A Clinical Approach to the Human Brain

Lecture Notes

SES #	TOPICS	LECTURE SUMMARIES
1	Brain Anatomy and Imaging	Brain as seat of consciousness: Historical introduction - Greeks, Descartes, 19th Century phrenology; British neurologist Hughlings Jackson and the modern era. Overview of the regional anatomy of the brain and spinal cord: The regions of the human brain that serve motor and sensory functions, vision, hearing, smell, coordination, language, memory and emotion Cerebral cortex and white matter Brain stem and cerebellum Thalamus and Hypothalamus Basal ganglia Ventricles Cranial nerves A quick tour of the regional anatomy of the brain is introduced using figures, computerized axial tomography (CT) images, and magnetic resonance images (MRI) from normal subjects and individuals with strokes and other diseases to illustrate brain function.
2	Cells and Brain Imaging
3	Synaptic Potentials	A general knowledge of the cellular basis of brain function is essential to understanding how drugs such as antidepressants, memory enhancing drugs, or stimulants such as Ritalin work. We will review: Neurons and supporting glia Axons: How neurons carry information from one part of the nervous system to another Axons and their surrounding insulation: The myelin sheath Synapses: How neurons communicate with one another Resting membrane potential: How neuronal membranes maintain a charge with the outside positive relative to the inside Action potential: How depolarization of the resting membrane potential results in a reversal in the charge of the membrane with the exterior becoming negative relative to the interior. How the action potential is propagated along the axon and how information is communicated along the axon up to 2 meters in length. How does synaptic transmission occur? The following will be discussed: Excitatory and inhibitory synapse Release of neurotransmitters and neuromodulators from presynaptic neurons Re-uptake of neurotransmitters The neuromuscular junction Classes of neurotransmitters and neuromodulators: Acetylcholine, amino acids, monoamines and peptides   Clinical Correlation Have you wondered what happens when you hit your “funny bone” or why your leg gets numb from crossing your legs? A common cause of fish poisoning in the tropics is due to a neurotoxin: Ciguatera poisoning from fish consumption. Seizures are caused by abnormally excitable nerve cell membranes. Some anti-seizure medications block membrane sodium channels and stabilize membranes. Seizures may cause involuntary movements or experiences e.g., olfactory and auditory hallucinations, deja vu, and other complex behaviors. See: Singing Seizure Video Neurotransmitters are chemicals which are released by one neuron, the presynaptic neuron, and pass across the synaptic cleft to stimulate the post-synaptic neuron. The post-synaptic neuron can be stimulated (depolarized) or inhibited (hyperpolarized) by the neurotransmitter. Increasing or decreasing the concentration of the neurotransmitter, therefore, can increase or decrease its effect on the post-synaptic neuron. Some diseases have a deficiency of a specific neurotransmitter. For example, in Parkinson’s disease there is a deficiency of dopamine in a specific pathway in the brain. In Alzheimer’s disease there is a deficiency of acetylcholine. In these two cases drugs are administered to patients to increase the concentration of these deficient neurotransmitters. In the case of depression, there is a deficiency of serotonin and norepinephrine. Antidepressants have been developed which will increase the concentration of these neurotransmitters. Early antidepressants, such as tricyclic antidepressants, increase the concentration of both of these neurotransmitters. In the past decade serotonin reuptake inhibitors (SSRI) such as Prozac have dominated the antidepressant market. As the article from the WSJ above indicates there is again a debate over the relative importance of these two neurotransmitters in depression. Readings from Oliver Sacks illustrate “how we know our bodies in space” and how we compensate when we lose one or more of our senses. In order to have an image of “where we are in space” our brain integrates information from our visual system, vestibular system (labyrinth of inner ear), and position sense of musculoskeletal system (proprioception). Information from each of these is integrated which leads to a “map of space” and where our bodies are in that space. Aberration of one of these inputs creates a disorienting experience. For example, alcohol impairs the vestibular system causing incoordination, staggering and falling. In diseases of the eyes, inner ear or nervous system there may be impairment of one of these inputs which leads to spatial disorientation. Some of Dr. Sacks’s cases illustrate how brain plasticity permits one to overcome loss of function of one of these sensory inputs.
4	fMRI of the Human Brain Prof. John Gabrieli, MIT
5	Seeing and Reading Others	The capacity to “read” another person’s emotional status, predict what they will do next or recognize what they think that you are thinking represent among the most important talents of the human brain. In a society where human interaction often determines success such abilities are highly valued. How does the human brain recognize the facial emotions of others or the sarcasm of a voice? It turns out that the neural systems responsible for recognizing facial and aural emotional content relies on the right cerebral hemisphere to a greater extent than the left where grammar and semantic meaning of words are stored.
6	Cognitive Enhancement through Neuropharmacology	Clinical Correlation The brains of patients with Alzheimer’s disease have a reduced amount of neurotransmitter acetylcholine. With our understanding of synaptic transmission, scientists have been able to develop drugs which increase the amount of acetylcholine available and modestly improve memory in Alzheimer’s patients. A recent study has shown that such drugs also work in normal individuals (Yesavage). Additionally, a race among several biotechnology companies now exists to develop memory enhancement drugs to improve normal human cognition (See “Quest for a Smart Pill”). It has been said that other drugs such as methylphenidate (Ritalin), which is prescribed for attention deficit disorder, have been used without a prescription as memory enhancing drugs. Such uses in normal individuals have unknown long term medical consequences and create ethical issues as do the use of steroids in athletes. (Possible final paper topic). Other clinical examples of drugs which affect neurotransmitter function are serotonin reuptake inhibitors (e.g. Prozac) which increases serotonin and alleviates depression but also may act by inducing neurogenesis. Antidepressants are widely accepted and improve memory in depressed patients since impaired memory is a common feature of depression. Does the role that antidepressants play in the modification of the brain affect the debate in regard to the use of memory enhancing drugs?
7	Oxytocin and Trust, Antidepressants and Neurogenesis
8	Neurogenesis: Teaching Old Dogs New Tricks	A surprising discovery in the last few years in neurobiology has been that neurons are born, neurogenesis, in the adult mammalian brain. Initially, this had been shown in animals and, more recently, in the humans hippocampus, the site of declarative memory formation. (See Greenough). Furthermore, the rate of neurogenesis in animals has been enhanced by experience, both physical activity and living in enriched environments (See Scientific American article by Gage). Provocative clinical human studies suggest that memory loss (dementia) can be forestalled by rich cognitive activities e.g. board games, crossword puzzles. These animal and clinical studies may lead to a strategy for preventing dementia in humans.
9	Test 1
10	Critical Periods: Implications for Education	The nervous system has a structural organization which is genetically determined to some degree but in order for the brain to develop normally, it requires experience. This is called experience-dependent brain development. An example is the child born with a cataract. If the cataract is not removed at an early age the person will never develop normal vision in the affected eye even if it is removed later. Alternatively, a person who acquires a cataract as an adult can have the cataract removed many years later and have normal vision after it is removed. The difference in outcome is due to the “critical period” of the visual system development in childhood. Neurobiological studies have shown that opportunities exist for brain development in childhood and that once the window of opportunity closes, it never reopens. The mechanism of this is being elucidated at a molecular level and is a major area of research. The implications for childhood development, public policy and educational programs are enormous; because, as outlined in subsequent classes, for many skills we seem to have an opportunity to learn at a young age which then closes later. For example, in the case of learning a foreign language with a native accent the window of opportunity closes at about puberty in most individuals. The articles by Christakis and Penn and Schatz demonstrate that the consequences of early experience have long-lasting behavioral and structural consequences. Throughout early childhood a much larger number of synapses form than ultimately exist in the adult. This is because those synapses which are ‘used’ in childhood survive and are strengthened at the expense of unused synapses which are pruned and die back during later childhood and adolescence; The ‘used’, and retained, synapses follow the rule first enunciated by Hebb, “neurons that fire together wire together.” Critical periods of brain development provide opportunities to permanently alter the brain wiring. Furthermore, knowledge of brain development provides a basis upon which to define educational programs. For example, the acquisition of a second language before puberty generally results in a native accent, whereas, learning a foreign language after puberty usually results in a foreign accent. The article by Kim demonstrates that when a second language is learned during early childhood the same region in Broca’s area (left frontal lobe) is used for both native and second language; alternatively, when the second language is learned later in life, the second language is located in a region adjacent but not superimposed to the native language. Accent may be one of the phenotypic expressions of this difference in localization.
11	Neuroplasticity in the Adult	Primary motor cortex in the frontal lobe is organized in such a way that the left side of the brain controls the right body and that the foot neurons are near the crown of the head and the hand is midway between the crown and the ear and the mouth is just above the ear (Homunculus). These neurons control individual movements according to this motor map of the cerebral cortex. The map was first discovered by Dr. Wilder Penfield a neurosurgeon who stimulated the brain in awake patients undergoing epilepsy surgery. He was able to map different parts of the brain to different motor and sensory functions. The premotor cortex lies in front (anterior) to the motor cortex and its role is to plan voluntary movements. It is activated in mental rehearsing of a movement such as piano playing or pole vaulting before the actual execution. Several studies have shown that even in adulthood the motor map of the brain can be modified. Studies in animals have shown that increased finger use enlarges the area of the “brain real estate” devoted to those fingers. In humans, Elbert has shown in string players that the size of the brain cortex, on the right side of the brain, devoted to the left hand is enlarged. Alternatively, if a finger or limb is amputated the adjacent functional areas “invade” the unused area and make use of it; another example of competition between neurons and the adage “use it or lose it”. Recent studies using a technique called constraint behavior therapy actually limits the use of a good limb to increase the function of the impaired limb such as in cases of cerebral palsy with promising results. This is an example of basic science leading to important clinical discoveries and benefits to patients.
12	Language, Dyslexia and Universal Grammar	Language which includes both oral and written forms of communication is lateralized to the left cerebral hemisphere in nearly all right-handed individuals and in most left-handed individuals. Disturbance of language function is called aphasia. When reading alone is disturbed it is termed dyslexia. Recent fMRI studies show that in dyslexia both cerebral hemispheres are activated (Simos). When children undergo successful treatment, activation is normalized to the left cerebral hemisphere. Functional imaging of the brain (fMRI) has permitted linguists to study the structure of language. Universal grammar has been proposed as an underlying structure of all languages. Recent studies have shown that if one learns a new foreign language with native grammar, Broca’s area, the region of the brain needed to use grammar, is engaged. However, if the new foreign language is learned with an artificial grammar, Broca’s area is not engaged to speak the new language; rather other areas of brain are used and the subjects have difficulty learning the new language. The findings of this study have been used as evidence to support the argument of universal grammar.
13	Visual System I	The visual system is the most studied system in the cerebral hemispheres and information learned here is often used as a model for understanding other systems such as auditory, olfaction, limbic, motor, and sensory. Visual information is relayed from the retina to the primary visual cortex of the occipital lobe. However, visual images achieve meaning when they are then analyzed in the adjacent parietal and temporal lobes. Because it is in these areas that remembered patterns, engrams, are stored from prior experience. For example the left temporal lobe is the site of recognizing letter symbols as words in reading; the right temporal and parietal lobes “contain the maps” and injury to this area can lead to topographic agnosia, such as the inability to find one’s way in one’s own house; injury to the undersurface of the temporal lobe can lead to inability to recognize faces, prosopagnosia. While we were able to localize these functional regions of the brain because patients with injuries to certain areas would manifest specific deficits (see Bisiach and Luzzatti above), we can now use functional imaging to study normal brain physiology in healthy individuals. Injury to the right side of the brain can result in neglect of the left side of the body or the entire left side of internal and external space. The case of the man who mistook his wife for a hat, which illustrates this phenomenon, will be discussed.
14	Visual Neglect and Prosopagnosia	The left temporal lobe is the site of recognizing letter symbols as words in reading; the right temporal and parietal lobes “contain the maps” and injury to this area can lead to topographic agnosia, such as the inability to find one’s way in one’s own house; injury to the undersurface of the temporal lobe can lead to inability to recognize faces, prosopagnosia. While we were able to localize these functional regions of the brain because patients with injuries to certain areas would manifest specific deficits (see Bisiach and Luzzatti above), we can now use functional imaging to study normal brain physiology in healthy individuals. Injury to the right side of the brain can result in neglect of the left side of the body or the entire left side of internal and external space. The case of the man who mistook his wife for a hat, which illustrates this phenomenon, will be discussed.
15	Rembrandt, Leonardo, Monet: How we See Them	The most sophisticated image processor imaginable, the brain uses several techniques to see. Among those that have been best studied, the visual system can sharpen borders and localize objects in space. We are beginning to understand some of these mechanisms. For example, an on-off (on-center and off-surround) organization of neurons from the retina to the primary visual cortex causes light objects bordered by dark objects to appear brighter than when they are not bordered by dark objects. An illustration would be a Rembrandt etching where a window is surrounded by darkness appears whiter or brighter than the paper it is printed on. In this case, the center-surround organization of the retinal cells and the visual cortex cause the light-stimulated neurons to actually have more activity (action potentials) when the surrounding cells are inactive than when the surrounding cells are stimulated. In the example of the “where pathway” in the parietal lobe, contrast in luminance (value in art parlance) is used to identify the location of things (Livingstone). When the contrast in luminosity of adjacent colors is low, the parietal lobe has difficulty in identifying where something is in relation to its surroundings. When the contrast in luminosity is high the parietal lobe can readily localize objects in relation to one another. Renaissance artists used high contrast in luminosity to create the appearance of mass and volume. In fact, Leonardo wrote about the importance in using paint with high contrast in order to create the appearance of volume. Michaelangelo used extreme contrasts in luminance to create massive figures. Alternatively, Impressionists such as Monet attempt to paint light and movement and avoid mass. They use subtle variation in luminance in order to achieve this effect. Modern artists use this knowledge to create visual illusions and “tricks.” By studying different paintings we shall explore how differences in luminance are interpreted by the brain and thus how the brain works. (See Livingstone for discussion)
16	Sensory System and Pain	Sensations from different regions of the body travel to different regions of the brain. This brain map is called a homunculus since the cartoon of the cerebral cortex illustrating different body regions looks like a person; foot at the crown, hand in the middle and face at the bottom of the parietal lobe. The homunculus can be modified based upon experience in both the child and the adult. Practicing piano changes the homunculus hand region in the brain. Cortical mapping studies of the homunculus in humans with syndactyly (fused fingers at birth) and experimental cortical mapping studies in monkeys will be discussed. Phantom limb syndromes (sensations experienced in amputated limbs) demonstrate the effect of amputation on the cortical map. These studies demonstrate that the homunculus is “plastic” or modifiable and have profound implications for teaching us how the brain learns. These studies also reveal the opportunities to improve function in the healthy and the brain injured. The sensation of pain includes both the sensory component as well as the emotional or suffering component. The sensory component is found in the thalamus and the parietal cortex, the somatosensory cortex. The emotional or suffering element of the experience has been reported to be in the anterior cingulate cortex, a region of brain within the limbic system. The limbic system is phylogenetically an old part of our brain and is concerned with emotions and feelings. Individuals who feel pain but do not experience the suffering or affective component of pain have been shown to have diminished activity in the anterior cingulate gyrus.
17	Placebo, Empathy, and Theory of Mind	Placebos are inert substances which have physiological consequences. It has been reported that the placebo response to pain remedies accounts for about 30% of the responses. Recent functional imaging studies have demonstrated that the placebo response is mediated by the frontal lobe which anticipates a pain stimulus; this activates the endogenous opiate pathway in the midbrain, the periaqueductal grey, which is known to send fibers to the spinal cord blocking (gate) the entrance of pain impulses into the spinal cord. This new imaging data explains why opiate antagonists block the placebo response. Thus the placebo response and the expectancy of pain response rests on a physiological mechanism. (Wager) Empathy is the feeling we experience when we share in the feelings of others. fMRI studies show the regions of brain which are activated during the experience of empathy. In the study by Singer, women were put in an fMRI scanner and were studied when they or their significant others were administered a painful stimulus. When they realized that their friend was being stimulated they showed activation of the affective region, the limbic system but not the sensory region of their own brains.
18	Test 2
19	Emotions and Feelings: Romantic and Maternal Love	Emotion-triggering sites of the brain are the limbic system - the amygdala, prefrontal cortex and the cingulate. Activation of these sites leads to activation of the hypothalamus which, in turn, causes visceral and musculoskeletal changes such as palpitations, goose bumps, sweaty palms, etc. Joy and sadness are associated with activation of different regions of the limbic system on fMRI. Painful stimuli also lead to activation of the limbic system. Placebos, pharmacologically inert substances, can alleviate pain in many individuals, which has been claimed to mean that the pain was imaginary. However, the placebo response is blocked by opiate antagonists revealing that the pain is not imagined. As discussed in the pain class, activation of the periaqueductal grey matter by placebos can block (gate) the entry of pain impulses in the spinal cord. Bartels et al. report that they have found the regions of brain activated during the experience of recently realized romantic love. As discussed in a later class, this is different from the region of brain activated in maternal love.
20	Neuroscience and Marketing: Hitting the “Sweet Spot”	Why are emotionally charged experiences remembered so well? Why does one sometimes get an unconscious feeling that someone is staring? The answer may be that the amygdala which sits near the hippocampus is activated when we are confronted with frightening experiences such as threatening facial expressions. In addition, if threatening expressions are visually presented to us for a few milliseconds which is too short to consciously see the image, the amygdala is activated as well. There is a visual pathway to the amygdala from the thalamus which does not pass through the visual cortex and thus the image does not reach consciousness. Advertisers and other marketers can use this to influence people’s emotions when presenting other information i.e., associating a product with the feeling of fear or joy at an unconscious level. Alternatively, the prefrontal cortex is reported to be the site stimulated when one feels the need to have an object. Advertisers are taking notice and a field of “neuroadvertising” is developing; see Thompson, NYT magazine. Emotionally-charged experiences are remembered more readily than others; consider 9/11. These memories are stored through both the hippocampus and limbic system. Drugs such as adrenergic blockers and benzodiazepines can block this effect. Some have tried to “unmake” emotionally charged memories through the use of drugs that block neurotransmitters in the limbic system. See Unmaking memories. Why we sleep is unknown. But according to a report in Nature this year, it may pay to “sleep on it.” Wagner et al. report that subjects who were presented a problem and then slept did better in solving the problem than if they did not sleep afterwards.
21	Learning and Memory: The Case of HM	Memory has been classified as explicit and implicit. Explicit memory is that for facts, dates, locations and the like. Examples of implicit memory are procedures and priming. Explicit memory requires the hippocampus for encoding new information. A tragic incident involving a man known as HM occurred when both his hippocampi were removed over 50 years ago in an effort to treat his epilepsy. It was not known that he would lose the ability to encode new memories. He thus can recall events in detail from before the surgery such as World War II but cannot recall people he has met repeatedly for the past 50 years. We shall discuss his findings including his MRI.
22	Structure and Function of Brains with Superior Memory	Explicit memories are stored in multiple locations distributed throughout the cerebral cortex. For example, spatial memories localize to the right cerebrum. Furthermore, experienced taxi drivers are reported to have larger right hippocampi than controls (Maguire). Recall of words activates the left hippocampus (Maguire). Individuals with superior memories often use a technique known for over 2500 years as the “Method of Loci” whereupon facts are related to locations. When these superior memorizers demonstrate their skill and undergo fMRI studies, the right cerebral hemisphere which is associated with spatial localization is activated, thereby corroborating the technique they report that they use. The hippocampus is needed to acquire new explicit memories, as shown with HM. Alzheimer’s Disease affects the hippocampus early in the disease process and not unexpectedly, memory loss for recent events is a dominant symptom. Although treatment with drugs which increase the neurotransmitter acetylcholine provide modest symptom relief, there is no cure or way of stemming the disease progression. There are, however, new imaging techniques which claim to diagnose the disease through reduced metabolism in certain brain regions, parietal lobes, or showing progressive atrophy of the hippocampi. Currently Medicare will not pay for these procedures. These tests have a high incidence of false positive results as well as false negative results. We will discuss specificity, false positive rate, and sensitivity, false negative rate; an inherent problem in all diagnostic tests in medicine. The question “Should Medicare pay for imaging to diagnose Alzheimer’s disease?” is a possible final paper topic.
23	How Emotion and Antidepressants Affect Memory	As common experience reveals, our recall for emotionally salient events is far superior to that of emotionally neutral experiences. The article by van Stegeren reveals that as in the case of blindsight the limbic system (amygdala in particular) is actively engaged in encoding emotionally charged experiences with both positive and negative valence. In addition, norepinephrine appears to be a major neurotransmitter necessary for this to occur. Administration of beta antagonists have been reported to mitigate the enhanced recall of emotionally charged experiences and are being investigated as a treatment to prevent post traumatic stress disorder. van stegeren and colleagues show through fMRI studies that activation of the amygdala occurs when emotionally charged material is presented to subjects. Moreover, the amygdala is attenuated with the administration of beta antagonists and the enhanced recall is diminished. Several corollary questions arise from these observations. Could memory be enhanced by stimulation of the norepinephrine system? It is known that tricyclic antidepressants which inhibit the reuptake of norepinephrine improve memory in depressed patients. Is this accomplished through this pathway or another pathway? Could other beta agonists be used in normal individuals as memory enhancing drugs? This article and the references cited emphasize the intimate interaction of the “rational” and “emotional” brain discussed in the neuroeconomics paper in the first classes.
24	Depression, Anxiety and Psychosis	Neuropsychiatric disorders such as anxiety and depression affect millions of Americans. Tens of billions of dollars are spent on the treatment of these disorders annually. Historically, psychoanalysis and behavioral therapies dominated the treatment milieu. In the past three decades, based upon our increased understanding of neurotransmitters, pharmacologic treatment has emerged as the dominant intervention in the medical community. However, pharmacologic and cognitive behavioral treatments are debated as to their relative efficacy. New imaging studies in the treatment of depression reveal that pharmacologic and cognitive behavioral therapies may work in different ways and have different durations of benefit. The study in Arch Psych 2004 above indicates that cognitive behavioral therapy has a more durable response. The debate is not showing any signs of resolution. A case report by Bejjani of a patient undergoing brain surgery with deep brain stimulation resulted in a depressive manifestations and feelings reported by the awake patient. It is an interesting article because it demonstrates that electrical activity in the brain is the cause of depressive manifestations and not the effect. Psychosis such as schizophrenia has been postulated in some cases to be due to an excess of monoamine neurotransmitters in selected pathways in the brain. This is based upon the observation that monoamines, such as dopamine, and drugs which cause an increase in monamines, such as LSD, cause psychosis. Alternatively, antidopaminergic drugs can effectively treat psychosis. Another example is in patients given the precursor to dopamine, L-DOPA, who can develop psychosis as seen in the movie, Awakenings, by Dr. Oliver Sacks.
25	Vision, Memory and Feelings: Binding them Together	When viewing a facial expression in a painting or a person, we often share a complex array of feelings and emotions. This is sometimes called “emotional contagion.” While empathy for pain activates the cingulate gyrus, fMRI studies now show us that the perception of facial expression of disgust activates the insula, the site of disgust activation when we personally experience it. In addition, the amygdala, a portion of the limbic system anterior to the hippocampus in the temporal lobe, is activated when viewing fearful and happy faces although the two patterns are different. Finally, the overwhelming love that a mother feels when she is viewing a photo of her newborn baby has been found to be associated with activation of the orbitofrontal cortex. Of interest, this is a different activation region from that seen in couples who are recently romantically involved; which provides a basis for the argument that there are different forms of love.
26	Music, Math and the Brain	Musicians with perfect pitch show unique activation of the brain. We will see how fMRI has revealed how the organization of the brain is modified by training and rehearsal. For example, we will see that the area of brain which allows our fingers to move and feel is reorganized in musicians who rehearse intensively (Schlaug). Indeed even mental rehearsing has been shown to cause the brain circuits to reorganize while at the same time improving performance (Pascual-Leone). Math prodigies show unique activation of the brain when performing calculations (Presenti).
	Additional Topic: Consciousness / Neuroeconomics	Consciousness, The Permanent Vegetative State, and Public Policy The “What if” and the “Governor Bush” articles (cited above) raise issues about consciousness and when patients should be allowed to die. Unlike brain death, the permanent vegetative state can last for years. The vegetative state has been a clinical diagnosis based upon the neurological examination (See Practice Parameter). However, functional imaging has suggested that there are “islands” of the cerebral cortex that are functioning at more than 50% of normal. However, ‘binding’ of multiple areas of brain (not just isolated islands) appears to be necessary for there to be consciousness. Nonetheless, these findings are generating a debate as to whether these patients should be permitted to die and whether there is more hope that they are conscious than had been thought. In addition, there is now a new diagnosis which has been proposed, “the minimally conscious state.” These complex medical issues have enormous personal, ethical, societal and legal implications as we grapple with patient management decisions. Neuroeconomics The brain provides the means by which we have thoughts, memories, reason, feelings, emotions, motor and sensory skills and social interaction. Many fields are emerging which undertake the study of the brain in order to better understand their own discipline. Examples of these fields have been termed neuro-esthetics, neuro-linguistics, neuro-ethics and neuro-economics. Neuro-economics is a fascinating field because it endeavors to understand both the rational and emotional components of social interactions (economics) which take place among people through study of the brain. I have chosen to select a paper on neuro-economics in order to introduce the concept that the human brain has both rational and emotional components which affect one another. Through functional imaging of normal subjects and patients with specific brain lesions we can learn how the brain works as illustrated by economic or social consequences. The brain contains about 100 billion neurons (nerve cells). These neurons are connected to one another at microscopic sites called synapses to form circuits. Neurons work in groups so that many neurons and synapses will function together in a circuit when the brain is undertaking a certain task. In order for neurons to function a large amount of energy requiring oxygen and glucose is necessary to maintain electrical gradients across their membranes. The brain is organized in such a way that different regions serve different functions. For example, there is a visual area that is used to see and a motor area which is used when executing a movement. There is even an area that plans the movement before it is actually executed. In the visual system there are associated areas which relate the visual information to previously learned information. When new information matches previous information it is recognized and recalled; sometimes with an emotional component, as when we see a loved one, which arises from a different part of the brain, the limbic system. Since this process requires abundant energy, there is an increase in blood flow, to carry oxygen and glucose, to the regions of brain that are doing the additional work. Since MRI can measure blood flow, we can map blood flow and thereby map the function of different regions of the brain when the subject is performing specific tasks. The technique called functional MRI (fMRI) has emerged in the past decade and has provided an enormous amount of new information about the functioning of the normal brain. Prior to this neurologists and other neuroscientists were dependent upon damage to the brain to determine its functional organization. Other techniques such as PET can be used to measure blood flow but require the administration of a radioactive isotope. However, one advantage of PET is that we can also measure transmitter function at synapses through the use of radio-isotopes. Another technique, magnetoencephalography (MEG) measures brain electrical activity directly and has also been used. Throughout the course we will read articles which use these new technologies to study how the brain is activated in several behaviors, both simple as well as complex. For example as subsequent class syllabi indicate we will look at learning and memory; language, both native and foreign; dyslexia; grammar; romantic love and maternal love; fear; empathy; the organization of musicians’ brains, among others.
	Additional Topic: Can Thinking Prevent Dementia?	There is considerable hope, and some limited evidence, that dementia can be avoided or delayed by engaging in cognitively stimulating activities (eg. crossword puzzles). This hope relies upon the ‘mutability’ or plasticity of the adult brain. If such a benefit occurs it may be based upon neurogenesis or plasticity of synapses. The clinical evidence is limited and based upon observational studies (See Verghese and Wilson) for the most part. The one prospective randomized trial (Ball) showed that engaging in cognitively stimulating activities improves testing results but does not change the performance of activities of daily living. The editorial by Coyle reviews the evidence. The major limitation of these studies is the question of whether it is the cognitive activities themselves which prevent dementia or whether individuals who at baseline perform more cognitive leisure activities do so because they have more cognitive reserves and, therefore, have a reduced risk of dementia. An oft-quoted retrospective study of nuns looked at the complexity of language structure which young nun novitiates had used to determine if it predicted later dementia; the authors found that those nuns which had used complex language structure had a lower late-life risk of dementia. The implication being that the ability to use complex language structure at a young age reflected increased cognitive reserves which somehow is associated with a reduced risk of late life dementia. Other studies have reported that there is a lower frequency of dementia in those with a higher level of education. Again, the mechanism of this is unknown but it is another incentive to study. For the athletes in the class, there may be an alternative; exercise has also been found in some animal studies to enhance neurogenesis. Recall that neurogenesis, which occurs in the hippocampus, may be associated with enhanced memory function. We will focus on the abstracts and the baseline characteristics of the clinical studies, including their limitations, and discuss the Coyle editorial. This clinical topic along with the animal studies from the neurogenesis literature is another suggestion for a final paper.