After studying this chapter, you should be able to:
Describe the various forms of memory.
Identify the parts of the brain involved in memory processing and storage.
Define synaptic plasticity, long-term potentiation (LTP), long-term depression (LTD), habituation, and sensitization, and their roles in learning and memory.
Describe the abnormalities of brain structure and function found in Alzheimer disease.
Define the terms categorical hemisphere and representational hemisphere and summarize the difference between these hemispheres.
Summarize the differences between fluent and nonfluent aphasia, and explain each type on the basis of its pathophysiology.
A revolution in our understanding of brain function in humans has been brought about by the development and widespread availability of positron emission tomographic (PET), functional magnetic resonance imaging (fMRI), computed tomography (CT) scanning, and other imaging and diagnostic techniques. PET is often used to measure local glucose metabolism, which is proportional to neural activity, and fMRI is used to measure local amounts of oxygenated blood. These techniques provide an index of the level of the activity in various parts of the brain in completely intact healthy humans and in those with different diseases or brain injuries (see Clinical Box 15–1). They have been used to study not only simple responses but complex aspects of learning, memory, and perception. Different portions of the cortex are activated when hearing, seeing, speaking, or generating words. Figure 15–1 shows examples of the use of imaging to compare the functions of the cerebral cortex in processing words in a male versus a female subject.
FIGURE 15–1 Comparison of the images of the active areas of the brain in a man (left) and a woman (right) during a language-based activity. Women use both sides of their brain whereas men use only a single side. This difference may reflect different strategies used for language processing. (From Shaywitz et al, 1995. NMR Research/Yale Medical School.)
CLINICAL BOX 15–1
Traumatic Brain Injury
Traumatic brain injury (TBI) is defined as a nondegenerative, noncongenital insult to the brain due to an excessive mechanical force or penetrating injury to the head. It can lead to a permanent or temporary impairment of cognitive, physical, emotional, and behavioral functions, and it can be associated with a diminished or altered state of consciousness. TBI is one of the leading causes of death or disability worldwide. According to the Center for Disease Control, each year at least 1.5 million individuals in the United States sustain a TBI. It is most common in children under age 4, in adolescents aged 15–19 years of age, and in adults over the age of 65. In all age groups, the incidence of TBI occurrence is about twice as high in males compared to females. In about 75% of the cases, the TBI is considered mild and manifests as a concussion. Adults with severe TBI who are treated have a mortality rate of about 30%, but about 50% regain most if not all of their functions with therapy. The leading causes of TBI include falls, motor vehicle accidents, being struck by an object, and assaults. In some cases, areas remote from the actual injury also begin to malfunction, a process called diaschisis. TBI is often divided into primary and secondary stages. Primary injury is that caused by the mechanical force (eg, skull fracture and surface contusions) or acceleration–deceleration due to unrestricted movement of the head leading to shear, tensile, and compressive strains. These injuries can cause intracranial hematoma (epidural, subdural, or subarachnoid) and diffuse axonal injury. Secondary injury is often a delayed response and may be due to impaired cerebral blood flow that can eventually lead to cell death. A Glasgow Coma Scale is the most common system used to define the severity of TBI and evaluates motor responses, verbal responses, and eye opening to assess the levels of consciousness and neurologic functioning after an injury. Symptoms of mild TBI include headache, confusion, dizziness, blurred vision, ringing in the ears, a bad taste in the mouth, fatigue, disturbances in sleep, mood changes, and problems with memory, concentration, or thinking. Individuals with moderate or severe TBI show these symptoms as well as vomiting or nausea, convulsions or seizures, an inability to be roused, fixed and dilated pupils, slurred speech, limb weakness, loss of coordination, and increased confusion, restlessness, or agitation. In the most severe cases of TBI, the affected individual may go into a permanent vegetative state.
The advancements in brain imaging technology have improved the ability of medical personnel to diagnose and evaluate the extent of brain damage. Since little can be done to reverse the brain damage, therapy is initially directed at stabilizing the patient and trying to prevent further (secondary) injury. This is followed by rehabilitation that includes physical, occupational, and speech/language therapies. Recovery of brain function can be due to several factors: brain regions that were suppressed but not damaged can regain their function, axonal sprouting and redundancy allows other areas of the brain to take over the functions that were lost due to the injury, and behavioral substitution, by learning new strategies to compensate for the deficits.
Other techniques that have provided information on cortical function include stimulation of the exposed cerebral cortex in conscious humans undergoing neurosurgical procedures and, in a few instances, studies with chronically implanted electrodes. Valuable information has also been obtained from investigations in laboratory primates. However, in addition to the difficulties in communicating with them, the brain of the rhesus monkey is only one-fourth the size of the brain of the chimpanzee, our nearest primate relative, and the chimpanzee brain is in turn one-fourth the size of the human brain.
LEARNING & MEMORY
A characteristic of animals and particularly of humans is their ability to alter behavior on the basis of experience. Learning is acquisition of the information that makes this possible and memory is the retention and storage of that information. The two are obviously closely related and are considered together in this Chapter.
FORMS OF MEMORY
From a physiologic point of view, memory is divided into explicit and implicit forms (Figure 15–2). Explicit or declarative memory is associated with consciousness, or at least awareness, and is dependent on the hippocampusand other parts of the medial temporal lobes of the brain for its retention. Clinical Box 15–2 describes how tracking a patient with brain damage has led to an awareness of the role of the temporal lobe in declarative memory. Implicit or nondeclarative memory does not involve awareness, and its retention does not usually involve processing in the hippocampus.
FIGURE 15–2 Forms of memory. Explicit (declarative) memory is associated with consciousness and is dependent on the hippocampus and other parts of the medial temporal lobes of the brain for its retention. It is for factual knowledge about people, places, and things. Implicit (nondeclarative) memory does not involve awareness, and it does not involve processing in the hippocampus. It is important for training reflexive motor or perceptual skills. (Modified from Kandel ER, Schwartz JH, Jessell TM [editors]: Principles of Neural Science, 4th ed. McGraw-Hill, 2000.)
CLINICAL BOX 15–2
The Case of HM: Defining a Link between Brain Function & Memory
HM was a patient who suffered from bilateral temporal lobe seizures that began following a bicycle accident at age 9. His case has been studied by many scientists and has led to a greater understanding of the link between the temporal lobe and declarative memory. HM had partial seizures for many years, and then several tonic-clonic seizures by age 16. In 1953, at the age of 27, HM underwent bilateral surgical removal of the amygdala, large portions of the hippocampal formation, and portions of the association area of the temporal cortex. HM’s seizures were better controlled after surgery, but removal of the temporal lobes led to devastating memory deficits. He maintained long-term memory for events that occurred prior to surgery, but he suffered from anterograde amnesia. His short-term memory was intact, but he could not commit new events to long-term memory. He had normal procedural memory, and he could learn new puzzles and motor tasks. His case was the first to bring attention to the critical role of temporal lobes in formation of long-term declarative memories and to implicate this region in the conversion of short-term to long-term memories. Later work showed that the hippocampus is the primary structure within the temporal lobe involved in this conversion. Because HM retained memories from before surgery, his case also shows that the hippocampus is not involved in the storage of declarative memory. HM died in 2008 and only at that time was his identity released. An audio-recording by National Public Radio from the 1990s of HM talking to scientists was released in 2007 and is available at http://www.npr.org/templates/story/story.php?storyId=7584970.
Explicit memory is for factual knowledge about people, places, and things. It is divided into semantic memory for facts (eg, words, rules, and language) and episodic memory for events. Explicit memories that are initially required for activities such as riding a bicycle can become implicit once the task is thoroughly learned.
Implicit memory is important for training reflexive motor or perceptual skills and is subdivided into four types. Priming is the facilitation of the recognition of words or objects by prior exposure to them and is dependent on the neocortex. An example of priming is the improved recall of a word when presented with the first few letters of it. Procedural memory includes skills and habits, which, once acquired, become unconscious and automatic. This type of memory is processed in the striatum. Associative learning relates to classical and operant conditioning in which one learns about the relationship between one stimulus and another. This type of memory is dependent on the amygdala for its emotional responses and the cerebellum for the motor responses. Nonassociative learning includes habituation and sensitization and is dependent on various reflex pathways.
Explicit memory and many forms of implicit memory involve (1) short-term memory, which lasts seconds to hours, during which processing in the hippocampus and elsewhere lays down long-term changes in synaptic strength; and (2) long-term memory, which stores memories for years and sometimes for life. During short-term memory, the memory traces are subject to disruption by trauma and various drugs, whereas long-term memory traces are remarkably resistant to disruption. Working memory is a form of short-term memory that keeps information available, usually for very short periods, while the individual plans action based on it.
NEURAL BASIS OF MEMORY
The key to memory is alteration in the strength of selected synaptic connections. Second messenger systems contribute to the changes in neural circuitry required for learning and memory. Alterations in cellular membrane channels are often correlated to learning and memory. In all but the simplest of cases, the alteration involves the synthesis of proteins and the activation of genes. This occurs during the change from short-term working memory to long-term memory.
In animals, acquisition of long-term learned responses is prevented if, within 5 min after each training session, the animals are anesthetized, given electroshock, subjected to hypothermia, or given drugs, antibodies, or oligonucleotides that block the synthesis of proteins. If these interventions are performed 4 h after the training sessions, there is no effect on acquisition. The human counterpart of this phenomenon is the loss of memory for the events immediately preceding a brain concussion or electroshock therapy (retrograde amnesia). This amnesia encompasses longer periods than it does in experimental animals (sometimes many days) but remote memories remain intact.
SYNAPTIC PLASTICITY & LEARNING
Short- and long-term changes in synaptic function can occur as a result of the history of discharge at a synapse; that is, synaptic conduction can be strengthened or weakened on the basis of past experience. These changes are of great interest because they represent forms of learning and memory. They can be presynaptic or postsynaptic in location.
One form of plastic change is posttetanic potentiation, the production of enhanced postsynaptic potentials in response to stimulation. This enhancement lasts up to 60 s and occurs after a brief tetanizing train of stimuli in the presynaptic neuron. The tetanizing stimulation causes Ca2+ to accumulate in the presynaptic neuron to such a degree that the intracellular binding sites that keep cytoplasmic Ca2+ low are overwhelmed.
Habituation is a simple form of learning in which a neutral stimulus is repeated many times. The first time it is applied it is novel and evokes a reaction (the orienting reflex or “what is it?” response). However, it evokes less and less electrical response as it is repeated. Eventually, the subject becomes habituated to the stimulus and ignores it. This is associated with decreased release of neurotransmitter from the presynaptic terminal because of decreased intracellular Ca2+. The decrease in intracellular Ca2+ is due to a gradual inactivation of Ca2+ channels. It can be short term, or it can be prolonged if exposure to the benign stimulus is repeated many times. Habituation is a classic example of nonassociative learning.
Sensitization is in a sense the opposite of habituation. Sensitization is the prolonged occurrence of augmented postsynaptic responses after a stimulus to which one has become habituated is paired once or several times with a noxious stimulus. At least in the sea snail Aplysia, the noxious stimulus causes discharge of serotonergic neurons that end on the presynaptic endings of sensory neurons. Thus, sensitization is due to presynaptic facilitation. Sensitization may occur as a transient response, or if it is reinforced by additional pairings of the noxious stimulus and the initial stimulus, it can exhibit features of short-term or long-term memory. The short-term prolongation of sensitization is due to a Ca2+-mediated change in adenylyl cyclase that leads to a greater production of cAMP. The long-term potentiation (LTP) also involves protein synthesis and growth of the presynaptic and postsynaptic neurons and their connections.
LTP is a rapidly developing persistent enhancement of the postsynaptic potential response to presynaptic stimulation after a brief period of rapidly repeated stimulation of the presynaptic neuron. It resembles posttetanic potentiation but is much more prolonged and can last for days. There are multiple mechanisms by which LTP can occur, some are dependent on changes in the N-methyl-D-aspartate (NMDA) receptor and some are independent of the NMDA receptor. LTP is initiated by an increase in intracellular Ca2+ in either the presynaptic or postsynaptic neuron.
LTP occurs in many parts of the nervous system but has been studied in greatest detail in a synapse within the hippocampus, specifically the connection of a pyramidal cell in the CA3 region and a pyramidal cell in the CA1 region via the Schaffer collateral. This is an example of an NMDA receptor-dependent form of LTP involving an increase in Ca2+ in the postsynaptic neuron. Recall that NMDA receptors are permeable to Ca2+ as well as to Na+ and K+. The hypothetical basis of the Schaffer collateral LTP is summarized in Figure 15–3. At the resting membrane potential, glutamate release from a presynaptic neuron binds to both NMDA and non-NMDA receptors on the postsynaptic neuron. In the case of the Schaffer collateral the non-NMDA receptor of interest is the α-amino-3-hydroxy-5-methylisoxazole-4 propionic acid (AMPA) receptor. Na+ and K- can flow only through the AMPA receptor because the presence of Mg2+ on the NMDA receptor blocks it. However, the membrane depolarization that occurs in response to high frequency tetanic stimulation of the presynaptic neuron is sufficient to expel the Mg2+from the NMDA receptor, allowing the influx of Ca2+ into the postsynaptic neuron. This leads to activation of Ca2+/calmodulin kinase, protein kinase C, and tyrosine kinase which together induce LTP. The Ca2+/calmodulin kinase phosphorylates the AMPA receptors, increasing their conductance, and moves more of these receptors into the synaptic cell membrane from cytoplasmic storage sites. In addition, once LTP is induced, a chemical signal (possibly nitric oxide, NO) is released by the postsynaptic neuron and passes retrogradely to the presynaptic neuron, producing a long-term increase in the quantal release of glutamate.
FIGURE 15–3 Production of LTP in Schaffer collaterals in the hippocampus. Glutamate (Glu) released from the presynaptic neuron binds to AMPA and NMDA receptors in the membrane of the postsynaptic neuron. The depolarization triggered by activation of the AMPA receptors relieves the Mg2+ block in the NMDA receptor channel, and Ca2+ enters the neuron with Na+. The increase in cytoplasmic Ca2+ activates Ca2+/calmodulin kinase, protein kinase C, and tyrosine kinase which together induce LTP. The Ca2+/calmodulin kinase II phosphorylates the AMPA receptors, increasing their conductance, and moves more AMPA receptors into the synaptic cell membrane from cytoplasmic storage sites. In addition, once LTF is induced, a chemical signal (possibly nitric oxide, NO) is released by the postsynaptic neuron and passes retrogradely to the presynaptic neuron, producing a long-term increase in the quantal release of glutamate. (Modified from Kandel ER, Schwartz JH, Jessell TM [editors]: Principles of Neural Science, 4th ed. McGraw-Hill, 2000.)
LTP identified in the mossy fibers of the hippocampus (connecting granule cells in the dentate cortex) is due to an increase in Ca2+ in the presynaptic rather than the postsynaptic neuron in response to tetanic stimulation and is independent of NMDA receptors. The influx of Ca2+ in the presynaptic neuron is thought to activate Ca2+/calmodulin-dependent adenylyl cyclase to increase cAMP.
Long-term depression (LTD) was first noted in the hippocampus but was subsequently shown to be present throughout the brain in the same fibers as LTP. LTD is the opposite of LTP. It resembles LTP in many ways, but it is characterized by a decrease in synaptic strength. It is produced by slower stimulation of presynaptic neurons and is associated with a smaller rise in intracellular Ca2+ than occurs in LTP. In the cerebellum, its occurrence appears to require the phosphorylation of the GluR2 subunit of the AMPA receptors. It may be involved in the mechanism by which learning occurs in the cerebellum.
INTERCORTICAL TRANSFER OF MEMORY
If a cat or monkey is conditioned to respond to a visual stimulus with one eye covered and then tested with the blindfold transferred to the other eye, it performs the conditioned response. This is true even if the optic chiasm has been cut, making the visual input from each eye go only to the ipsilateral cortex. If, in addition to the optic chiasm, the anterior and posterior commissures and the corpus callosum are sectioned (“split-brain animal”), no memory transfer occurs. Experiments in which the corpus callosum was partially sectioned indicate that the memory transfer occurs in the anterior portion of the corpus callosum. Similar results have been obtained in humans in whom the corpus callosum is congenitally absent or in whom it has been sectioned surgically in an effort to control epileptic seizures. This demonstrates that the neural coding necessary for “remembering with one eye what has been learned with the other” has been transferred to the opposite cortex via the commissures. Evidence suggests that similar transfer of information is acquired through other sensory pathways.
It is now established that the traditional view that brain cells are not added after birth is wrong; new neurons form from stem cells throughout life in at least two areas: the olfactory bulb and the hippocampus. This is a process called neurogenesis. There is evidence implicating that experience-dependent growth of new granule cells in the dentate gyrus of the hippocampus may contribute to learning and memory. A reduction in the number of new neurons formed reduces at least one form of hippocampal memory production. However, a great deal more work is needed before the relation of new cells to memory processing can be considered established.
ASSIOCIATIVE LEARNING: CONDITIONED REFLEXES
A classic example of associative learning is a conditioned reflex. A conditioned reflex is a reflex response to a stimulus that previously elicited little or no response, acquired by repeatedly pairing the stimulus with another stimulus that normally does produce the response. In Pavlov’s classic experiments, the salivation normally induced by placing meat in the mouth of a dog was studied. A bell was rung just before the meat was placed in the dog’s mouth, and this was repeated a number of times until the animal would salivate when the bell was rung even though no meat was placed in its mouth. In this experiment, the meat placed in the mouth was the unconditioned stimulus (US), the stimulus that normally produces a particular innate response. The conditioned stimulus (CS) was the bell ringing. After the CS and US had been paired a sufficient number of times, the CS produced the response originally evoked only by the US. The CS had to precede the US. An immense number of somatic, visceral, and other neural changes can be made to occur as conditioned reflex responses.
Conditioning of visceral responses is often called biofeedback. The changes that can be produced include alterations in heart rate and blood pressure. Conditioned decreases in blood pressure have been advocated for the treatment of hypertension; however, the depressor response produced in this fashion is small.
As noted above, working memory keeps incoming information available for a short time while deciding what to do with it. It is that form of memory which permits us, for example, to look up a telephone number, and then remember the number while we pick up the telephone and dial the number. It consists of what has been called a central executive located in the prefrontal cortex, and two “rehearsal systems:” a verbal system for retaining verbal memories and a parallel visuospatial system for retaining visual and spatial aspects of objects. The executive steers information into these rehearsal systems.
HIPPOCAMPUS & MEDIAL TEMPORAL LOBE
Working memory areas are connected to the hippocampus and the adjacent parahippocampal portions of the medial temporal cortex (Figure 15–4). Output from the hippocampus leaves via the subiculum and the entorhinal cortex and somehow binds together and strengthens circuits in many different neocortical areas, forming over time the stable remote memories that can now be triggered by many different cues.
FIGURE 15–4 Areas concerned with encoding explicit memories. The prefrontal cortex and the parahippocampal cortex of the brain are active during the encoding of memories. Output from the hippocampus leaves via the subiculum and the entorhinal cortex and strengthens circuits in many neocortical areas, forming stable remote memories that can be triggered by various cues. (Modified from Rugg MD: Memories are made of this. Science 1998;281:1151.)
In humans, bilateral destruction of the ventral hippocampus, or Alzheimer disease and similar disease processes that destroy its CA1 neurons, can cause striking defects in short-term memory. Humans with such destruction have intact working memory and remote memory. Their implicit memory processes are generally intact. They perform adequately in terms of conscious memory as long as they concentrate on what they are doing. However, if they are distracted for even a very short period, all memory of what they were doing and what they proposed to do is lost. They are thus capable of new learning and retain old prelesion memories, but they cannot form new long-term memories.
The hippocampus is closely associated with the overlying parahippocampal cortex in the medial frontal lobe (Figure 15–4). Memory processes have now been studied not only with fMRI but with measurement of evoked potentials (event-related potentials; ERPs) in epileptic patients with implanted electrodes. When subjects recall words, activity in their left frontal lobe and their left parahippocampal cortex increases, but when they recall pictures or scenes, activity takes place in their right frontal lobe and the parahippocampal cortex on both sides.
The connections of the hippocampus to the diencephalon are also involved in memory. Some people with alcoholism-related brain damage develop impairment of recent memory, and the memory loss correlates well with the presence of pathologic changes in the mamillary bodies, which have extensive efferent connections to the hippocampus via the fornix. The mamillary bodies project to the anterior thalamus via the mamillothalamic tract, and in monkeys, lesions of the thalamus cause loss of recent memory. From the thalamus, the fibers concerned with memory project to the prefrontal cortex and from there to the basal forebrain. From the nucleus basalis of Meynert in the basal forebrain, a diffuse cholinergic projection goes to all of the neocortex, the amygdala, and the hippocampus. Severe loss of these fibers occurs in Alzheimer disease.
The amygdala is closely associated with the hippocampus and is concerned with encoding and recalling emotionally charged memories. During retrieval of fearful memories, the theta rhythms of the amygdala and the hippocampus become synchronized. In normal humans, events associated with strong emotions are remembered better than events without an emotional charge, but in patients with bilateral lesions of the amygdala, this difference is absent.
Confabulation is an interesting though poorly understood condition that sometimes occurs in individuals with lesions of the ventromedial portions of the frontal lobes. These individuals perform poorly on memory tests, but they spontaneously describe events that never occurred. This has been called “honest lying.”
While the encoding process for short-term explicit memory involves the hippocampus, long-term memories are stored in various parts of the neocortex. Apparently, the various parts of the memories—visual, olfactory, auditory, etc—are located in the cortical regions concerned with these functions, and the pieces are tied together by long-term changes in the strength of transmission at relevant synaptic junctions so that all the components are brought to consciousness when the memory is recalled.
Once long-term memories have been established, they can be recalled or accessed by a large number of different associations. For example, the memory of a vivid scene can be evoked not only by a similar scene but also by a sound or smell associated with the scene and by words such as “scene,” “vivid,” and “view.” Thus, each stored memory must have multiple routes or keys. Furthermore, many memories have an emotional component or “color,” that is, in simplest terms, memories can be pleasant or unpleasant.
STRANGENESS & FAMILIARITY
It is interesting that stimulation of some parts of the temporal lobes in humans causes a change in interpretation of one’s surroundings. For example, when the stimulus is applied, the subject may feel strange in a familiar place or may feel that what is happening now has happened before. The occurrence of a sense of familiarity or a sense of strangeness in appropriate situations probably helps the normal individual adjust to the environment. In strange surroundings, one is alert and on guard, whereas in familiar surroundings, vigilance is relaxed. An inappropriate feeling of familiarity with new events or in new surroundings is known clinically as the déjà vu phenomenon, from the French words meaning “already seen.” The phenomenon occurs from time to time in normal individuals, but it also may occur as an aura (a sensation immediately preceding a seizure) in patients with temporal lobe epilepsy.
ALZHEIMER DISEASE & SENILE DEMENTIA
Alzheimer disease is the most common age-related neurodegenerative disorder. Memory decline initially manifests as a loss of episodic memory, which impedes recollection of recent events. Loss of short-term memory is followed by general loss of cognitive and other brain functions, agitation, depression, the need for constant care, and, eventually, death. Clinical Box 15–3 describes the etiology and therapeutic strategies for the treatment of Alzheimer disease.
CLINICAL BOX 15–3
Alzheimer disease was originally characterized in middle-aged people, and similar deterioration in elderly individuals is technically senile dementia of the alzheimer type, though it is frequently just called Alzheimer disease. Both genetic and environmental factors are thought to contribute to the etiology of the disease. Most cases are sporadic, but a familial form of the disease (accounting for about 5% of the cases) is seen in an early-onset form of the disease. In these cases, the disease is caused by mutations in genes for the amyloid precursor protein on chromosome 21, presenilin I on chromosome 14, or presenilin II on chromosome 1. It is transmitted in an autosomal dominant mode, so offspring in the same generation have a 50/50 chance of developing familial Alzheimer disease if one of their parents is affected. Each mutation leads to an overproduction of the β-amyloid protein found in neuritic plaques. Senile dementia can be caused by vascular disease and other disorders, but Alzheimer disease is the most common cause, accounting for 50–60% of the cases. Alzheimer disease is present in 8–17% of the population over the age of 65, with the incidence increasing steadily with age (nearly doubling every 5 years after reaching the age of 60). In those who are 95 years of age and older, the incidence is 40–50%. It is estimated that by the year 2050, up to 16 million people age 65 and older in the US alone will have Alzheimer disease. Although the prevalence of the disease appears to be higher in women, this may be due to their longer life span as the incidence rates are similar for men and women. Alzheimer disease plus the other forms of senile dementia are a major medical problem.
Research is aimed at identifying strategies to prevent the occurrence, delay the onset, slow the progression, or alleviate the symptoms of Alzheimer disease. The use of acetylcholinesterase inhibitors (eg, rivastigmine, donepezil,or galantamine) in early stages of the disease increases the availability of acetylcholine in the synaptic cleft. It has shown some promise in ameliorating global cognitive dysfunction, but not learning and memory impairments in these patients. These drugs also delay the worsening of symptoms for up to 12 months in about 50% of the cases studied. Antidepressants (eg, paroxetine, imipramine) have been useful for treating depression in Alzheimer patients. Memantine (an NMDA receptor antagonist) prevents glutamate-induced excitotoxicity in the brain and is used to treat moderate to severe Alzheimer disease. It has been shown to delay the worsening of symptoms in some patients. Drugs used to block the production of β-amyloid proteins are under development. An example is R-flurbiprofen. Also attempts are underway to develop vaccines that would allow the body’s immune system to produce antibodies to attack these proteins.
Figure 15–5 summarizes some of the risk factors, pathogenic processes, and clinical signs linked to cellular abnormalities that occur in Alzheimer disease. The cytopathologic hallmarks of Alzheimer disease are intracellular neurofibrillary tangles, made up in part of hyperphosphorylated forms of the tau protein that normally binds to microtubules, and extracellular senile plaques, which have a core of β-amyloid peptides surrounded by altered nerve fibers and reactive glial cells. Figure 15–6 compares a normal nerve cell to one showing abnormalities associated with Alzheimer disease.
FIGURE 15–5 Relationships of risk factors, pathogenic processes, and clinical signs to cellular abnormalities in the brain during Alzheimer disease. (From Kandel ER, Schwartz JH, Jessell TM [editors]: Principles of Neural Science, 4th ed. McGraw-Hill, 2000.)
FIGURE 15–6 Comparison of a normal neuron and one with abnormalities associated with Alzheimer disease. The cytopathologic hallmarks are intracellular neurofibrillary tangles and extracellular senile plaques that have a core of β-amyloid peptides surrounded by altered nerve fibers and reactive glial cells. (From Kandel ER, Schwartz JH, Jessell TM [editors]: Principles of Neural Science, 4th ed. McGraw-Hill, 2000.)
The β-amyloid peptides are products of a normal protein, amyloid precursor protein (APP), a transmembrane protein that projects into the extracellular fluid (ECF) from all nerve cells. This protein is hydrolyzed at three different sites by α-secretase, β-secretase, and γ-secretase, respectively. When APP is hydrolyzed by α-secretase, nontoxic peptide products are produced. However, when it is hydrolyzed by β-secretase and γ-secretase, polypeptides with 40–42 amino acids are produced; the actual length varies because of variation in the site at which γ-secretase cuts the protein chain. These polypeptides are toxic, the most toxic being Aβσ1–42. The polypeptides form extracellular aggregates, which can stick to AMPA receptors and Ca2+ ion channels, increasing Ca2+ influx. The polypeptides also initiate an inflammatory response, with production of intracellular tangles. The damaged cells eventually die.
An interesting finding that may well have broad physiologic implications is the observation—now confirmed in a rigorous prospective study—that frequent effortful mental activities, such as doing difficult crossword puzzles and playing board games, slow the onset of cognitive dementia due to Alzheimer disease and vascular disease. The explanation for this “use it or lose it” phenomenon is as yet unknown, but it certainly suggests that the hippocampus and its connections have plasticity like other parts of the brain and skeletal and cardiac muscles.
LANGUAGE & SPEECH
Memory and learning are functions of large parts of the brain, but the centers controlling some of the other “higher functions of the nervous system,” particularly the mechanisms related to language, are more or less localized to the neocortex. Speech and other intellectual functions are especially well developed in humans—the animal species in which the neocortical mantle is most highly developed.
COMPLEMENTARY SPECIALIZATION OF THE HEMISPHERES VERSUS “CEREBRAL DOMINANCE”
One group of functions localized to the neocortex in humans consists of those related to language; that is, the understanding of the spoken and printed word and expressing ideas in speech and writing. It is a well-established fact that human language functions depend more on one cerebral hemisphere than on the other. This hemisphere is concerned with categorization and symbolization and has often been called the dominant hemisphere. However, the other hemisphere is not simply less developed or “nondominant;” instead, it is specialized in the area of spatiotemporal relations. It is this hemisphere that is concerned, for example, with the identification of objects by their form and the recognition of musical themes. It also plays a primary role in the recognition of faces. Consequently, the concept of “cerebral dominance” and a dominant and nondominant hemisphere has been replaced by a concept of complementary specialization of the hemispheres, one for sequential-analytic processes (the categorical hemisphere) and one for visuospatial relations (the representational hemisphere). The categorical hemisphere is concerned with language functions, but hemispheric specialization is also present in monkeys, so it predates the evolution of language. Clinical Box 15–4 describes deficits that occur in subjects with representational or categorical hemisphere lesions.
CLINICAL BOX 15–4
Lesions of Representational & Categorical Hemispheres
Lesions in the categorical hemisphere produce language disorders, whereas extensive lesions in the representational hemisphere do not. Instead, lesions in the representational hemisphere produce astereognosis—the inability to identify objects by feeling them—and other agnosias. Agnosia is the general term used for the inability to recognize objects by a particular sensory modality even though the sensory modality itself is intact. Lesions producing these defects are generally in the parietal lobe. Especially when they are in the representational hemisphere, lesions of the inferior parietal lobule, a region in the posterior part of the parietal lobe that is close to the occipital lobe, cause unilateral inattention and neglect. Individuals with such lesions do not have any apparent primary visual, auditory, or somatesthetic defects, but they ignore stimuli from the contralateral portion of their bodies or the space around these portions. This leads to failure to care for half their bodies and, in extreme cases, to situations in which individuals shave half their faces, dress half their bodies, or read half of each page. This inability to put together a picture of visual space on one side is due to a shift in visual attention to the side of the brain lesion and can be improved, if not totally corrected, by wearing eyeglasses that contain prisms. Hemispheric specialization extends to other parts of the cortex as well. Patients with lesions in the categorical hemisphere are disturbed about their disability and often depressed, whereas patients with lesions in the representational hemisphere are sometimes unconcerned and even euphoric. Lesions of different parts of the categorical hemisphere produce fluent, nonfluent, and anomic aphasias. Although aphasias are produced by lesions of the categorical hemisphere, lesions in the representational hemisphere also have effects. For example, they may impair the ability to tell a story or make a joke. They may also impair a subject’s ability to get the point of a joke and, more broadly, to comprehend the meaning of differences in inflection and the “color” of speech. This is one more example of the way the hemispheres are specialized rather than simply being dominant and nondominant.
Treatments for agnosia and aphasia are symptomatic and supportive. Individuals with agnosia can be taught exercises to help them identify objects that are a necessity for independence. Therapy for individuals with aphasia helps them to use remaining language abilities, compensate for language problems, and learn other methods of communicating. Some individuals with aphasia experience recovery but often some disabilities remain. Factors that influence the degree of improvement include the cause and extent of the brain damage, the area of the brain that was damaged, and the age and health of the individual. Computer assisted therapies have been shown to improve retrieval of certain parts of speech as well as allowing an alternative way to communicate.
Hemispheric specialization is related to handedness. Handedness appears to be genetically determined. In 96% of right-handed individuals, who constitute 91% of the human population, the left hemisphere is the dominant or categorical hemisphere, and in the remaining 4%, the right hemisphere is dominant. In approximately 15% of left-handed individuals, the right hemisphere is the categorical hemisphere and in 15%, there is no clear lateralization. However, in the remaining 70% of left-handers, the left hemisphere is the categorical hemisphere. It is interesting that learning disabilities such as dyslexia (see Clinical Box 15–5), an impaired ability to learn to read, are 12 times as common in left-handers as they are in right-handers, possibly because some fundamental abnormality in the left hemisphere led to a switch in handedness early in development. However, the spatial talents of left-handers may be well above average; a disproportionately large number of artists, musicians, and mathematicians are left-handed. For unknown reasons, left-handers have slightly but significantly shorter life spans than right-handers.
CLINICAL BOX 15–5
Dyslexia, which is a broad term applied to impaired ability to read, is characterized by difficulties with learning how to decode at the word level, to spell, and to read accurately and fluently despite having a normal or even higher than normal level of intelligence. It is frequently due to an inherited abnormality that affects 5% of the population with a similar incidence in boys and girls. Dyslexia is the most common and prevalent of all known learning disabilities. It often coexists with attention deficit disorder. Many individuals with dyslexic symptoms also have problems with short-term memory skills and problems processing spoken language. Although its precise cause is unknown, dyslexia is of neurological origin. Acquired dyslexias often occur due to brain damage in the left hemisphere’s key language areas. Also, in many cases, there is a decreased blood flow in the angular gyrus in the categorical hemisphere. There are numerous theories to explain the causes of dyslexia. The phonological hypothesis is that dyslexics have a specific impairment in the representation, storage, and/or retrieval of speech sounds. The rapid auditory processing theory proposes that the primary deficit is the perception of short or rapidly varying sounds. The visual theory is that a defect in the magnocellular portion of the visual system slows processing and also leads to phonemic deficit. More selective speech defects have also been described. For example, lesions limited to the left temporal pole cause inability to retrieve names of places and persons but preserves the ability to retrieve common nouns, that is, the names of nonunique objects. The ability to retrieve verbs and adjectives is also intact.
Treatments for children with dyslexia frequently rely on modified teaching strategies that include the involvement of various senses (hearing, vision, and touch) to improve reading skills. The sooner the diagnosis is made and interventions are applied, the better the prognosis.
Some anatomic differences between the two hemispheres may correlate with the functional differences. The planum temporale, an area of the superior temporal gyrus that is involved in language-related auditory processing, is regularly larger on the left side than the right (see Figure 10-13). It is also larger on the left in the brain of chimpanzees, even though language is almost exclusively a human trait. Imaging studies show that other portions of the upper surface of the left temporal lobe are larger in right-handed individuals, the right frontal lobe is normally thicker than the left, and the left occipital lobe is wider and protrudes across the midline. Chemical differences also exist between the two sides of the brain. For example, the concentration of dopamine is higher in the nigrostriatal pathway on the left side in right-handed humans but higher on the right in left-handers. The physiologic significance of these differences is unknown.
In patients with schizophrenia, MRI studies have demonstrated reduced volumes of gray matter on the left side in the anterior hippocampus, amygdala, parahippocampal gyrus, and posterior superior temporal gyrus. The degree of reduction in the left superior temporal gyrus correlates with the degree of disordered thinking in the disease. There are also apparent abnormalities of dopaminergic systems and cerebral blood flow in this disease.
PHYSIOLOGY OF LANGUAGE
Language is one of the fundamental bases of human intelligence and a key part of human culture. The primary brain areas concerned with language are arrayed along and near the sylvian fissure (lateral cerebral sulcus) of the categorical hemisphere. A region at the posterior end of the superior temporal gyrus called Wernicke’s area (Figure 15–7) is concerned with comprehension of auditory and visual information. It projects via the arcuate fasciculusto Broca’s area in the frontal lobe immediately in front of the inferior end of the motor cortex. Broca’s area processes the information received from Wernicke’s area into a detailed and coordinated pattern for vocalization and then projects the pattern via a speech articulation area in the insula to the motor cortex, which initiates the appropriate movements of the lips, tongue, and larynx to produce speech. The probable sequence of events that occurs when a subject names a visual object is shown in Figure 15–8. The angular gyrus behind Wernicke’s area appears to process information from words that are read in such a way that they can be converted into the auditory forms of the words in Wernicke’s area.
FIGURE 15–7 Location of some of the areas in the categorical hemisphere that are concerned with language functions. Wernicke’s area is in the posterior end of the superior temporal gyrus and is concerned with comprehension of auditory and visual information. It projects via the arcuate fasciculus to Broca’s area in the frontal lobe. Broca’s area processes information received from Wernicke’s area into a detailed and coordinated pattern for vocalization and then projects the pattern via a speech articulation area in the insula to the motor cortex, which initiates the appropriate movements of the lips, tongue, and larynx to produce speech.
FIGURE 15–8 Path taken by impulses when a subject identifies a visual object, projected on a horizontal section of the human brain. Information travels from the lateral geniculate nucleus in the thalamus to the primary visual cortex, to higher order visual critical areas, and to the angular gyrus. Information then travels from Wernicke’s area to Brocas’s area via the arcuate fasciculus. Broca’s area processes the information into a detailed and coordinated pattern for vocalization and then projects the pattern via a speech articulation area in the insula to the motor cortex, which initiates the appropriate movements of the lips, tongue, and larynx to produce speech.
It is interesting that in individuals who learn a second language in adulthood, fMRI reveals that the portion of Broca’s area concerned with it is adjacent to but separate from the area concerned with the native language. However, in children who learn two languages early in life, only a single area is involved with both. It is well known, of course, that children acquire fluency in a second language more easily than adults.
Aphasias are abnormalities of language functions that are not due to defects of vision or hearing or to motor paralysis. They are caused by lesions in the categorical hemisphere (see Clinical Box 15–4). The most common cause is embolism or thrombosis of a cerebral blood vessel. Many different classifications of the aphasias have been published, but a convenient classification divides them into nonfluent, fluent, and anomic aphasias. In nonfluent aphasia, the lesion is in Broca’s area. Speech is slow, and words are hard to come by. Patients with severe damage to this area are limited to two or three words with which to express the whole range of meaning and emotion. Sometimes the words retained are those that were being spoken at the time of the injury or vascular accident that caused the aphasia.
In one form of fluent aphasia, the lesion is in Wernicke’s area. In this condition, speech itself is normal and sometimes the patients talk excessively. However, what they say is full of jargon and neologisms that make little sense. The patient also fails to comprehend the meaning of spoken or written words, so other aspects of the use of language are compromised.
Another form of fluent aphasia is a condition in which patients can speak relatively well and have good auditory comprehension but cannot put parts of words together or conjure up words. This is called conduction aphasiabecause it was thought to be due to lesions of the arcuate fasciculus connecting Wernicke’s and Broca’s areas. However, it now appears that it is due to lesions near the auditory cortex in the posterior perisylvian gyrus.
When a lesion damages the angular gyrus in the categorical hemisphere without affecting Wernicke’s or Broca’s areas, there is no difficulty with speech or the understanding of auditory information; instead there is trouble understanding written language or pictures, because visual information is not processed and transmitted to Wernicke’s area. The result is a condition called anomic aphasia.
The isolated lesions that cause the selective defects described above occur in some patients, but brain destruction is often more general. Consequently, more than one form of aphasia is often present. Frequently, the aphasia is general (global), involving both receptive and expressive functions. In this situation, speech is scant as well as nonfluent. Writing is abnormal in all aphasias in which speech is abnormal, but the neural circuits involved are unknown. In addition, deaf subjects who develop a lesion in the categorical hemisphere lose their ability to communicate in sign language.
Stuttering has been found to be associated with right cerebral dominance and widespread overactivity in the cerebral cortex and cerebellum. This includes increased activity of the supplementary motor area. Stimulation of part of this area has been reported to produce laughter, with the duration and intensity of the laughter proportional to the intensity of the stimulus.
RECOGNITION OF FACES
An important part of the visual input goes to the inferior temporal lobe, where representations of objects, particularly faces, are stored (Figure 15–9). Faces are particularly important in distinguishing friends from foes and the emotional state of those seen. In humans, storage and recognition of faces is more strongly represented in the right inferior temporal lobe in right-handed individuals, though the left lobe is also active. Damage to this area can cause prosopagnosia, the inability to recognize faces. Patients with this abnormality can recognize forms and reproduce them. They can recognize people by their voices, and many of them show autonomic responses when they see familiar as opposed to unfamiliar faces. However, they cannot identify the familiar faces they see. The left hemisphere is also involved, but the role of the right hemisphere is primary. The presence of an autonomic response to a familiar face in the absence of recognition has been explained by postulating the existence of a separate dorsal pathway for processing information about faces that leads to recognition at only a subconscious level.
FIGURE 15–9 Areas in the right cerebral hemisphere, in right-handed individuals, that are concerned with recognition of faces. An important part of the visual input goes to the inferior temporal lobe, where representations of objects, particularly faces, are stored. In humans, storage and recognition of faces is more strongly represented in the right inferior temporal lobe in right-handed individuals, though the left lobe is also active. (Modified from Szpir M: Accustomed to your face. Am Sci 1992;80:539.)
LOCALIZATION OF OTHER FUNCTIONS
Use of fMRI and PET scanning combined with study of patients with strokes and head injuries has provided further insight into the ways serial processing of sensory information produce cognition, reasoning, comprehension, and language. Analysis of the brain regions involved in arithmetic calculations has highlighted two areas. In the inferior portion of the left frontal lobe is an area concerned with number facts and exact calculations. Frontal lobe lesions can cause acalculia, a selective impairment of mathematical ability. There are areas around the intraparietal sulci of both parietal lobes that are concerned with visuospatial representations of numbers and, presumably, finger counting.
Two right-sided subcortical structures play a role in accurate navigation in humans. One is the right hippocampus, which is concerned with learning where places are located, and the other is the right caudate nucleus, which facilitates movement to the places. Men have larger brains than women and are said to have superior spatial skills and ability to navigate.
Other defects seen in patients with localized cortical lesions include, for example, the inability to name animals, though the ability to name other living things and objects is intact. One patient with a left parietal lesion had difficulty with the second half but not the first half of words. Some patients with parietooccipital lesions write only with consonants and omit vowels. The pattern that emerges from studies of this type is one of precise sequential processing of information in localized brain areas. Additional research of this type should greatly expand our understanding of the functions of the neocortex.
Memory is divided into explicit (declarative) and implicit (nondeclarative). Explicit is further subdivided into semantic and episodic. Implicit is further subdivided into priming, procedural, associative learning, and nonassociative learning.
Declarative memory involves the hippocampus and the medial temporal lobe for retention. Priming is dependent on the neocortex. Procedural memory is processed in the striatum. Associative learning is dependent on the amygdala for its emotional responses and the cerebellum for the motor responses. Nonassociative learning is dependent on various reflex pathways.
Synaptic plasticity is the ability of neural tissue to change as reflected by LTP (an increased effectiveness of synaptic activity) or LTD (a reduced effectiveness of synaptic activity) after continued use. Habituation is a simple form of learning in which a neutral stimulus is repeated many times. Sensitization is the prolonged occurrence of augmented postsynaptic responses after a stimulus to which one has become habituated is paired once or several times with a noxious stimulus.
Alzheimer disease is characterized by progressive loss of short-term memory followed by general loss of cognitive function. The cytopathologic hallmarks of Alzheimer disease are intracellular neurofibrillary tangles and extracellular senile plaques.
Categorical and representational hemispheres are for sequential-analytic processes and visuospatial relations, respectively. Lesions in the categorical hemisphere produce language disorders, whereas lesions in the representational hemisphere produce astereognosis.
Aphasias are abnormalities of language functions and are caused by lesions in the categorical hemisphere. They are classified as fluent (Wernicke’s area), nonfluent (Broca’s area), and anomic (angular gyrus) based on the location of brain lesions.
For all questions, select the single best answer unless otherwise directed.
1. A 17-year-old male suffered a traumatic brain injury as a result of a motor cycle accident. He was unconscious and was rushed to the emergency room of the local hospital. A CT scan was performed and appropriate interventions were taken. About 6 months later he still had memory deficits. Which of the following is correctly paired to show the relationship between a brain area and a type of memory?
A. Hippocampus and implicit memory
B. Neocortex and associative learning
C. Medial temporal lobe and declarative memory
D. Angular gyrus and procedural memory
E. Striatum and priming
2. The optic chiasm and corpus callosum are sectioned in a dog, and with the right eye covered, the animal is trained to bark when it sees a red square. The right eye is then uncovered and the left eye covered. The animal will now
A. fail to respond to the red square because the square does not produce impulses that reach the right occipital cortex.
B. fail to respond to the red square because the animal has bitemporal hemianopia.
C. fail to respond to the red square if the posterior commissure is also sectioned.
D. respond to the red square only after retraining.
E. respond promptly to the red square in spite of the lack of input to the left occipital cortex.
3. A 32-year-old male had medial temporal lobe epilepsy for over 10 years. This caused bilateral loss of hippocampal function. As a result, this individual might be expected to experience a
A. disappearance of remote memories.
B. loss of working memory.
C. loss of the ability to encode events of the recent past into long-term memory.
D. loss of the ability to recall faces and forms but not the ability to recall printed or spoken words.
E. production of inappropriate emotional responses when recalling events of the recent past.
4. A 70-year-old woman fell down a flight of stairs, hitting her head on the concrete sidewalk. The trauma caused a severe intracranial hemorrhage. The symptoms she might experience are dependent on the area of the brain most affected. Which of the following is incorrectly paired?
A. Damage to the parietal lobe of the representational hemisphere : Unilateral inattention and neglect
B. Loss of cholinergic neurons in the nucleus basalis of Meynert and related areas of the forebrain : Loss of recent memory
C. Damage to the mammillary bodies : Loss of recent memory
D. Damage to the angular gyrus in the categorical hemisphere : Nonfluent aphasia
E. Damage to Broca’s area in the categorical hemisphere : Slow speech
5. The representational hemisphere is better than the categorical hemisphere at
A. language functions.
B. recognition of objects by their form.
C. understanding printed words.
D. understanding spoken words.
E. mathematical calculations.
6. A 67-year-old female suffered a stroke that damaged the posterior end of the superior temporal gyrus. A lesion of Wernicke’s area in the categorical hemisphere causes her to
A. lose her short-term memory.
B. experience nonfluent aphasia in which she speaks in a slow, halting voice.
C. experience déjà vu.
D. talk rapidly but make little sense, which is characteristic of fluent aphasia.
E. lose the ability to recognize faces, which is called prosopagnosia.
7. Which of the following is most likely not involved in production of LTP?
C. NMDA receptors
D. Membrane hyperpolarization
E. Membrane depolarization
8. An 79-year-old woman has been experiencing difficulty finding her way back home after her morning walks. Her husband has also noted that she takes much longer to do routine chores around the home and often appears to be confused. He is hoping that this is just due to “old age” but fears it may be a sign of Alzheimer disease. Which of the following is the definitive sign of this disease?
A. Loss of short-term memory.
B. The presence of intracellular neurofibrillary tangles and extracellular neuritic plaques with a core of β-amyloid peptides.
C. A mutation in genes for amyloid precursor protein (APP) on chromosome 21.
D. Rapid reversal of symptoms with the use of acetylcholinesterase inhibitors.
E. A loss of cholinergic neurons in the nucleus basalis of Meynert.
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