of EEG techniques over MEG?

EEG is much less expensive than MEG.

Deep-brain stimulation

Electrodes implanted in the brain stimulate a targeted area with a low-voltage electrical current to facilitate behavior Used for Parkinson disease, depression, OCD

Describe briefly how epigenetic studies have led to the recognition that life experience and the environment can alter brain function.

Epigenetic studies show that life experience can alter gene expression and that these changes are associated with changes in neuronal structure and connectivity. Altered neuronal organization in turn is associated with changes in behavior.

Mapping Brain Function with Event- Related Potentials

Event-Related Potentials (ERPs) Largely the graded potentials on dendrites that a sensory stimulus triggers Complex electroencephalographic waveforms are related in time to a specific sensory event. To counter noise effects, the stimulus is presented repeatedly, and the recorded responses are averaged.

Brain Stimulation

First used by Wilder Penfield to stimulate the cerebral cortex of humans during neurosurgery Rats with electrodes in the lateral hypothalamus eat whenever the stimulation is turned on. Self-stimulation: given the opportunity, rats will press a lever to obtain the current. The stimulation affects a neural circuit involving both eating and pleasure. Electrically stimulating the intact cortex adjacent to cortex injured by a stroke leads to improvement in motor behaviors. Teskey and colleagues restored motor deficits in a rat model of Parkinson disease by electrically stimulating a specific brain nucleus

compensation

Following brain damage, the neuroplastic ability to modify behavior from that used prior to the damage.

Optical Tomography

Functional near-infrared spectroscopy (fNIRS) Form of optical tomography Technique that operates on the principle that an object can be reconstructed by gathering light transmitted through it Reflected infrared light is used to determine blood flow because oxygen-rich hemoglobin and oxygen-poor hemoglobin differ in their absorption spectra.

Epigenetics

Genes that are expressed can change dramatically in response to environment and experience Epigenetic changes can persist throughout a lifetime and even across multiple generations. Wide range of experiential factors Chronic stress, traumatic events, drugs, culture, and disease are factors. Cumulative experiences affect how genes work - epigenetic drift.

EEG measures ____ potentials on the cell membrane.

Graded

electrocorticography (ECoG)

Graded potentials recorded with electrodes placed directly on the surface of the brain.

Techniques for neuroanatomy

Histological: brains sectioned postmortem and tissue stained with different dyes Contemporary techniques identify molecular, neurochemical, and morphological (structural) differences among neuronal types to relate these characteristics to behavior.

Positron Emission Tomography (PET)

Imaging technique that detects changes in blood flow by measuring changes in the uptake of compounds such as oxygen or glucose Used to analyze the metabolic activity of neurons Radioactive molecules are injected into the bloodstream. Advantages Can detect the decay of hundreds of radiochemicals and allows the mapping of a wide range of brain changes and conditions Can detect relative amounts of a given neurotransmitter, the density of receptors, and metabolic activities associated with learning, brain poisoning, and degenerative processes Widely used to study cognitive function

Detecting ERPs

In the averaging process for an auditory ERP, a tone is presented at time 0, and EEG activity in response is recorded. After many successive presentations of the tone, the EEG wave sequence develops a distinctive shape that becomes extremely clear after 100 responses are averaged (bottom panel). Positive and negative waves that appear at different times after the stimulus presentation are used for analysis.

alpha rhythm

Large, extremely regular brain waves with a frequency ranging from 7 to 11 Hz; found in most people when they are relaxed with eyes closed.

Magnetic resonance spectroscopy (MRS)

MRI method that uses the hydrogen proton signal to determine the concentration of brain metabolites, such as N- acetylaspartate. Useful in detecting persisting abnormalities in brain metabolism in disorders such as concussion

magnetoencephalogram (MEG)

Magnetic potentials recorded from detectors placed outside the skull.

functional magnetic resonance imaging (fMRI)

Magnetic resonance imaging technique that measures brain activity indirectly by detecting changes associated with blood flow; often used to measure cerebral blood flow during cognitive testing or resting.

How Do We Study the Brain's Structure and Functions?

Measuring and manipulating brain and behavior Measuring the brain's electrical activity Anatomical imaging techniques: CT and MRI Functional brain imaging Chemical and genetic measures of brain and behavior Comparing neuroscience research methods Using animals in brain-behavior research

Recording Action Potentials from Single Cells

Measuring single-neuron action potentials with fine electrodes Electrodes placed next to cells (extracellular recording) or inside them (intracellular recording) Extracellular recording techniques make it possible to distinguish the activity of as many as 40 neurons at once. Intracellular recording allows study and recording of a single neuron's electrical activity.

Behavioral analysis of rodents

Morris (1980) swimming task Place learning Rat must find platform using external cues. • Matching-to-place learning: Platform is in the same location each trial but a different location each day. Landmark version: Platform is identified by a cue on the wall.

Animal Welfare and Scientific Experimentation

Most governments regulate the use of animals in research. Universities and other research organizations have additional rules governing animal use.

diffusion tensor imaging (DTI)

Movement of ions from an area of higher concentration to an area of lower concentration through random motion.

Magnetoencephalography

Neural activity, by generating an electrical field, also produces a magnetic field. Magnetic potentials are recorded from detectors placed outside the skull. Permit a three-dimensional localization of the cell groups generating the measured field Higher resolution than ERP Disadvantage: high cost

Chemical and Genetic Measures of Brain and Behavior

Neurons are regulated by genes that encode the synthesis of particular proteins within cells. Genes control the cell's production of chemicals, so it is possible to relate behavior to genes and to chemicals inside and outside the cell.

deep-brain stimulation (DBS)

Neurosurgery in which electrodes implanted in the brain stimulate a targeted area with a low-voltage electrical current to produce or facilitate behavior.

functional near-infrared spectroscopy (fNIRS)

Noninvasive technique that gathers light transmitted through cortical tissue to image oxygen consumption; form of optical tomography.

Genetic Manipulations and Combinations with Light and Drugs

Optogenetics and chemogenetics Proteins can occur naturally or can be inserted into cells. Fiber-optic light can be delivered to selected brain regions such that all neurons exposed to the light respond immediately Drug activates only the genetically modified receptors, and the receptors are activated only by the designer drug, not by endogenous molecules.

Neuropsychological testing of humans

People with damage to the temporal lobes often complain of memory disturbance. Memory is not a single function (memory for events, colors, names, places, and motor skills). It is rare for someone to be impaired in all forms of memory, so each must be measured separately.

Transcranial magnetic stimulation (TMS)

Procedure in which a magnetic coil is placed over the skull to stimulate the underlying brain Used either to induce behavior or to disrupt ongoing behavior

Magnetic resonance imaging (MRI)

Produces a static, three-dimensional brain image by passing a strong magnetic field through the brain, followed by a radio wave, then measuring the radiation emitted from hydrogen atoms

Kyoto SHR rat

Proposed as a good model for ADHD • Known abnormalities in prefrontal dopaminergic innervation that correlate with behavioral abnormalities such as hyperactivity Dopamine agonists such as methylphenidate (Ritalin) can reverse behavioral abnormalities, both in children with ADHD and in SHR rats.

Skilled reaching task (Whishaw and Kolb, 2005)

Rats are trained to reach through a slot to obtain food. Movements can be broken down into segments, which are differently affected by different types of neurological perturbation.

Benefits of Animal Models of Disease

Some disorders are easy to model (e.g., stroke). Behavioral disorders are more difficult. Attention-deficit/hyperactivity disorder (ADHD) Developmental disorder characterized by core behavioral symptoms of impulsivity, hyperactivity, and/or inattention Kyoto SHR rat

Comparing Neuroscience Research Methods

Some researchers focus on morphology (structure) in postmortem tissue. Other investigators focus more on the ways neurons generate electrical activity in relationship to behavior or on functional changes in brain activity during specific types of cognitive processing Considerations Temporal resolution (how quickly the measurement or image is obtained) Spatial resolution (how accurate localization is in the brain) Degree of invasiveness Studying brain and behavior linkages by perturbing the brain is generally less costly than some imaging methods, many of which require expensive machinery.

Behavioral neuroscience

Study of the biological bases of behavior Includes the study of both humans and laboratory animals Major challenge is to develop methods for studying both normal and abnormal behavior

behavioral neuroscience

Study of the biological bases of behavior in humans and other animals.

Neuropsychology

Study of the relationships between brain function and behavior, with emphasis on humans Origins: Paul Broca discovered the link between specific damage located in the left frontal lobe region and language difficulties.

Chemogenetics

Synthetic genetic sequence codes for a G protein-coupled receptor engineered to respond exclusively to a synthetic small-molecule designer drug. Designer receptor exclusively activated by designer drugs (DREADD)

magnetic resonance imaging (MRI)

Technique that produces a static three-dimensional brain image by passing a strong magnetic field through the brain, followed by a radio wave, then measuring a radiofrequency signal emitted from hydrogen atoms.

Microdialysis

Technique used to determine the chemical constituents of extracellular fluid Semipermeable membrane is placed in the brain. Fluid flows in where it passes along the membrane. Diffusion drives the passage of extracellular molecules across the membrane. Fluid containing the molecules from the brain exits through tubing and is collected for analysis.

microdialysis

Technique used to determine the chemical constituents of extracellular fluid in freely moving animals.

cerebral voltammetry

Technique used to identify the concentration of specific chemicals in the brain as animals behave freely.

Measuring the Brain's Electrical Activity

The brain is always electrically active. Electrical measures of brain activity are important for studying brain function. Four major techniques Single-cell recording Electroencephalography (EEG) Event-related potentials (ERP) Magnetoencephalography (MEG)

Measuring Genes in Brain and Behavior

Variations in gene sequences contribute to brain organization. Studying twins and adopted children allows us to tease apart environmental and genetic contributions to behavior. We can also relate the alleles of specific genes to behaviors. Brain-derived neurotrophic factor (BDNF) Plays an important role in stimulating neural plasticity The gene related to BDNF has two alleles: Val 66Met and Val 66Val. Bueller and colleagues (2006) The Met allele is associated with an 11% reduction in hippocampal volume and poorer memory for specific events (episodic memory).

Manipulating Brain-Behavior Interactions

We can modify the brain and see how behavior is altered. Two reasons for doing so Develop hypotheses about how the brain affects behavior and then test the hypotheses Develop animal models of neurological and psychiatric disorders

Functional Brain Imaging

When a brain region is active, the amount of blood, oxygen, and glucose flowing to the region increases. Possible to infer changes in brain activity by measuring either blood flow or levels of the blood's constituents, such as oxygen, glucose, and iron.

Functional Magnetic Resonance Imaging (fMRI)

When human brain activity increases, the increase in oxygen produced by increased blood flow actually exceeds the tissue's need for oxygen. The amount of oxygen in an activated brain area increases. • Changes in the oxygen content of the blood alter the magnetic properties of the water in the blood. fMRI allows for good spatial resolution of the brain activity's source. Because changes in blood flow take as long as one-third of a second, the temporal resolution of fMRI is not as precise as that of EEG recordings and ERPs.

computed tomography (CT)

X-ray technique that produces a static three-dimensional image (called a CT scan) of the brain in cross section.

PET Scanner and Image

a small amount of radioactively labeled water is injected into a subject. Active areas of the brain use more blood and thus have more radioactive labels Positrons from the radioactivity are released; they collide with electrons in the brain, and protons, exit the head, and are detected

Which of the following is one of the principal anatomical brain-imaging methods?

a. CT (correct) b. EST c. DBS d. EEG

_____ is a technique used to determine the chemical constituents of extracellular fluid in freely moving animals.

a. Cerebral voltammetry b. Microdialysis (correct) c. Epigenetics d. fMR

_____ is an imaging technique that detects changes in blood flow by measuring changes in the uptake of compounds such as oxygen or glucose and is used to analyze the metabolic activity of neurons.

a. DTI (correct) b. PET c. fMRI d. CT

EEG measures _____ potentials on the cell membrane.

a. anterior b. posterior c. alpha d. graded (correct)

At the beginning of the twentieth century, the primary tools of neuroanatomy were ____.

a. chronological b. anatomical c. histological (correct) d. psychologica

Which of the following is not one of the four major techniques for tracking the brain's electrical activity?

a. electroencephalography (EEG) b. event-related potentials (ERP) c. magnetoencephalography (MEG) d. active X-ray radiation (correct)

A new innovation in behavioral testing in rodents uses automated ___________, which removes the variation and stress that humans introduce when testing animals.

a. food delivery system b. water bowl c. touchscreen platform (correct) d. stereotaxic apparatus

Cerebral voltammetry is used to identify the concentration of specific _____ in the brain as animals behave freely.

a. hormones b. neurons c. chromosomes d. chemicals (correct)

Single-cell recording measures ___ potentials from a single neuron.

action

Relative to the expense of fMRI and PET imaging, noninvasively perturbing the brain using methods such as ____ or administering neuropsychological testing is _____.

any one or more: EEG, ERP, and/or fNIRS; less expensive or inexpensive

Gene-environment interactions can be investigated in human populations by comparing ____ of behavioral traits in identical twins and adopted children.

concordance rates

The principal methods of functional brain imaging are ____, ____, and ____.

in any order: functional magnetic resonance imaging or fMRI; optical tomography or fNIRS; functional positron emission tomography or PET

The four major techniques for tracking the brain's electrical activity are ____, ____, ___, and ____.

in any order: single-cell recording; EEG; ERP; MEG

Neuroscience measurements and imaging vary along the dimensions ____, ____, and ____.

in any order: temporal resolution; spatial resolution; degree of invasiveness

Behavioral neuroscience is the study of relationships between ____ and ____.

in either order: brain function; behavior

The principal anatomical brain-imaging methods are ____ and ___.

in either order: computed tomography or CT scan; magnetic resonance imaging or MRI

Measuring brain and behavior

increasingly includes noninvasive imaging, complex neuroanatomical measurement, and sophisticated behavioral analyses.

Magnetoencephalography measures the ____ and also provides a(n) ______.

magnetic activity of many neurons; three-dimensional localization of the cell groups generating the measured field

Diffusion tensor imaging identifies ____, whereas magnetic resonance spectroscopy determines ____.

neural connections or fiber pathways; concentrations of brain metabolites

PET uses ____ to measure brain processes and to identify _____ changes in the brain.

radioactively labeled molecules; neurochemical

A new innovation in behavioral testing in rodents uses automated _____, which removes the variation and stress that humans introduce when testing animals.

touchscreen platforms