Why are patients with Alzheimer’s disease so forgetful?

  Neuroscientists have learned quite a lot about the role of acetylcholine and glutamate by investigating what happens when the neurons that release these neurotransmitters are injured or diseased. In the brains of people with Alzheimer’s disease, acetylcholine neurons that project into the hippocampus and cortex slowly die. Glutamate’s penchant for pruning that was so beneficial when the brain was young now becomes responsible for the death of acetylcholine neurons, as well as many other neurons, in the brains of patients with Alzheimer’s disease. The loss of normal acetylcholine and glutamate function in the cortex may be why patients with Alzheimer’s disease have difficulty paying attention to important events in their daily lives. The impaired function of acetylcholine and glutamate within the hippocampus may underlie the debilitating memory loss that is the earliest hallmark of this disease. The impaired function of these neurotransmitter systems in the brains of patients with Alzheimer’s disease has led scientists to design treatments that might enhance the function of acetylcholine.

  How is the memory loss treated?

  Sometimes, the severity of the cognitive symptoms in Alzheimer’s disease can be reduced, at least to some degree, by drugs and dietary nutrients that enhance the function of acetylcholine in the brain. To understand how this is possible, we need to look at how acetylcholine is produced in the brain. Neurons synthesize acetylcholine from choline, which is obtained from the diet, and from acetyl groups that originate in mitochondria from the metabolism of sugar. Sugar is a vital nutrient for your brain’s normal function. The synthesis of acetylcholine occurs within the cytoplasm of your neurons and it is then released to communicate with neurons that are important for learning and memory to occur.

  Many health food stores across America sell choline powder under the pretense that consuming more choline will enable the brain to make more acetylcholine. Given the vital role of acetylcholine in learning and memory, this is an alluring claim. Regrettably, it has no basis in fact. An important thing to realize is that the brain responds only to deficits, not surpluses, in the diet. The brain always has a ready source of choline from the diet (in donuts, cookies, cakes, eggs, beef, and fish) or from stores in the liver and, in fact, never develops a deficit in choline, even in patients with Alzheimer’s disease. Thus, consuming extra choline does not induce your brain to make more acetylcholine. Instead, it only results in a gaseous byproduct that you exhale and that smells like rotting fish. Rather than enhancing your cognitive abilities, choline supplements merely generate a terrible case of bad breath. Once released, the action of acetylcholine is terminated by an enzyme called acetylcholinesterase. Many different drugs are capable of inhibiting this enzyme, causing synaptic levels of acetylcholine to rise. Today, these drugs are given to patients with Alzheimer’s disease to improve their ability to pay attention or remember the day’s events. Although the benefits tend to be limited for most patients, neuroscientists are experimenting with better ways to enhance the action of acetylcholine and thus improve learning and memory abilities for patients with Alzheimer’s disease.

  It is also worth considering what would happen if a neuron could not release acetylcholine at all. The botulinum toxin released by the Clostridium botulinum bacteria that is sometimes found in the foods we eat can inhibit the release of acetylcholine from nerve terminals. Fortunately for your brain, this toxin cannot cross the blood–brain barrier. There is, however, more to you than just your brain. Botulinum toxin can significantly impair the ability of your vagus nerve to control your breathing. Your vagus nerve is responsible for causing the contraction of your diaphragm muscle; when this muscle contracts, it pulls air into your lungs. However, if your brain cannot communicate with your diaphragm via the release of acetylcholine from the vagus nerve, you will stop breathing and die. The botulinum toxin is exceptionally potent; 1 gram is sufficient to kill approximately 350,000 people!

  When acetylcholine and glutamate are functioning normally, however, memories are easily made and stored. The sights, sounds, smells, tastes, and feel of life events are processed by the back half of the human brain; this information then is funneled into the temporal lobe where it becomes organized—primarily by the hippocampus—for long-term storage. We know from many investigations over the past few decades that memories are quite vulnerable to loss during this early stage of processing within the hippocampus. Once the memory is initially processed, it is transferred, usually while you are sleeping, to other brain regions for long-term storage. The most important thing to realize is that a single memory is not located in a single place in the brain; rather, various components of the memory are distributed throughout the brain.

  The best evidence today indicates that a memory involves specific series of structural and biochemical modifications on both sides of the synapse. Simply stated, a memory involves making a change in the efficiency of neuronal connections. If you could miniaturize yourself within a brain, you would see that not every connection between neurons is equally efficient; there is typically quite a lot of noise and error in most neural circuits within the brain. In spite of all of this noise in the circuitry, however, your brain manages to store quite a lot of information.

  What does a memory look like?

  Memory-induced changes can be visualized by currently available techniques; they appear as structural changes in how two neurons form the synapse that connects them to each other. The structural changes often look like raised bumps on the surface of neurons. Learning leads to an increase in the number of these bumps; although they look a lot more like lollipops, they are called dendritic spines. Roughly speaking, bigger dendritic spines indicate stronger connections between neurons and stronger memories.

  Studies have shown that people who extensively utilize their hippocampus, for example, very experienced London taxi cab drivers, actually have significantly bigger hippocampi than do cab drivers who are new on the job. Yes, as the cabby spent his days driving around London, his brain was busy growing and strengthening these connections between neurons in the hippocampus, which allowed him to form mental maps of the city. Drivers with better maps could get their passengers to their destinations faster and more efficiently, a process of path finding that was mirrored deep inside the cabby’s hippocampus.

  Animal studies have confirmed that the density of dendritic spines within the hippocampus also varies according to the stage of the menstrual cycle; the number of dendritic spines decreases after the surge of progesterone at the time of ovulation. If humans demonstrate a similar pattern of changes, then women are most likely to become pregnant when they are least able to remember the circumstances surrounding the event.

  How does nicotine influence brain function?

  Nicotine affects brain function in a dose-dependent fashion via its actions upon the brain’s acetylcholine system. Low doses tend to activate your left hemisphere and produce mental stimulation and a feeling of arousal and attentiveness, whereas high doses tend to activate your right hemisphere more strongly and are closely associated with the sedative effects of nicotine. Therefore, when doing boring tasks, you could take a low dose of nicotine by, say, smoking one cigarette that would increase your subjective feelings of arousal and attention. In contrast, during anxious or stressful situations, you could take a high dose of nicotine by chain-smoking a few cigarettes and actually reduce your stress by activating the right hemisphere and producing a bit of sedation. These findings nicely demonstrate the competing roles of nicotine receptors in the two brain hemispheres and provide some insights into how the two halves of the brain normally function to produce a balance of emotions (in the right side of your brain) and attention and arousal (in the left side of your brain). Acetylcholine nicotinic receptors play an important role in attention; it is now known that 60% of adults diagnosed with attention deficit hyperactivity disorder (ADHD) smoke cigarettes as compared with less than 30% of the rest of the population. These adult ADHD patients are fi
nding ways of self-medicating themselves to improve brain function while simultaneously increasing their risk of developing lung cancer.

  Schizophrenia patients have fewer and more poorly functioning nicotinic receptors, especially in brain areas involved in the expression of their specific cognitive and sensory deficits. For example, the loss of function of these nicotinic receptors in their brains may contribute to impaired attentional abilities and memory. The important role of nicotinic receptors in schizophrenia was inferred based on patients’ distinctive cigarette-smoking habits. Ninety percent of schizophrenic patients smoke; they smoke more cigarettes per day, inhale more deeply, and smoke their cigarettes to the butt more often than non-schizophrenic patients. This smoking behavior is not seen in other mentally ill patients or in other people taking similar antipsychotic medications. The patients claim that smoking improves the clarity of their thoughts and their ability to pay attention to and remember the events of their lives.

  2

  WHY DO I FEEL THIS WAY?

  “How do you feel?” You have asked, and been asked, this question many times. How does your brain answer this question? How you feel is determined by far more factors than your level of happiness or depression. Maybe you feel thirsty or hungry or cold; all of these would affect your answer to the question. Your answer to the question of how you feel is intimately connected with your survival.

  The purpose of your emotions is to control evolutionarily conserved behaviors that are critical to your survival. If you are cold or hungry, you need to act upon this information in order to increase your likelihood of survival. For this reason, your brain has evolved a series of interwoven systems that work together with sensory inputs from inside your body to answer the question of how you feel; this brain network is called the limbic system. The limbic system controls many aspects of your survival, including the balance of energy and water, body temperature, hormones, sexual behavior, and your ability to experience pleasure. The limbic system also influences what you learn and remember. Your limbic system encourages the brain to remember those things, events, or people who pleased or frightened you in order to control future behaviors related to your survival. We rely upon our memory to make decisions about who we like, what foods made us sick, and what places or things frightened us.

  A few cortical regions are considered to be part of the limbic system and play important roles in the expression of emotion; I will focus on just two. The first one is deep inside the brain and is called the cingulate gyrus. Imaging studies have discovered that this part of the brain determines the perceived level of pleasantness and unpleasantness of sensory stimuli, such as pain or the taste of chocolate. When you enjoy the smooth richness and flavor of a piece of chocolate, you can thank your cingulate gyrus. One Freudian psychologist summed up the function of the cingulate gyrus as where your superego and id compete to determine what you will do at any given moment. Another important role of the cingulate gyrus is the control of punishable behaviors; this region provides inhibitory control of behaviors that you have learned to avoid. For example, when you were young, you might have been punished for making loud sounds in public or jumping up and down on the sofa. Many years ago neurosurgeons discovered that if they destroyed small regions at the front end of the cingulate gyrus, patients were better able to control their symptoms of obsessive compulsive disorder, such as repeated handwashing.

  The second cortical limbic region of interest is called the insula; this brain region interprets for us whether we like or dislike complex sensory inputs. The insula lies in a crevice, called the lateral fissure, deep on the side of the brain at about the level of the top of your ear. The insula is activated when we are listening to music that we like, when we hear the voice of someone we like, or when someone we like is stroking our arm. The insula also is activated by disgust, such as having a stranger on a bus begin stroking your arm or begin touching you, or by watching videos of unpleasant or repulsive images. I mentioned these two limbic cortical areas for another reason: the cingulate and insula are selectively activated when subjects report that their minds are wandering. Possibly, when our mind wanders, we activate these brain regions in order to judge the degree to which we like or dislike the contents of our daydream.

  What is fear?

  Judging what you like or dislike allows you to enjoy life. In addition, knowing what you should fear, and quickly recognizing the biological changes in your body that indicate fear, could save your life. This critical task is largely handled by a small almond-shaped structure, the amygdala, which lies deep within the bottom of the brain, not far from your ears. The amygdala receives information from many brain regions, your internal organs, and external sensory systems, such as your eyes and ears. The amygdala integrates this information with various internal drives, such as whether you are hungry or thirsty or in pain; it then assigns a level of emotional significance to whatever is going on. For example, when the amygdala becomes aware that you are alone and hearing unfamiliar sounds in the dark, it initiates a fear response, such as panic or anxiety. It then activates the appropriate body systems, the release of hormones, and specific behaviors to respond to the (real or imagined) threat. The amygdala also is activated by sensory stimuli that seem ambiguous or unfamiliar to us, such as unfamiliar sounds or people. In response to ambiguous or unfamiliar stimuli, we become vigilant and pay closer attention to what is happening in our immediate environment. If you were a dog, your ears would perk up. Your amygdala gathers as much sensory information as possible, compares it to what you already know, and then instructs other brain regions to respond.

  Almost without fail, and regardless of the nature of the information gathered by your vigilant brain, the amygdala usually comes to the same conclusion: be afraid. If a sensory event, such as a sight or sound or taste, is unfamiliar; your limbic system almost always assumes that the situation is potentially dangerous and should be treated as such. If everything is assumed to be dangerous until proven otherwise, you are much more likely to survive the experience and pass on your be-fearful-first genes. Thus, humans fear everything that is unfamiliar or not-like-me: we fear unfamiliar dogs, people who look or dress differently, unfamiliar places, unfamiliar odors, things that go bump in the night, people who stare at us for too long, heights, enclosed small spaces, dark alleys, unknown people who follow us, etc. You get the idea. We all have witnessed the consequences of fear: we hide behind closed doors, we hide in protected or gated communities, we keep a loaded gun by every door and under the pillow, we hire bodyguards, we install security systems, we build walls. Brains evolved to perform one primary function: survival of the individual and the species; fear plays a critical role in survival. Unfortunately, your fear-inducing amygdala occasionally overreacts to trivial or harmless stimuli. Sometimes the amygdala induces behaviors that may get a person mentioned on the evening news.

  Consider the following scenario: You are walking in an unfamiliar wooded area and you are aware of recent reports that snakes have been spotted along your current route. Then, without warning, you spot something brown, round, and coiled up on the ground next to a fallen tree. Your flight-or-fight response to this potential threat is activated immediately, quickly increasing your heart rate, respiration, and blood pressure; then, you realize that it is only a coil of discarded rope. Was your physiological response reasonable and appropriate? Yes, it was, because it prepared you to escape or defend yourself from a perceived danger. Your physiological response was so fast that it preceded recognition of the actual stimulus, the rope, due to the fact that your amygdala appears to receive partially processed sensory information before the more complex parts of your brain have had a chance to identify the true nature of the threat. Your brain evolved to help you survive to pass on your genes to the next generation. The best way to achieve this goal is to induce a response immediately to imagined threats regardless of whether that response is appropriate or not. Whether you are walking down a dark alley or are in a landscape full of snakes
does not make any difference to your brain; you need to prepare yourself for fight or flight to defend your be-fearful-first genes so that you can pass those be-fearful-first genes along to your offspring.

  By now you have clearly gotten the point that being frightened of everything all of the time is a safe and effective way to maintain your species. Unfortunately, it is also quite stressful, and chronic stress ultimately will have negative consequences upon your health. The brain, due to the impact of evolution, does not concern itself with the long-term effects of chronic stress on the body because these negative consequences usually appear long after you have finished reproducing and passing on your be-fearful-first genes to the next generation.

  Due to its control over your emotional response, the amygdala plays a critical role in the decision-making processes in your brain. In order to achieve this goal, the amygdala influences the function of many other brain regions. It activates the frontal lobes of your brain to increase your vigilance to potential threats. The amygdala also controls how your brain processes sensory inputs that are associated with emotional experiences. This is an extremely important function because it determines whether you will remember the details of fearful events. For example, mugging victims tend to distort the details of the tragic event by “remembering” that the mugger was bigger and uglier, the gun was bigger, the alley was darker, etc. Recall my point from Chapter 1, the brain is not an accurate recording device; the influence of the amygdala makes memories more interesting or frightening than the events truly were. The influence of the amygdala, however, also makes it less likely that you will walk down that alley alone again. Your amygdala has succeeded again and your be-fearful-first genes live to breed another day!