"Higher Functions of the Nervous System": Conditioned Reflexes, Learning, & Related Phenomena

METHODS A revolution in our understanding of brain function in humans has been brought about by the development and now the widespread availability of PET (positron emission tomography) scanning, functional MRI (fMRI) and related techniques Neuronal activation when subjects performed various activities. a) Looking at words activated the primary visual cortex and part of the visual association cortex. b) Listening to words activated an area at the junction of the temporal and the parietal cortex. c) Speaking words activated Broca's area (the posterior part of the inferior frontal gyrus of the left or dominant hemisphere, corresponding approximately to Brodmann area 44; Broca identified this region as an essential component of the motor mechanisms governing articulated speech) and the adjacent frontal lobe. d) Thinking about words activated large areas, including much of the frontal lobe. 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. LEARNING & MEMORY Introduction A characteristic of animals and particularly of humans is the 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. Forms Memory is appropriately divided into explicit and implicit forms. Explicit memory, which is also called declarative or recognition memory, is associated with consciousness at least awareness-and is dependent for its retention on the hippocampus or and other parts of the medial temporal lobes of the brain. It is divided into the memory for events (episodic memory) and the memory for words, rules, and language, etc (semantic memory). Implicit memory does not involve awareness and is also called nondeclarative or reflexive memory. Its retention does not involve processing in the hippocampus, at least in most instances, and it includes, among other things, skills, habits, and conditioned reflexes. However, explicit memories initially required for activities such as riding a bicycle can become implicit once the task is thoroughly learned. 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. Implicit Memory Implicit memory includes skills and habits which, once acquired, become unconscious and automatic.

 It also includes priming, which is facilitation of recognition of words or objects by prior

exposure to them. An example is improved recall of a word when presented with the first few letters of it. The other forms of implicit memory can be divided into nonassociative and associative forms. In nonassociative learning, the organism learns about a single stimulus. In associative learning, the organism learns about the relation of one stimulus to another.

Habituation & Sensitization 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. Sensitization is in a sense the opposite reaction. A repeated stimulus produces a greater response if it is coupled one or more times with an unpleasant or a pleasant stimulus. It is common knowledge that intensification of the arousal value of stimuli occurs in humans. The mother who sleeps through many kinds of noise but wakes promptly when her baby cries is an example. Habituation is a classic example of nonassociative learning. A classic example of associative learning is a conditioned reflex. Conditioned Reflexes 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 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. This is so-called classic conditioning. Conditioning of visceral responses is often called biofeedback. The changes that can be produced include alterations in heart rate and blood pressure If the CS is presented repeatedly without the US, the conditioned reflex eventually dies out. This process is called extinction or internal inhibition. If the animal is disturbed by an external stimulus immediately after the CS is applied, the conditioned response may not occur (external inhibition). However, if the conditioned reflex is reinforced from time to time by again pairing the CS and US, the conditioned reflex persists indefinitely. Conditioned reflexes are difficult to form unless the US is associated with a pleasant or unpleasant affect. Stimulation of the brain reward system is a powerful US (pleasant or positive reinforcement), and so is stimulation of the avoidance system or a painful shock to the skin (unpleasant or negative reinforcement). Operant conditioning is a form of conditioning in which the animal is taught to perform some task ("operate on the environment") in order to obtain a reward or avoid punishment. The US is the pleasant or unpleasant event, and the CS is a light or some other signal that alerts the animal to perform the task. Conditioned motor responses that permit an animal to avoid an unpleasant event are called conditioned avoidance reflexes. For example, an animal is taught that by pressing a bar it can prevent an electric shock to the feet. Another example is food aversion conditioning. An animal exposed to the taste of a food develops a strong aversion to the food if the tasting is coupled with injection of a drug that produces nausea or illness.

These conditioned responses are very strong, can sometimes be learned with a single pairing of the CS and the US, and, unlike other conditioned responses, will develop when the CS and US are separated by an hour or more. The survival value of food aversion conditioning is obvious in terms of avoiding poisons, and it is not surprising that the brain is probably genetically "programmed" to facilitate the development of food aversion responses.

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. Partial callosal section experiments 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. There is evidence for similar transfer of information acquired through other sensory pathways. Molecular Basis of Memory The key to memory is alteration in the strength of selected synaptic connections. In all but the simplest of cases, the alteration involves protein synthesis and activation of genes. This occurs during the change from short-term working memory to long-term memory. The human is the loss of memory for the events immediately preceding brain concussion or electroshock therapy (retrograde amnesia). This amnesia encompasses longer periods than it does in experimental animals sometimes many days remote memories remain intact. but Habituation is due to a decrease in Ca2+ in the sensory endings that mediate the response to a particular stimulus, and sensitization is due to prolongation of the action potential in these endings with a resultant increase in intracellular Ca2+ that facilitates release of neurotransmitter by exocytosis. Classic conditioning also occurs in Aplysia, and in mammals, in the isolated spinal cord. In Aplysia, the US acts presynaptically on the endings of neurons activated by the CS. This leaves free Ca2+ in the cell, leading to a long-term change in the adenylyl cyclase molecule, so that when this enzyme is activated by the CS, more cAMP is produced. This in turn closes K+ channels and prolongs action potentials. The key point in this case is the temporal association, with the US coming soon after the CS. In Aplysia, there are morphologic correlates to learning and memory. For example, 40% of the relevant sensory terminals normally contain active zones, whereas in habituated animals, 10% have active zones, and in sensitized animals, 65% have active zones. Long-term memory leads to activation of genes that produce increases in synaptic contacts. Encoding Implicit Memory in Mammals Molecular events similar to those occurring in Aplysia underlie some aspects of implicit memory in mammals. However, events involving various parts of the CNS also contribute. Some investigators argue that the striatum is involved, and it is known that learning of some habit tasks is disrupted by lesions of the basal ganglia. There is other evidence that the cerebellum is involved.

Encoding Explicit Memory Encoding explicit memories involves working memory in the frontal lobes and unique processing in the hippocampus. Working Memory 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. In humans, bilateral destruction of the ventral hippocampus or Alzheimer's disease and similar disease processes that destroy its CA1 neurons 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 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 When subjects recall words, there is increased activity in their left frontal lobe and their left parahippocampal cortex, but when they recall pictures or scenes, there is activity 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. The amygdala is closely associated with the hippocampus and is concerned with encoding emotional memories. Amygdaloid lesions make animals less fearful. 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 a 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." Long-Term Memory While the encoding process for short-term explicit memory involves the hippocampus, longterm memories are stored in various parts of the neocortex. Apparently, the various parts of the memoriesvisual, olfactory, auditory, etcare 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, there must be multiple routes or keys to each stored memory. Furthermore, many memories have an emotional component or "color" in simplest terms, ie, 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 deja 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. Summary Information from the senses is temporarily stored in various areas of the prefrontal cortex as working memory. The information in working memory is relayed to the medial temporal lobe, and specifically to the parahippocampal gyrus. From there, it enters the hippocampus and is processed. At this time, the activity is vulnerable 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. FUNCTIONS OF THE NEOCORTEX Introduction 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 humansthe animal species in which the neocortical mantle is most highly developed. Anatomic Considerations From the comparative point of view, the most prominent gross feature of the human brain is the immense growth of the three major association areas: 1. The frontal, in front of the premotor area; 2. The parietal-temporal-occipital, between the somatesthetic and visual cortices, extending into the posterior portion of the temporal lobe; and 3. The temporal, extending from the lower portion of the temporal lobe to the limbic system The association areas are part of the six-layered neocortical mantle of gray matter that spreads over the lateral surfaces of the cerebral hemispheres from the concentric allocortical and juxtallocortical rings around the hilum.

 The descending axons of the larger cells in the pyramidal cell layer give off collaterals that feed back via association neurons to the dendrites of the cells from which they originate, laying the foundation for complex feedback control. The recurrent collaterals also connect to neighboring cells. The large, complex dendrites of the deep cells receive specific and nonspecific thalamic afferents, reticular afferents, and association fibers from other cortical areas. Specific thalamic afferents end in layer IV of the cortex.

Complementary Specialization of the Hemispheres versus "Cerebral Dominance" One group of functions more or less localized to the neocortex in humans consists of those related to language, i.e., to understanding the spoken and printed word and to 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, it is clear that 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. 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-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 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. Moreover, patients with representational hemisphere lesions have trouble recognizing emotions in other individuals. Physiology of Language

 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 is concerned with comprehension of auditory and visual information. It projects via the arcuate fasciculus to Broca's area (area 44) 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 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. 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, there is only a single area involved with both. It is well known, of course, that children acquire fluency in a second language more easily than adults. Recognition of Faces In humans, the fusiform gyrus on the interior surface of the right temporal lobe in right-handed individuals processes the information necessary for analyzing faces and, with neighboring areas, permits their recognition Lesions in this area 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. Localization of Other Functions Analysis of the brain regions involved in arithmetic calculations has highlighted two areas. In the inferior portion of the left frontal lobe there is an area concerned with number facts and exact calculations. Frontal lobe lesions can cause acalculia, a selective impairment of mathematical ability. In the areas around the intraparietal sulci of the parietal lobes bilaterally, there are areas 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. It has been suggested, partly in jest, that the greater brain weight of men is due to more neural components involved in getting from place to place and that this is why men resist asking directions when lost, whereas women do not hesitate to seek help. Experimental Neurosis Animals can be conditioned to respond to one stimulus and not to another even when the two stimuli are very much alike. However, when the stimuli are so nearly identical that they cannot be distinguished, the animal becomes upset, whines, fails to cooperate, and tries to escape. Pavlov

called these symptoms the experimental neurosis. If connections between the frontal lobes and the rest of the brain are cut, animals still fail to discriminate but their failure does not upset them. Because of those results in animals, prefrontal lobotomy