Brain Scans

FUNDAMENTAL 

NEUROSCIENCE FOR NEUROIMAGING

PART 2: Functional Neuroanatomy of the Human Brain

Methods of Communication in the Brain, Part 1

Welcome to this module. In this module, we'll discuss methods of communication in the brain, essentially how neurons Communicate with each other in the brain. If you remember from one of our previous modules, we discussed that the neuron is the essential processing unit of the brain consisting of dendrites, a cell body, axons that transport the signal, and nerve endings that communicate the signal to the downstream neuron or the next neuron. There are two theories, at least historically, about how neurons communicate with each other. A theory supported by Golgi referred to as Reticular theory proposes that neurons form a continuous reticular net and are continuously connected with each other.A second theory proposed by Cajal, through his very meticulous neuron staining work that he did using a microscope to review the connections between neurons, 

suggested that neurons in fact are structurally independent, and that units interact by contiguity and not by continuity. This theory is referred to as the neuron doctrine, and has found a lot of support later, particularly in the 1950s through the development of the electron microscope.Neurons receive and process information. They transmit information both chemically and electrically. They pass information downstream to adjoining neurons. And they form neural networks that collectively support brain function. In this module, we'll go through a little bit of how they communicate with each other and how they support that collective brain function. There are essentially three types of neurons. There's the sensory neuron, which converts an external stimulus into an electrical signal that can be processed by the brain. There are interneurons, which process and relay information once it's been received from, for example, a sensory neuron. And finally, there are motor neurons, which convert electrical signal processed in the brain into muscle or gland movements, if you will, into physical action.On the membrane of each neuron are ion channels and ion pumps. They establish a difference in concentration of sodium, potassium, chloride, and calcium within the cell versus the outside of the cell. This establishes an electrical charge or what's called a resting state potential in the

neuron. There's a voltage difference between the inside of the cell and the outside of the cell that is established by this ion channels and these ion pumps.At the synapse, at the communication point where external nerve endings form synapses with dendrites of adjoining neurons, this forms the site of the basic communication where electrical and chemical signals are transferred from one neuron to another. Now how exactly does that work? The flow of information goes from the presynaptic terminal as you see on the right, through the synaptic cleft to the what's called postsynaptic terminal or postsynaptic spine.Synapses from the primary site of interneuronal communication. Now, through the next few slides, we'll go through the individual steps that facilitate this synaptic transmission.So first, here's an example of a synapse.By opening one of the ion channels, an influx of calcium, for example, through this ion channel, causes available synaptic vesicles to fuse with the presynaptic membrane as you see in the image on the right-hand side.In the second step, this transmitter is released into the synaptic cleft from these synaptic vesicles.The transmitter, through the synaptic cleft, then binds with the post-synaptic member or receptors on the post-synaptic membrane. And these post-synaptic channels then either open or close based on this binding.The opening of ion channels in the postsynaptic membrane causes either an influx of ions into the postsynaptic neuron, or the ion channels close up and prevent an influx of ions into the postsynaptic neuron.The change in the balance of post-synaptic ions in the post-synaptic spine, causes the post-synaptic cell to either depolarize or further hyper polarize.If the post-synaptic voltage changes are large enough enough, an electrochemical pulse is generated which is referred to as an action potential. This action potential then travels rapidly along the axon where it can then in turn activate synaptic vesicle release downstream in synapses with other neurons.The change in the balance of post-synaptic ions in the post-synaptic spine, causes the post-synaptic cell to either depolarize or further hyper polarize.If the post-synaptic voltage changes are large enough enough, an electrochemical pulse is generated which is referred to as an action potential.This action potential then travels rapidly along the axon where it can then in turn activate synaptic vesicle release downstream in synapses with other neurons.At the same time, the used synaptic vesicle is retrieved in the presynaptic terminal. And it's retrieved from the membrane and recycled. And new transmitter is synthesized by the cell's metabolic apparatus and stored in vesicles for future synaptic transmission.Post-synaptic stimulation changes the excitability of the post-synaptic cell.If this stimulation is excitatory, it depolarizes the membrane potential and makes it easier to reach an action potential threshold. And if the stimulation is inhibitory, it hyper polarizes the membrane potential, making it harder to reach the action potential threshold.Excitatory post-synaptic potentials are commonly referred to as EPSPs. Single EPSPs do not always cause a post-synaptic action potential. In some cases, neurons that form many connections with many synapses with adjoining cells, require a summation of EPSPs to generate an action potential. So here on the figure on the right, you will see that the accumulation of three EPSPs reaches the threshold to generate an action potential in the post-synaptic cell.We can record these post-synaptic potentials by the placement of an electrode. The electrode can be placed either inside the cell, as is indicated by number 1 in the right-hand figure, or on the outside of the neuron, as indicated by the number 2 in the right-hand figure. In the instance where the recording is done on the inside of the neuron, the influx of ions causes an increase in voltage inside the cell which are reflected in the voltage read up that will result from a reading like this.In case of recording from the outside of the neuron, positive ions float away from the extracellular electrode, causing a decrease in voltage that is recorded on the outside of the cell. So, there's a different voltage signature that can be obtained from recording on the inside of the cell, versus outside of the cell.Neurons are densely packaged and highly interconnected. The extracellular electrode cannot assess which neuron is causing the voltage change.Extracellular recordings thus measure activity of a local neuronal environment, and are therefore referred to as local field potentials.These local field potentials are incredibly important when we talk about the basis of the MRI signal in one of our future models about MRI image generation.So we've now talked about some basic communication principles that occur within the brain that allow cells to communicate with one another. In the next module, we'll discuss some of the functional differences between different types of neurons and brain circuits that support brain function that we are all familiar with.

Methods of Communication in the Brain, Part 2

In the previous module we discussed how action potentials are generated within a brain cell, within a neuron, and used to convey information from the cell body through the axon. In this module, we will discuss how brain cells communicate with each other and with the rest of the body. As we saw in the previous module, communication between neurons heavily relies on electrical signals. The concentration of sodium and potassium inside and outside of the cell creates a membrane potential that serves as an electrical current or an action potential that travels along the cell. We then saw that there are neurotransmitters that are released into the synapse that will stimulate the postsynaptic cell to continue to communicate from one neuron on to the next. As you may recall from the previous module, neurons are not continuous. They are separated by a small synaptic cleft across which the electrical current cannot travel. Chemical neurotransmitters are used in that synaptic cleft to activate a postsynaptic neuron. Now, the mechanisms of electrical transmission are highly similar between neurons. They all rely on roughly the same mechanisms, but there's a great variety in neurotransmitters that are being employed to communicate across these synaptic clefts. The different neurotransmitters have very different effects on the postsynaptic cell. There's a great number of categories of different neurotransmitters. Some fall in the category of amino acids, like glutamate, aspartate, glycine and D-serine. Some of them are peptides, like somastostatin, vasopressin, oxytocin, and opioid peptides. And there are other categories as well, that includes serotonin or epinephrine, histamine, melatonin and others. In fact, overall there are over 50 neurotransmitters that have been identified, each having slightly different neurochemistry 

and each having slightly different functions.The function that the effect that the neurotransmitter will have on the postsynaptic cell, 

largely depends on the type of neurotransmitter or neuroreceptors that are on the postsynaptic cell. Different neurotransmitters act on different receptors, and depending on what nueroreceptor the postsynaptic cell has they will respond to one neurotransmitter or another, essentially defining their function. Now, another way of categorizing neurotransmitters is by excitatory neurotransmitters like epinephrine or norepinephrine which excite the postsynaptic cell or inhibitory neurotransmitters, those that inhibit or deactivate, 

if you will, the postsynaptic cell. Those include serotine and GABA. Now there's another category of neurotransmitters that can 

actually do both, depending on the cell and depending on the receptors that are available locally. Dopamine is an example of a neurotransmitter that can both have an excitatory function or an inhibitory function depending on the local environment. Now let's step through a couple of examples of neurotransmitters and their known functions. Acetylcholine is a very well-known neurotransmitter. It's an excitatory neurotransmitter that activates the motor system, is very important for control of skeletal muscles and motor tone, if you will. It regulates brain activity associated with attention, arousal, but also learning and memory. In fact, abnormally low levels of acetylcholine in the brain has been observed in patients with Alzheimer's disease who have clear deficits in their memory function. Another example is dopamine. Dopamine is critically important for motor control and movement of the body, particularly fine motor movements. It is also involved in reward and positive emotion, feeling a sense of well-being, if you will. Abnormally low levels of dopamine have been observed in patients with Parkinson's disease, particularly in the Substantia nigra which produces dopamine. Its relation to the motor symptoms that I just described can than explain the Parkinsonism and the bradykinesia that you see in patients with Parkinson's disease. On the other hand, elevated levels of dopamine are observed in patients with schizophrenia, particularly in the frontal areas, which could account for some of the symptoms that patients with schizophrenia are experiencing. Another neurotransmitter is glutamate, that's most commonly found neurotransmitter in the nervous system and it's mainly associated with learning and memory, in fact, it is critically important for learning and memory, but excessive production of glutamate is toxic to neuron and can lead to diseases like ALS later in life. These are just a few examples of the neurotransmitters and what their known functions are. As I mentioned before, there are over 50 different kinds of neurotransmitters that have been identified and they all have similar functional properties or functional characteristics. Let's look a little bit more about glutamate. So glutamate binds postsynaptically to an AMPA receptor. So when we're talking about learning and memory, the AMPA receptor, as you see in the left schematic, is very important.When glutamate binds to a receptor, it actually opens that receptor channel, allowing the influx of sodium into the postsynaptic cell. It also bounds to the NMDA receptor, as you can see in the green receptor on the left schematic. The NMDA receptor actually has a magnesium plug inside of it which prevents the influx of ions into the cell. Glutamate binding to the NMDA receptor will expel that magnesium plug and allow for the influx of calcium into the cell. The combined influx of sodium and calcium has some downstream effect. They have a number of effects within the cell, and there are chemical changes that occur that are all critically important for LTP, which stands for Long-term Potentiation, a critical mechanism in learning and memory and our ability to learn and remember information. So here's an example of how glutamate acts on a postynaptic cell and again, all the other neurotransmitters have similar mechanisms yet different affinities depending on their receptor that they're binding to. So on the far left schematic here you see an example of an unbound receptor, which is typically a closed channel, not allowing any transfer of either ion, sodium, calcium, from the outside of the cell to the inside of the cell. If you have an agonist, for example, glutamate could be an agonist that binds the receptor and then opens the channel, so influx is possible and deep polarization or firing of the cell is possible. You can also have a receptor agonist which is a drug or an artificial compound, if you will, that acts like a neurotransmitter and artificially binds to the receptor and opens the channel that way. So in patients who have a deficit in a certain neurotransmitter, chemical compounds can be used like drugs to take over that role and open the receptor channel that way. You can also create a competitive agonist. So this is a drug, usually a foreign compound that's introduced, that binds to the receptor site, but keeps the receptor closed, keeps the channel close, but prevents a naturally occurring agonist from binding to it. So it's basically preve ting the opening of the channel by blocking it from other compounds. Then finally there's a noncompetitive antagonist which bind but the transmitter, binds but does not activate, so it doesn't bind them the same side, it binds in a different side, but it prevents the naturally occurring transmitter from executing its function on the channel and keeping the channel closed, if you will. So these are different mechanisms by which neural signaling or synaptic transmission is influenced either by the naturally occurring neurotransmitters or by drugs that are artificially introduced into the system. Now we've talked about communication between different neurons within the brain. How do these different neurons communicate with the rest of the body? How is the communication between the brain and the rest of the nervous system occur and between the muscles and all the other organs of the human body?There's direct innervation through the spinal cord and the peripheral nervous system.So from the brain projections long nerve endings go to the spinal cord which then form and directly innervate the rest of the body. There's also possible secretion through hormones that diffuse throughout the vascular system. So these are hormones that are excreted in the blood system and through the blood travel throughout the entire body, forming a mechanism of communication that way. I'm going to show you some examples of each of those. So a direct innervation consists of cranial nerves that are extending from the brain stem to the face to the upper body, as you can see here, and there are cortical spinal tracks, those are tracks that go down into the spinal cord and provide sensory and motor information from the entire body through the spinal cord up to the brain. There are 12 cranial nerves in total that, as you can see in the left image, service different areas of the head and upper body and the cortical spinal tracks go all the way down to the tailbone providing innervation of the guts and respiration, heart, lungs and all the other systems that are important for survival. Hormones follow a slightly different method of communication. Hormones are signaling molecules, produced by glands throughout the entire body. The system of glands throughout the body is referred to as the endocrine system. The hormones are transported by the circulatory system to distant target organs and these hormones are used to communicate between organs and tissue. And it regulates the physiological and behavioral activities, such as heart rate, breathing, digestion, metabolism, sleep, reproduction, mood, and lots of other common behaviors, most of them critical for survival. An example of a very common well-known hormone, for example, is adrenaline. And on the right hand schematic you can see the major glands that are in the body producing these hormones, again, secreting them into the blood system where they can influence all the other organs and systems. The brain is neurochemically protected through a blood brain barrier. So the endothelial cells line blood vessels and they prevent entry of microscopic objects like bacteria and macroscopic large sized molecules from entering the brain, preventing things like brain infections through bacteria or other toxins that may be available in the blood from entering the nervous system, the brain. Only small hydrophobic molecules like oxygen are allowed through and others are actively transported by the blood brain barrier into the brain, like glucose which is necessary for brain function. So the blood brain barrier serves as a protective barrier around the brain, again, protecting it from toxins in the blood and from other large molecules of bacteria that could be harmful. Now, if that's the case, then how do hormones interact with the brain? Well, there are several brain areas that are not protected by the blood brain barrier that are also considered glands that produced these hormones that are part of the brain. So the hypothalamus, the pituitary and the pineal glands are part of the human brain, are not protected by the blood brain barrier and secrete hormones into the blood system, so that they can be used to communicate with the other organs and essentially the rest of the body. This is a very important mode of communication that, again, regulates very important features like temperature regulation, thirst, hunger, circadian rhythm or sleep wake cycles and, very importantly, the stress response. The communication using hormones is bidirectional. It is a method by which the brain communicates with the rest of the brain, but it is also a way for the body to send back signals to the brain. Hormone secreted in the blood by other glands outside of the brain can influence brain function fairly directly. For example, if we're in a dangerous situation or there we have a startling response to something, the adrenal glands can excrete adrenaline into the blood system. Through the blood that adrenaline will activate the sympathetic nervous system. The sympathetic nervous system is responsible for dilating your pupils, inhibiting saliva production. It increases your respiration, you start to breathe faster, your heart rate goes up and all of this is in preparation of the so-called flight response, getting ready to avoid danger to protect yourself from danger. Epinephrine is a hormone that is not able to directly travel through the blood brain barrier. Instead what it does, is it binds to receptors on the vagal nerve which then release glutamate, a neurotransmitter we've discussed before, on to synapses in the brain stem. From there, projections to areas in the brain important for memory will allow us to encode or remember that dangerous event so that we can try to avoid it in the future. So here we see an example of hormones and neurotransmitters as two different methods that the brain uses to communicate within the brain with other neurons or through the vascular system with the entire rest of the body, as well as providing a mechanism of hormones from the rest of the body, the testes, the ovaries or the gut to provide communication back to the brain about the status of the body. In the next module we'll discuss several functional systems in the brain, depending on the type of neurotransmitter and the type of brain cells that are there and the functions of those different circuits in the context of cognition.

Functional Anatomy of the Brain

In this model we will be discussing the functional anatomy of the brain. In our previous models, we've discussed some of the anatomical properties of the brain and then this module will be discussing some of the functional properties of the brain. We've seen that neurons form the fundamental information processing unit of the brain. And that neurons can vary tremendously in type for example the sensory neurons, which take in information and translate information into electrical signals. The interneurons which transmit information over shorter or longer distances and the motor neurons which will take in electrical stimulus or an action potential and translate it into a motor movement or a muscle contraction. Neurons also vary tremendously in length and complexity. Some neurons have very dense dendritic sprouting, dendritic connection whereas others are very simple and only have a few dendrites. Some neurons transmit information over a distance of just a few millimeters whereas, others particularly those in the spinal cord that send electrical signals to our muscles in our legs can have an extensive length sometimes up to three feet over which they transmit the information. Neurons also vary tremendously in the type of receptors in the neurotransmitters that they utilize as we've discussed in a previous module. The receptors on the postsynaptic connection will determine to what neurotransmitter a particular neuron will respond to. We've seen a great variety in neurotransmitters and the type of functions that they are or the type of functions that they're typically associated with and a number of different receptors that we can see on a postsynaptic connection. The combination of the receptor and neurotransmitter also determines whether or not a neuron is Excitatory or Inhibitory. With excitatory neurons providing an excitation of the network that they're part of whereas, inhibitory neurons inhibit the system, prevent action potentials from further propagating through that network. We've also seen in the developmental module that the brain is highly organized, developmentally progresses through a number of stages in which these neurons form brain networks and systems in a highly organized fashion. On the right two images you can see an artist's rendering of that organization where neurons are organized both in columns, as well as in layers. Columns providing certain neuron information processing that takes place whereas, the layers are most often involved in transmitting information from one area of a network to another area of a network. So, now let's look at

a few systems or aspects of the human brain and what their functions are. For example, here we see in the schematic representation on the left as well as the MRI images that you see on the right. Certain areas that are black indicated by the yellow arrows. Those are actually areas containing cerebral spinal fluid or CSF. CSF is a fluid that basically encapsulates the brain makes the brain float in that fluid and protects it from external trauma. Such that if we move our head, our brain doesn't bump into the inside of our skull and potentially cause damage to our brain. There are CSF all around the brain. There's also two areas or several areas within the brain called Ventricles. In this particular case in the center of the far right image you see two yellow arrows indicating the third and the fourth ventricle respectively. In the ventricles there are choroid plexus which create the CSF. And from there it surrounds the brain again protecting it from external trauma. In addition to protecting it from trauma, CSF also provides key nutrients to the brain, and plays an important role in disposal of waste that is discarded from the brain. In addition to CSF, on these images that we see here we also see grey matter which is aptly referred to as grey matter. The grey matter on these images essentially forms the neuronal cell bodies that we see in the brain. These are basically the information processing components of the brain, the cell bodies that determine whether or not an action potential will get propagated to the next cell or not. Finally then, we see white matter on these images as indicated here by the yellow arrow again. White matter are basically fiber bundles of axon projections which are responsible for translating, or transmitting the information from one area to the next. In the blue arrow here of the top, there is the Anterior Cingulate, which is an important fiber bundle of axon projections from the left to the right hemisphere. Similarly, in the green arrow shows the Posterior Cingulate. And the red arrow on the right hand image in the bottom image shows the corpus callosum, which is the major information transmission bundle of fibers between the left and the right hemispheres. Now, let's take a look at a couple of examples of areas of the brain for which we know quite a bit about the function of that area. For example, the primary motor cortex. Highlighted here in red is the dorsal portion of the frontal lobe which is critically important for planning and execution of movements. From this area, cortical neurons are sent along the axons down to the spinal cord where it initiates and continues the muscle movements that are necessary for us to move. Within this area of the primary motor cortex, we see that it is highly orderly arranged from head to toe. With the foot and the leg and hip area being the most medial aspect of the most middle aspect of that cortical area. And the hand, face, tongue and other areas being the most more lateral aspect of that cortex. And as you can see in the far right image, it is a highly organized way of representing the motor movements or motor cortex driving motor movements for those areas. Very similarly, and immediately posterior or behind the primary motor cortex lies the primary somatosensory cortex which receives sensory input from the entire body. It represents the tactile representation which is also very orderly arranged as you can see. The amount of cortex is not proportional to the size of the body part but instead it's proportional to the density of the tactile receptors in this area. So, as you can see in the far right image the face, the nose, and the lips and the eyes receive far greater proportion of cortical representation than for example the shoulder or the top of the torso does. These areas are much more sensitive, or will have a much better definition, or resolution of tactile representation than our upper torso or our shoulder as we all know. Another example is the Thalamus, which is a structure that sits at the center at the base of the brain. It consists of a number of subnuclei and it is essentially the relay station of the brain. It relays the sensory and motor information from the spinal cord to the primary motor cortex and the somatosensory motor cortex among a number of other different functions that the thalamus controls. It's also important for the regulation of sleep, as well as consciousness. Now, it is important to note that the left side of the brain receives sensory information from the right side of the body and motor information or motor actions from the motor cortex in the left side of the brain will drive right side motor movements of our body. These representations or this information actually transverses from the left side to the right side at the level of the medulla, which is in the midbrain, translating over to the other side such again that the cortex on the left side of the brain controls the contralateral side of the body or receive sensory information from the controlateral side of the body. Another example is the visual cortex. It is highly organized in columns, as we will see in a moment. And it processes orientation, motion, and color as well as lots of other visual features. It is organized by visual field, such that as you can see in the middle image, the right visual field is processed by the left hemisphere and the left visual field is processed by the right hemisphere. The visual cortex can be further subdivided in different subregions as you can see at the top right image, the different colors provide a different level of complexity of processing for this area. Here you see another example of that. In the bottom left you can see that there are orientation columns. Neurons are organized in these orientation columns and each neuron is sensitive to a particular orientation of the stimuli. By dividing lots of different neurons and making them sensitive to lots of different orientations, the population firing of such a set of neurons represents the directionality, the orientation, as well as the color and shape of the visual field that we're experiencing. The primary information is processed in V one as you can see in the schematic on the top right, which is then subdivided into a where and a what pathway. The top part of the image V2, MT, MST and the Parietal Regions essentially process information regarding the directionality, the speed, the where the item is and where the item is going. Part of the information stream whereas, the more ventral aspect of the projection V2, V4 and then down to the medial temporal lobe will process more of what the item is. What is the object, how is it identified and how is it recognized. Object recognition, complex shapes and body parts. So, visual information is initially processed in V1 and depending on what type of information it is separated into a what and a where pathway that are sent to different parts of the brain. The cerebellum is yet another aspect of a structure that is very well described. It's a separate structure at the base of the brain which has a very complex organization. It receives information from sensory systems and the spinal cord. And it is thought to be very important in coordinating posture, balance coordination and in general for me supporting smooth activity and smooth transition. However, in recent studies it's also thought to play an important role in cognition.Although exactly how the cerebellum supports those types of functions remains somewhat unclear. So, in this module we've seen that there are separate functional systems in the brain, consisting of the primary motor cortex, somatosensory cortex, the visual cortex which processes visual information and the what and where dorsal and ventral streams of what we see and what we can do with it, as well as motor control and sensory information that we receive. These all have to do with how we perceive and how we move about in the world. In the next module, we will talk about some of the higher cognitive functions such as language and memory and attention, and try to determine where in the brain those functions are supported.

Organization of Cognitive Domains

In previous module, we discussed some basic functions of the human brain including motor control, sensation, vision, and fine motor movements. In this module, we will be discussing some of the higher functions or cognitive functions if you will and how those are represented in brain systems. Cognition is the mental action or process of acquiring knowledge and understanding through thought, experiences and the senses. And it usually includes reasoning, memory, attention, and language. So I'll now step through a couple of examples of brain systems that support these types of cognitive function. Obviously, there's a continued research going on trying to figure out exactly how those systems give rise to cognition. But there are number of aspects that we will know, how they work and how they are supported in the brain. For example, in language, Pierre Paul Broca was a French surgeon and an anatomist who describes among several others, but two important patients. Leborgne was unable to produce any words or phrases, when he was evaluated back in 1861 by Broca. And a second patient Lelong had severely reduced ability to produce speech. Upon autopsy Broca as an anatomist and surgeon examined their brains and noticed that in both patients there was a very specific area that was damaged, as you can see in the bottom center image. It was damaged to the posterior inferior frontal gyrus which has now become known as the Broca's area. Patients who have this difficulty with language due to damage to Broca's area, are referred to as aphasia patients. They can understand words and simple sentences, they know what they want to say. But they're absolutely unable to generate fluent speech. They're unable to create the grammatical structure of a sentence and express their thought. In the example of patient Leborgne, in fact he was only able to express one word, which was ten, which became his nickname. Lelong was able to utter some very simple words, just a few of them and some simple verbs, but could otherwise not produce significant or complicated speech. Carl Wernicke was a German psychiatrist and neuropathologist and he know that at certain patients had language problems and had not had any damage to Broca's area. Upon autopsy, he noticed a different area of the brain was affected, as you can see again in the center bottom image. It included damage to a posterior section of the superior temporal gyrus, which became known as Wernicke's area. Patients with Wernicke's

aphasia, which is known as receptive aphasia, have an impaired comprehension of spoken and written word. So they're able to generate words, they're able to generate basic language, but they have significant difficulty understanding either spoken or written language. Again, they're unable to departs the sentence structure that we are normally able to decipher and understand the meaning of. So when we combine these findings from these two scientists, we note that receptive language, what was said or read, depends on an area defined by Wernicke. In the posterior aspect of the brain, there is what to say, which is usually processed by the frontal areas of the brain in response to what we heard. Then there's a determination of expressive language which is how do we explain ourselves, how do we prepare our response which depends on Broca’s area. This can be either in silent, or in writing, or speaking. Depending on the Wernicke or the motor cortex such that expressive language gets sent to the motor cortex if we want to employ our vocal chords or use handwriting to express ourselves. Or when it concerns silent thought, which still contains language, that information is sent back to one of these area, so here we see a network of brain areas that is responsible for both receptive and expressive language. Another example was the famous case of Phineas Gage. He was a railroad worker who back in 1848 was involved in a horrible accident. He was responsible for blowing up rocks using explosives and he was using an iron rod to temp down an explosive compound in a hole. He stopped paying attention for a just a minute and unfortunately, with the metal rod caused a spark on the rock which ignited the gun powder that he was using, and set the rod through his skull. It entered on the left side of his face as you can see on the right hand side image and exited the top of his head, causing extensive damage to the frontal lobes. Now this explosion was massive, ultimately they found the metal rod some 80 feet from where Phineas Gage was working. So it caused a tremendous amount of damage and the recovery was fairly extensive, but he does survive the accident. On the very right hand side, again you can see the trajectory of the metal rod and the type of damage that it caused to the brain. Again, as I said he survived the accident and he was able to function in many different ways. His speech and motor control were largely preserved, he was able to understand other people and express himself, or be it rudimentary, but he had a severe personality change. He became very irritable and aggressive and in the expression of his peers he was very hard to along with. So he displayed very significant portionality changes as a result of this accent, as a result of the damage to his frontal lobes. In the memory domain, we've learned a lot from patient, H.M., who was arguably one of the most famous neuroscience patients ever described. H.M., depicted here on the far left suffer from severe epileptic seizures. He saw a neurosurgeon, Dr. Scoville, who in 1953 performed a brain surgery to remove bilaterally the hippocampus, amygdala, and the surrounding cortex. As you can see in the schematic on the right hand side. These are important structures in the medial temporal lobes of the brain. On the MRI images on the bottom, you can see the amount of tissue that was excised by the surgeon bilaterally. The green demarcation shows the medial temporal lobes, both on the left and the right. And what is outlined in pink or reddish color is the extent of the resection that was performed on this patient. The surgery that was done before by the surgeon but never on both sides of the brain simultaneously. After recovery, the surgeon and neuropsychologists noted that H.M., had intact language. He had a normal IQ and working memory, had no trouble with motor control. But he had a very significant inability to learn new information. He was unable to learn or form new memories. He was also unable to remember anything from after the surgery and for a distinct period of time prior to the surgery. The only things that he could remember were essentially memories from his childhood. So from these studies, it was concluded that the structures of the medial temporal lobe are critically important for memory. Here's a quote from patient H.M., which gives a very nice example of what that's like. He says, right now I'm wondering have I done or said anything amiss? You see at this very moment everything looks clear to me, but what happened just before? That's what worries me. It's like awakening from a dream, I just don't remember. So he lived very moment to moment in the sense that he was unable to retain what was going on or what his history was for more than just a few minutes at a time. Similarly patient E.P., suffered from a herpes simplex virus which also affected the hippocampus in the medial temporal lobe. Causes severe damage, as you can see in the MRI image at the bottom. On the left hand side is patient H.M. with the surgical resection that we just discussed. On the right-hand side, you can see patient E.P., who has less extensive but similar damage on both sides of the brain to the medial temporal lobe as shown here. He also experienced an intact language ability, intact IQ, working memory, as well as motor control. But again, had a very significant impairment in retaining new information and creating new memories. From this research and a lot of research since then we have learned that the structures of the middle temple of as indicated in the top left are critically important for forming and creating new memories. Particularly memories for facts and events or episodes from our personal lives. In the bottom, you can see a cross section of the brain and as well as the hippocampus, the structure that is thought to be very critically important for this type of memory. Refer to as the hippocampus which is Latin for sea-horse to which is perceived it's name as you can see in the bottom image. On the right side, we see the hierarchy of the structures of the medial temporal lobe, that have since been studied extensively, to determine and to conclude that this area of the brain is critically important again for that type of memory. But patient H.M., was tested with a number of different tasks. In one task, he was asked to draw a star, you see the star on the bottom of the screen, with two double lines. He was asked to use a pencil and draw between those two lines, draw the star without touching the lines. So this is obviously a somewhat tricky task. It was made even more difficult by asking him to do it while looking in a mirror. So he wasn't able to directly observe his hand in his work. He had to do it in a mirror image. Now what you see on the right hand side in the diagram, is that over the course of several days he did improve by making fewer and fewer errors completing this task. That is, he was learning how to do this task. He was making improvements in his performance on the task. Yet when you asked him if he had completed this task before, he would say that he had no memory of ever doing this task before. This led Brenda Milner a famous neuropsychologist who studied H.M., extensively to conclude that there must be multiple memory systems in the brain. The medial temporal system which I just talked about, responsible for memory for facts and events as well as a different memory system which may be important for motor learning. And in fact from much subsequent research we have learned that there are multiple systems in the brain in fact that support memory functions. The medial temporal lobe being the most prominent one but also the basal ganglia which consists of a number of brain structures as shown in the bottom right hand image. Including the caudate nucleus and the thalamus as well as the putamen. The basal ganglia are critically important for fine motor planning and movements. And the striatum which is predominantly the caudate and putamen are involve in the reward learning, reward reinforcement as well as some forms of learning, particularly motor learning and stimulus response types of learning. So here we see examples of different systems in the brain that support our different types of memory functions. There are other areas of the brain that have very, very specific cognitive functions. Highly specialized areas. For example, the fusiform face area, as shown here on the top right is critically important for recognizing faces. The extrastriate body area, shown in the red circle on the bottom image, is critically important for recognizing body parts or parts of the body as whole or individual parts of the body. So highly specialized areas in the brain that form a very specific function. People with damage to the fusiform face area are called prosopagnosia patients. Even though they're able to recognize the individual pieces of a face they're unable to recognize the person and name the person. They often have to identify a person by listening to them talk, or some other means. They're not able to recognize the face as a person they know. So they have an inability to recognize familiar faces. So, in this module, we've discussed a number of cognitive functions that have known structures in the brain that support them. In the previous module, we discussed the primary motor cortex and the somatosensory cortex. We've talked about visual processing and motor planning. We've also talked about the basal ganglia in this particular module, supporting memory function, language functions in the Broca and Wernicke's areas, and several other areas that we have well established the known functions of. But as you can see from this module, a lot of this information was learned from studying patients who have extensive damage to the brain. Patients who were involved in accidents or patients that experienced viruses that caused damage to the brain. Really significant trauma that allowed us to draw these types of conclusions. In the next module, we're going to talk about neuropsychological assessment. Which is a fine tuned assessment method for trying to figure out what areas of the brain are responsible for very specific functions that are important for cognition.

Neuropsychological Assessment of Cognition

In the previous module, we discussed different brain systems and what their functions are based on extensive research of the cell properties, the neurotransmitters, and the behavior that's associated with these brain areas. In this module, we're going to talk about neuropsychological assessment of cognition which is a method that is commonly used to try to assess the function of different brain areas in healthy control subjects with normal cognitive function as well as patient who have impaired cognitive function. Neuropsychology is an applied science concerned with the behavioral expression of brain function. Again, in normal healthy subjects with normal cognition but especially in patients with impaired cognitive function. The purpose is often on diagnosis to try to figure out what brain disorder or brain disease a patient may have based on their behavioral performance. Patient care and planning, how to best take care of a patient depending on their cognitive abilities and understanding and plan what cognitive areas need the most attention going forward. As well as rehabilitation and treatment planning. And finally, obviously, very commonly used in research to try to assess, behaviorally, what brain areas are responsible for what type of behavior and give rise to what type of cognition. Behavior is very complex and it is important to remember the cognition performance distinction. For example, if we try to assess memory function in a particular person, we can observe their behavior and try to determine if they have learned and remembered a certain piece of information. However, we must also keep in mind other factors that could contribute to that performance, to that behavior. Sensory abilities, are they able to see and hear the instructions of the task? Attentional abilities, are they paying attention or are they capable of attending to the instructions on the task at hand? Can they perceive the information? Are they motivated to participate in the test? Are they emotionally capable of participating in the task and following the instructions? And do they have the motor capacity to execute the behavior if it concerns drawing or writing or anything that requires a motor response? Although we are trying to assess something about learning and memory in these particular situations, all the other aspects listed here contribute to the overall performance and must be evaluated to determine if the impairment is truly due to memory or some other type of impairment in one of the other domains listed here. In

general, in neuropsychological assessments, we're focusing predominantly on three dimensions of behavior: cognition, very importantly emotionality, and finally executive functions. And we're going to step through some of these and talk about tests that are used to assess these functions. Initially, the assessment of cognition was generally thought to be a single function known as intelligence. It was used very commonly particularly in the army enrollment as a single measure of ability defined by IQ, the intelligence quotient. They used standardized tests in decided verbal and performance IQ. And the score was centered around 100, in the sense that a person with a score of 100 had a perfectly average IQ whereas 60s and 70s would be very low IQ and 132 or 140 score would represent a very high IQ. A lot of data was collected from the general population to establish these norms and evaluate what the general capacity or the general ability was of a single person compared to that population. Since then, IQ is still considered to be a very valid measure but it has clearly been shown to not be sufficient to be a measure of a person's overall cognitive ability or cognitive ability in certain specific domains. IQ tests are still being used today but, in addition, cognitive functions in specific domains are very frequently assessed including receptive functions – the ability to understand spoken language or written text. Memory and learning – our ability to learn and retain information over short periods of time or over longer periods of time. Thinking – our ability to problem solve, to do mental tasks, to do arithmetic, for example, and provide the answer. And finally, expressive functions – our ability to express the correct answer or express the correct response through motor control, expressive language, or anything that requires sort of an expressive answer to the question. There are many types of assessments that have been developed to address each of these categories. There are still in use very frequently intelligence tests that are used to assess the person's overall cognitive ability. There are specific tests to examine perception, examine language both receptive language and expressive language. There's a host of memory tests that are used to determine if a person can learn and remember novel information and to what extent they're able to do that, visuospatial abilities, and finally executive function. Again, we're going to go through a couple of examples of tests to show how these things are evaluated and how these things are tested. Assessment through these types of methods, a presupposes some ideal, normal or prior level of functioning against which the person's performance is evaluated. Often this is done by means of a population average just like the intelligence testing that was done in the past. Tests are designed and tested on a large number of people in the general population. And a mean in standard deviation is established to determine if a person is one or two or three standard deviations above or below the mean compared to that population. Very often, the population is broken down by gender and in some cases also by education to provide smaller populations and provide the best comparison for a person's individual score. The important aspect from this comparison to the general population is that it requires very strict conditions to equate the possibility of performance. In the testing environment, all the conditions must be the same for the individual subjects as they were for the general population to make a reasonable comparison. This includes simple things like lighting and a quiet environment to perform as best as the person can but also very strict and standardized instructions and methodologies of administration. Again, to make sure that the person's response is the same as a person in the general population. Ideally, information is available from a person's individual performance from past assessment from a past measurement. Very often such baseline information is not available but if it is in longitudinal assessments, it provides a very strong measure of a person's change in a certain cognitive ability over time. Or, a change from prior to an accident or a stroke or some type of insult that occurred to the brain to determine how a person's cognition changed after the injury versus before the injury. There are several approaches to neuropsychological testing. There's a screening approach, a hypothesis testing approach, or a battery approach. For the screening approach, is designed to determine if a person meets certain criteria, for example, for enrollment in a study. If you're conducting a memory study and you want to make sure that a person has a memory impairment you could just do a memory screening assessment to determine if a person has a deficit in memory or not and not evaluate the other cognitive domains. You can also employ that screening to see if additional testing is necessary. If you have a sensitive tool for general cognitive function, you could use that to say if a person is normal, no additional testing is needed. But if a person scores poorly on the general assessment, additional testing would be required. Screening approaches are very flexible and very efficient. They usually don't take a lot of time and there's numerous test that are designed exactly for this purpose. This includes the RBANS, the MMSE which is the Mini-mental Status Exam or the MOCA, the Montreal Assessment of Cognitive Function, all designed to be very brief assessments of general cognition that can be employed in almost any situation. Hypothesis Testing has a slightly different goal. It assesses a specific question or a cognitive domain and it requires a detailed evaluation of that specific cognitive domain or a specific research question that a person is pursuing. Usually, a number of tests are employed to test that one single domain and create a comprehensive assessment of that one function. But the risk of that approach is that you overlook other areas that may be impaired or other areas of cognition that may contribute to the performance of the area that you're interested in. So, hypothesis testing has significant limitations. The neuropsychological battery approach provides the most comprehensive assessment of cognition over all cognitive domains. It requires detailed testing to provide a complete profile of all the different cognitive domains, and it uses a variety of tests to assess each domain. This provides obviously a very comprehensive information of the person's cognitive abilities, but it's very time consuming and expensive sometimes. And it can be very tiresome to the participants as testing can take sometimes six to eight hours to accomplish such a comprehensive assessment. To give you a couple of examples of commonly used neuro psychological assessments, I will now discuss a couple of specific tasks in the cognitive domain that they're designed to assess. For example, if you wish to assess a person's memory very commonly the Wechsler memory scale is used, which is a comprehensive battery to assess the ability to learn and remember information of an individual. Numerous population norms are available, stratified both by gender and by age, to provide the best comparison possible. The scale consists of seven subtests including personal and current information, assessing a person's ability to remember personal details as well as current information such as who the current president of the United States is. It also includes the subscale and orientation both to time and to place, a subscale on mental control and logical memory. For the logical memory component, a person is read a short story about a paragraph long. After completion of the story, the person is asked to remember as many of the details as possible from that story, and the story is repeated several times to see if a person learns more information with additional exposures. For digit span, a person is provided with a series of numbers and asked to recall those numbers. The length of the series has increased to determine how much information a person can retain. For visual reproduction, a person is asked to recall simple figures from memory and draw them. And for the paired associates subtest, a person is given word pairs and asked to remember the pairing of the words. After a short delay, the person is given the first word and asked which is the word that goes with it as they learned in the pairing. Some of these tests include a delayed component. For example, for logical memory after a 20-minute delay, a person is asked to recall how many details they can still remember from that story that they heard a little while ago. Similarly, for the paired associates after a 20-minute delay, a person is again given the first word of the pair and asked to remember what the word pair was. Delayed recall is a particularly sensitive measure of a person's ability to learn and remember information and potential damage to the brain affecting their ability to learn and remember information. An alternative to the works of the memory scale are word list of learning tasks. For word list learning task, a person has read a list of words. After reading the list, a person is asked to recall as many of the words as they can. After which the person is given the list, again and again, to see how many words they can learn over repeated presentations. Commonly, after a delay of about 20 minutes again, a person is again asked how many words they remember from the original list. Providing a measure of their learning and their memory over time. There are many variants of list learning tasks available varying in the length of the list as well as the complexity of the instructions. It's very commonly used to assess the ability to learn and remember information and it correlates significantly with impairment in memory domain and cognitive memory domain and brain injury associated with memory impairment. It provides again measurements of both learning, recall and recognition and its assessment of impairments of encoding and retrieval of new information. And as I mentioned before it very often includes a delayed recall. For executive function, there's a wide variety of tests that are designed to assess executive functioning consisting of four major components: volition, planning, purpose action, effective performance and is often associated with functioning of the frontal lobes. For example, there is Stroop color word test. In this task, the person is asked to read the top row out loud. So read the words out loud from left to right. In the second part of the test, a person is asked to indicate the color of the ink that the Xs are printed in. And again, reading from left to right and reading out loud the colors that they see. For the final condition of the task, the person is again asked to read out loud what the color of the ink is that the word is printed in. We have a propensity to read the word rather than to look at the physical objects of the word. So in this particular task, a person must inhibit their pre-post response not reading the word but instead focusing on the color of the ink that the word is printed in. So this is an assessment of executive function, assessment of attentional control and inhibitory control. An alternative is the Tower of London test. In this task, the person is provided with the following example, a starting position and a goal position. And the problem is the person is asked to determine how many individual moves it takes to make the starting position look like the goal position. The complexity of this task can be increased by providing more balls or by requiring more moves to figure out what the problem is. These are just some examples of neuropsychological assessments for both memory domains and executive functions. But there are many different specialized instruments available. Test batteries can provide a comprehensive assessment of cognitive function and emotional functions and it can provide a relative measure against, against themselves or as a population as a whole. Again, controlling of the administration and standardization is key in order to be able to compare a person's performance against another person's performance, the examination conditions must be made identical. Overall, neuropsychological assessment is a very powerful method to evaluate behavior that comes from brain damage or from normal function. Next, we will start to talk about some other methods by which we evaluate brain function particularly neuroimaging techniques.

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