Lecture Notes

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:

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.

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:

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.

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.

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.

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)

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.

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.

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.