Chapter 7: Intellectual and Memory Impairments PDF

 7 Intellectual and Memory Impairments Howard S. Kirshner, Katherine A. Gifford OUTLINE Neural Basis Of Cognition, 58 Amnestic Syndrome, 62 Cerebral Cortex, 58 Syndromes of Partia...

 7 Intellectual and Memory Impairments Howard S. Kirshner, Katherine A. Gifford OUTLINE Neural Basis Of Cognition, 58 Amnestic Syndrome, 62 Cerebral Cortex, 58 Syndromes of Partial Memory Loss, 64 Consciousness, 59 Transient Amnesia, 64 Memory, 61 Other Types of Memory (Nondeclarative or Implicit Memory), 64 Forms and Stages of Declarative Memory, 61 Bedside Tests of Memory and Cognitive Function, 65 Formation and Retrieval of Episodic Memories, 62 The term intellect designates the totality of the mental or cognitive sensory functions but rather interrelate the functions of the primary operations that compose human thought—the higher cortical func- motor and sensory areas. According to Nauta and Feirtag’s (1986) text, tions that make up the conscious mind. The intellect and its faculties, 70% of neurons in the human central nervous system reside in the the subject matter of human psychology, are the qualities that most cerebral cortex, and 75% of those are in the association cortex. Higher separate human beings from other animals. Memory is a specific cog- cortical functions, with few exceptions, take place in the association nitive function: the storage and retrieval of information. As such, it is cortex. the prerequisite for learning, the building block of all human knowl- The neuroanatomy of the cerebral cortex has been known in con- edge. Other “higher” functions such as language, calculations, spatial siderable detail since the 1800s. Primary cortical sensory areas include topography and reasoning, executive function, music, and creativity the visual cortex in the occipital lobe, the auditory cortex in the tem- all represent functions of specific brain systems. The relationship of poral lobe, the somatosensory cortex in the parietal lobe, and proba- the mind and brain has long been of philosophical interest. Recent bly gustatory and olfactory cortices in the frontal and temporal lobes. advances in cognitive neuroscience have made mind-brain questions Each of these primary cortices receives signals in only one modality the subject of practical scientific and clinical study. It is now possible (vision, hearing, or sensation) and has cortical-cortical connections to study how the metabolic activation of brain regions and the firing only to adjacent portions of the association cortex also dedicated to patterns of neurons give rise to the phenomenon of consciousness, the this modality, called unimodal association cortex. Sensory information sense of self, the ability to process information, and the development is sequentially processed in an increasingly complex fashion, leading of decisions and attitudes. The pattern of an individual’s habitual deci- from raw sensory data to a unified percept. Within each cortical area sions and attitudes becomes one’s personality. are columns of cells with similar function, called modules. Francis Crick (1994), who with James Watson won the Nobel Prize The organization of the primary sensory cortex and unimodal asso- for the discovery of the structure of DNA, expressed the “astonishing ciation cortex has been especially well worked out in the visual system hypothesis” that “you, your joys and your sorrows, your sense of per- through the Nobel Prize–winning research of Hubel and Wiesel and sonal identity and free will, are in fact no more than the behavior of a others. Retinal ganglion cells are activated by light within a bright cen- vast assembly of nerve cells and their associated molecules” (p. 3). This ter, with inhibition in the surround. These cells project through the chapter considers our knowledge of intellect and memory, mind and optic nerve to the lateral geniculate body of the thalamus, then via the brain, from the perspective of the clinical neurologist who must assess optic radiations to the primary visual cortex in the occipital lobes. In disorders of the higher functions. the primary visual cortex, a vertical band of neurons may be dedicated to the detection of a specific bright area, but in the cortex this is usually NEURAL BASIS OF COGNITION a bar or edge of light rather than a spot. These “simple” cells of the visual cortex respond to bright central bars with dark surroundings. Cerebral Cortex Several such cells project to complex cells, which may detect an edge The cognitive operations discussed in this chapter take place among a or line with a specific orientation, or a specific direction of movement, large network of cortical cells and connections, the neural switchboard but with less specificity about the exact location within the visual field. that gives rise to conscious thinking. The cortical mantle of the human Visual shapes are perceived by the operation of these cells. Complex brain is very large compared with animal brains, containing more than cells in turn project to cells in the visual unimodal association cortex 14 billion neurons. The information stored in the human cerebral cor- (the Brodmann areas 18 and 19), where cells may detect movement or tex rivals that found in large libraries. Within the cortical mantle, the patterns. Complex cells also respond to movement anywhere in the areas that have expanded the most from animal to human are the asso- visual field, an important characteristic because of the organism’s need ciation cortices, cortical zones that do not carry out primary motor or to maintain visual attention for possible hazards in the environment. In 58 @ @ @ D D D D @ D1 F CD @ 2C @ C C@ @ ). @ 4 C F  CHAPTER 7 Intellectual and Memory Impairments 59 the visual association cortex, columns may respond to specific shapes, Until recently, many neuroscientists left the study of consciousness colors, or qualities such as novelty. In this fashion, the functions of to the realm of religion and philosophy. Even Hippocrates knew that cell columns or modules become more sophisticated from the primary consciousness emanated from the brain, “to consciousness the brain cortex to the association cortex. In Fodor’s model, the modules of pri- is messenger.” Francis Crick devoted the last part of his career to the mary visual perception project to central systems. Cognitive science understanding of consciousness. For Crick, the best model for the has made tremendous strides in the understanding of the neurobiology study of consciousness is visual awareness because the anatomy and of specific functions such as vision, but it has yet to fathom the higher physiology of the visual system are well understood. Crick argued that perceptual functions such as the concept of beauty in a starry sky or in neurons in the primary visual cortex likely do not have access to con- a painting or the cross-modality processes that underlie, for example, scious awareness. Stated another way, we do not pay attention to much the adaptation of a ballet to a specific musical accompaniment. of what our eyes see and our visual cortex analyzes. However, a per- Unimodal association cortices communicate with each other via ceived object excites neurons in several areas of the visual association still more complex connections to the heteromodal association cortex, cortex, each with associations that enter consciousness or are stored in of which there are two principal sites. The posterior heteromodal asso- short-term memory. ciation cortex involves the posterior inferior parietal lobe, especially Activation of the frontal cortex is necessary for visual percepts to the angular gyrus. The posterior heteromodal cortex makes it possible enter consciousness (Crick and Koch, 1995; Gelbard-Sagiv et al., 2018), to perceive an analogy between an association in one modality (e.g., a although subconscious awareness in the form of blindsight may exist picture of a boat and the printed word boat in the visual modality) with within the occipital cortex and subcortical structures (Celeghin et al., a percept in a different modality (e.g., the sound of the spoken word 2018). Conscious visual perception involves interactions between the boat). These intermodality associations are difficult for animals, even visual parts of the brain and the prefrontal systems for attention and chimpanzees, but easy for human beings. Cross-sensory associations working memory (Ungerleider et al., 1998). The orbitofrontal cortex involve the functioning of cortical networks of multitudes of neurons; contains neurons that integrate interoceptive stimuli related to changes the analogy drawn by neuroscientists is to the vast arrays of circuits in the internal milieu with exteroceptive sensory inputs such as vision. active in computer networks. The product of such associations is a Ortinski and Meader (2004) also point out the varying latencies of per- concept. ception of specific sensory stimuli, such as color versus identification The second heteromodal association cortex involves the lateral of a visual object. A synchronization of inputs through the thalamus to prefrontal region (Goldman-Rakic, 1996). This region is thought to the cortex may be necessary before the perception becomes conscious. be involved with attention or “working memory” and with sequential As stated earlier, the interaction between attention to external stimuli processes such as storage of temporally ordered stimuli and the plan- and internal stimuli underlies conscious awareness. ning of motor activities. This temporal sequencing of information and In the visual system, Goodale and Milner, (1992); Milner and motor planning is referred to by neuropsychologists as the executive Goodale, (2008); and also McIntosh and Schenk, (2009) have divided function of the brain—the decisions we make every instant regarding the visual system, after processing in the occipital cortex, into a ven- which of the myriad of sensory stimuli reaching the sensory cortices tral and a dorsal stream. The ventral stream, involved in perception merit attention, which require a motor response, and in what sequence of objects, is usually subject to conscious awareness and involves an and timing these motor responses will occur. occipital-temporal pathway, whereas the dorsal stream, involved in Another frontal cortical area, the orbitofrontal portion of the pre- spatial localization of perceived objects to plan action, is usually less frontal cortex, is thought to be involved in emotional states, appetites, conscious. and drives, or in the integration of internal bodily states with sensa- There are many clinical examples of “unconscious” mental pro- tions from the external world. The orbitofrontal cortex is known as the cessing, and a number of these involve vision. Patients with cortical supramodal cortex (Benson, 1996) because it relates the functions of the blindness sometimes show knowledge of items they cannot see, a phe- heteromodal cortex regarding attention and sequencing of responses nomenon called blindsight. Patients with right hemisphere lesions who with interoceptive inputs from the internal milieu of the body. The extinguish objects in the left visual field when presented with bilateral orbitofrontal area has close connections with the limbic system and stimuli nonetheless show activation of the right visual cortex by func- autonomic, visceral, and emotional processes. In studying brain evo- tional magnetic resonance imaging (MRI), indicating that the objects lution from primitive reptiles to humans, the neurobiologist Paul are perceived, although not with conscious awareness (Rees et al., MacLean hypothesized that the internal and emotional parts of the 2000). Libet (1999) demonstrated experimentally that visual and other brain, the limbic system, must be tied into the newer neocortical areas sensory stimuli have to persist at least 500 msec to reach conscious responsible for intellectual function, and that the linking of these two awareness, yet stimuli of shorter duration can elicit reactions. An systems must underlie the phenomenon of consciousness. In a review experimental example of unconscious visual processing comes from of neuronal mechanisms of consciousness, Ortinski and Meador (2004) Gur and Snodderly (1997), who tested color vision in monkeys. When defined conscious awareness as “the state in which external and inter- two colors were projected at a frequency of greater than 10 Hz, the nal stimuli are perceived and can be intentionally acted on” (p. 1017). monkey perceived a fused color, yet cellular recordings clearly demon- Benson and Ardila (1996), in reviewing clinical data from individuals strated coding of information about the two separate colors in the with frontal lobe damage, state that the supramodal cortex is the brain monkey’s visual cortex. Motor responses to sensory stimuli can occur system that “anticipates, conjectures, ruminates, plans for the future, before conscious awareness, as in the ability to pull one’s hand away and fantasizes.” In other words, this part of the brain brings specific from a hot stove before feeling the heat. Racers begin running before cognitive processes to conscious awareness and may be responsible for they are aware of having heard the starting gun (Crick and Koch, the phenomena of consciousness and self-awareness themselves. 1998). A familiar example of unconscious visual processing is the drive home from work; most individuals can remember very little they see Consciousness on the trip, yet they avoid oncoming vehicles and obstacles, stop for All human beings have a subjective understanding of what it means red lights, and drive without accidents. Crick and Koch (1998) refer to be conscious and to have a concept of self, yet the neural basis for to the unconscious visual processing as an “online” visual system. We conscious awareness and the sense of self remains poorly understood. shall discuss unconscious or “implicit” memories later in this chapter. @ @ @ D D D D @ D1 F CD @ 2C @ C C@ @ ). @ 4 C F 60 PART I Common Neurological Problems In language syndromes, patients can match spoken to written words include Broca aphasia from a left frontal lesion, Wernicke aphasia without knowledge of their meaning, suggesting that there are uncon- from a left temporal lesion, Gerstmann syndrome (acalculia, left-right scious rules of language. Brust (2000) has called all of these uncon- confusion, finger agnosia, and agraphia) from a left parietal lesion, scious mental processes the “non-Freudian unconscious.” visual agnosia or failure to recognize visual objects (usually from bilat- Research has linked the right frontal cortex to the sense of self. eral posterior lesions), apraxia from a left parietal lesion, and construc- Keenan and colleagues (2001) studied patients undergoing the Wada tional impairment from a right parietal lesion. Multiple focal lesions test, in which a barbiturate is injected into the carotid artery to deter- can affect cognitive function in a more global fashion, as in the demen- mine cortical language dominance. They presented subjects with a tias (Chapter 66). Some authorities separate “cortical” dementias such self-photograph and a photograph of a famous person, followed by as Alzheimer disease, in which combinations of cortical deficits are a “morphed” photograph of a famous person and the patient. When common, from “subcortical” dementias, in which mental slowing is the left hemisphere was anesthetized, the subjects said that the mor- the most prominent feature. phed photograph represented the subject himself, whereas with right The frontal lobes are heavily involved in integration of the func- hemisphere anesthesia, the subject selected the famous face. Patients tions provided by other areas of cortex, and lesions there may affect with frontotemporal dementia also indicate a relationship between personality and behavior in the absence of easily discernible deficits the right frontal lobe and self-concept. In the series by Miller and of specific cognitive, language, or memory function. In severe form, colleagues (2001), six of the seven patients who developed a major extensive lesions of the orbitofrontal cortex may leave the individ- change in self-concept during their illness had predominant atrophy ual awake but staring, unable to respond to the environment, a state in the nondominant frontal lobe. A last example of the sense of self is called akinetic mutism. With lesser lesions, patients with frontal lobe the so-called Theory of Mind, which alludes to the understanding of lesions may lose their ability to form mature judgments, reacting another person as a conscious human being. Keenan and colleagues impulsively to incoming stimuli in a manner reminiscent of animal (2005) cite evidence that the right hemisphere frontotemporal cortex is behavior. Such patients may be inappropriately frank or disinhibited. dominant for both the sense of self and the recognition of other people. A familiar example is the famous case of Phineas Gage, a worker who The frontal lobes, as the executive center of the brain and the sustained a severe injury to the frontal lobes. Gage became irritable, determining agent for attention and motor planning, are the origin of impulsive, and so changed in personality that coworkers said he was several critical networks for cognition and action. Cummings (1993) “no longer Gage.” Bedside neurological testing and even standard neu- described five frontal networks for consciousness and behavior. These ropsychological tests of patients with frontal lobe damage may reveal networks function as a circuit between the frontal lobe and subcortical normal intelligence except for concrete or idiosyncratic interpretation regions: the frontal cortex projects to the basal ganglia, then to tha- of proverbs and similarities. Experimentally, subjects with frontal lobe lamic nuclei, and back to the cortex. lesions can be shown to have difficulty with sequential processes or Clinical neurology provides important information about how shifting of cognitive sets, as tested by the Wisconsin Card Sorting Test lesions in the brain impair consciousness. The functioning of the or the Category Test of the Halstead-Reitan battery. Luria introduced awake mind requires the ascending inputs referred to as the reticular a simple bedside test of sequential shapes (Fig. 7.1) to assess for deficits activating system, with its way stations in the brainstem and thalamus, indicative of frontal lesions. In contrast to the subtlety of these deficits as well as an intact cerebral cortex. Bilateral lesions of the brainstem or to the examiner, the patient’s family may state that there is a dramatic thalamus produce coma. Very diffuse lesions of the hemispheres pro- change in the patient’s personality. duce an “awake” patient who shows no responsiveness to the environ- Another clinical window into the phenomena of consciousness ment, a state sometimes called coma vigil or persistent vegetative state, comes from surgery to separate the hemispheres by cutting the corpus as in the well-known Terri Schiavo case (Bernat, 2006; Perry et al., callosum. In split-brain or commissurotomized patients, each hemi- 2005). Patients with very slight responses to environmental stimuli sphere seems to have a separate consciousness. The left hemisphere, are said to be in a minimally conscious state (Wijdicks and Cranford, which has the capacity for speech and language, can express this con- 2005). Recently, functional brain imaging studies have suggested that sciousness in words. For example, a split-brain patient can report at least in a few patients labeled as having persistent vegetative state words or pictures that appear in the right visual field. The right hemi- or minimally conscious state after traumatic brain injury, patients can sphere cannot produce verbal accounts of items seen in the left visual think of playing tennis or standing in their home and seeing the other field, but the subject can choose the correct item by pointing with the rooms, and the brain areas activated are similar to those of normal sub- left hand; at the same time, the subject claims to have no conscious jects. These same subjects, a small minority of patients with chronically knowledge of the item. In terms of the speaking left hemisphere, the impaired consciousness secondary to traumatic brain injury, showed right hemisphere has “unconscious” visual knowledge, or blindsight. evidence of conscious modulation of brain activity to indicate “yes” or At times, the left hand of the patient may seem to operate under a “no” responses (Monti et al., 2010). This report has engendered con- different agenda from the right hand. A split-brain patient may select troversy over our ability to determine when a patient truly lacks con- a dress from a rack with the right hand while the left hand puts it back sciousness. In an accompanying editorial, Ropper noted that activation or selects a more daring fashion. This rivalry of the left hand with on brain imaging studies does not equal conscious awareness, and the the right is called the alien hand syndrome, a striking example of the concept that “I have brain activation, therefore I am … would seriously put Descartes before the horse” (Ropper, 2010). Still less severe diffuse abnormalities of the association cortex pro- duce encephalopathy, delirium, or dementia. These topics involve very common syndromes of clinical neurology. Stupor and coma are dis- Fig. 7.1 Luria’s Test of Alternating Sequences. (Adapted from Luria, cussed in Chapter 5, and encephalopathy, or delirium, is covered in A.R., 1969. Frontal lobe syndromes. In: Vynken, P., Bruyn, G.W. (Eds.), Chapter 4. Handbook of Clinical Neurology, vol. 2, Elsevier, New York. Reprinted Focal lesions of the cerebral cortex generally produce deficits in with permission from Kirshner, H.S., 2002. Behavioral Neurology: Prac- specific cognitive systems. A detailed listing of such disorders would tical Science of Mind and Brain, second ed. Butterworth-Heinemann, include much of the subject matter of behavioral neurology. Examples Boston.) @ @ @ D D D D @ D1 F CD @ 2C @ C C@ @ ). @ 4 C F  CHAPTER 7 Intellectual and Memory Impairments 61 separate consciousnesses of the two divided hemispheres (Gazzaniga, memory filing cabinet,” where recent memories are stored. Patients 1998). Callosal syndromes, including the alien hand syndrome, have with medial temporal lobe damage (e.g., Alzheimer disease) have a also been described in patients with strokes involving the corpus cal- damaged file cabinet, in which memories are unable to be stored. In losum (Chan and Ross, 1997) or the medial frontal lobe (Scepkowski contrast, patients with frontal lobe damage (e.g., stroke, tumor) have and Cronin-Golomb, 2003). difficulty in properly organizing the files in the cabinet or difficulty locating them during retrieval. Finally, in patients with subcortical MEMORY white matter pathology (e.g., ischemic disease, multiple sclerosis), the file clerk has difficulty gaining access to the file cabinet, which Forms and Stages of Declarative Memory makes retrieval difficult. However, once given an option between Generally defined, memory refers to the ability of the brain to store and multiple files—through a recognition or multiple-choice test—the retrieve information, the necessary prerequisite for all learning. Some file clerk can correctly identify the needed file. Commonly used bed- memories are so vivid they seem like a reliving of a prior experience, side tests assess recent episodic memory. The patient is asked to recall as in Marcel Proust’s sudden recollections of his youth on biting into a three to five unrelated items at 5 minutes (testing the file cabinet). madeleine pastry. Other memories are more vague or bring up a series For any unrecalled words, the patient is given a hint or cue (test- of facts rather than a perceptual experience. Memory has been divided ing the file clerk). Questions about this morning’s breakfast are also into several types and stages, leading to a confusing set of terms and effective. It is relatively easy to test for impairment in recent episodic concepts. Clinical neurologists have historically divided memory into memory by including general questions about recent events in one’s three temporal stages. These stages can be helpful when conceptual- life or the news in rapport building and interview. izing diagnosis and difficulties in independent living and have a gen- The third stage, referred to as remote or long-term episodic mem- eral correspondence to the stages and concepts of memory proposed ory, refers to the ability to retrieve specific items, such as words or by cognitive neuroscientists. The first stage, referred to as immediate events, after a delay of weeks, months, or years. An example of this memory by clinicians, corresponds to Baddeley’s concept of working would be asking patients about the last movie they have seen or what memory (Baddeley, 2010). Immediate or working memory refers to the they did on their last birthday. Retrieval of remote episodic memories system that actively holds pieces of transitory information in conscious tends to require less hippocampal and medial temporal lobe involve- awareness, where it can be subsequently manipulated or used to per- ment (Dudai, 2004). Consolidation of long-term memories can occur form a task. There has been recent debate over the true capacity of at the synaptic and systems levels. Synaptically, consolidation occurs working memory (Cowan, 2001), but the general consensus is that the through long-term potentiation and protein synthesis in the hippo- normal adult human being can retain 5–9 meaningful items in working campus during the first few hours of learning (Roediger et al., 2007). memory (Miller, 1956). This information can generally reside in con- In contrast, on a systems level, consolidation occurs over long periods scious awareness indefinitely with attention and rehearsal. However, of time where hippocampal-dependent memory representations are without rehearsal, this information is lost in approximately 18–20 sec- stored in the neocortex. Hippocampal activation appears to decline onds (Brown, 1958; Peterson and Peterson, 1959). As an example, most linearly as time passes (Frankland and Bontempi, 2005; Squire et al., people can hear or see a telephone number, walk across the room, and 2015. In other words, the older the memory, the less the hippocampus dial the number without difficulty. Once the number is dialed and con- and medial temporal regions are needed for retrieval. This was previ- versation is started, the number fades from working memory. Relying ously demonstrated through patient H.M. and patients with Alzheimer primarily on prefrontal brain regions, working memory declines with disease who cannot retrieve recent information or events, but can normal aging. Furthermore, disorders of attention, focal lesions of easily recall events from many years ago. Similarly to short-term epi- the superior frontal neocortex affecting Brodmann areas 8 and 9, and sodic memory, the frontal lobes are required to retrieve memories, but patients with aphasia secondary to left frontal lesions can show pro- rather than the hippocampus, the file clerk must access memories in found impairment in working memory (Goldman-Rakic, 1996). cortical regions. The second stage of memory, referred to by clinicians as short- Remaining within the realm of long-term declarative memory, term or recent memory, involves the ability to encode and retrieve there appears to be overlap in the type of information retrieved for specific items, such as words or events, after a delay of minutes or remote memories. In addition to episodic memory, which according hours. Some of the aforementioned confusion over terminology to Tulving (1985) requires some type of “mental time travel” to revisit comes from the fact that cognitive psychologists posit that work- the original experience, semantic memories can be retrieved. Semantic ing memory underlies short-term memory and consider it distinct memory is referred to as factual knowledge that includes memory of from episodic learning and memory. In clinical parlance, short-term meanings, understandings, and other concept-based knowledge as memory is synonymous with recent episodic memory, whereas some well as general knowledge about the world. Recall of famous figures or cognitive psychologists use “short-term” to mean immediate mem- events, such as presidents or wars, and knowledge of semantic infor- ory. Short-term or recent episodic memory requires the function of mation, such as the definitions of words and the differences between the hippocampus and parahippocampal areas of the medial tempo- words, are examples of semantic memory. Semantic memory differs ral lobe for both encoding and storage. The amygdala, a structure from personal long-term memory in that the subject can continuously adjacent to the medial temporal cortex, is not essential for episodic replenish such knowledge by reading and conversation. memory but seems crucial for the encoding of emotional or social Semantic memory is thought to reside in multiple cortical regions contexts of specific events (Markowitsch and Staniloiu, 2011). In such as the visual association cortex for visual memories and the tem- contrast, the retrieval of recent episodic memories tends to rely on poral cortex for auditory memories. This concept of multiple localiza- a delicate interaction between prefrontal regions and medial tempo- tions of semantic memory is supported by functional brain imaging ral regions. Budson and Price (2005) provide a simple analogy for research (Cappa, 2008). Specific semantic knowledge of word meanings remembering the anatomical organization of recent episodic mem- is thought to reside in the left lateral temporal cortex. Remote memory, ory. In this analogy, the frontal lobes are considered the “filing clerk” as we shall see later, resists the effects of medial temporal damage; once of the memory system, deciding what memories to retrieve and from memory is well stored in the neocortex, it can be retrieved without use where to retrieve them. The medial temporal lobes are the “recent of the hippocampal system. @ @ @ D D D D @ D1 F CD @ 2C @ C C@ @ ). @ 4 C F 62 PART I Common Neurological Problems TABLE 7.1 Memory Stages Traditional Term Cognitive Neuroscience Term Awareness Level Anatomy Immediate memory Working memory Explicit Prefrontal cortex Short-term memory Episodic memory Explicit Medial temporal lobe Long-term memory Semantic memory Explicit Lateral temporal and other cortices Motor memory Procedural memory Implicit Basal ganglia, cerebellum Other nondeclarative categories of memory, such as motor and in both hippocampi, and faces mainly activated the right hippocampus procedural memories, will be discussed later in this chapter. Table 7.1 (Fliessbach et al., 2010; Rosazza et al., 2009). In studies of the recogni- is a classification of memory stages. tion of visual designs, Petersson and colleagues (1997) found that the medial temporal cortex activates more during new learning tasks than Formation and Retrieval of Episodic Memories during previously trained and practiced memory tasks. Other areas Recently, the use of functional brain imaging in healthy human sub- activated during the new learning task included the prefrontal and ante- jects and computational modeling has contributed to knowledge of rior cingulate areas, more on the right side, and the parieto-occipital the anatomy of episodic memory function. A network of structures lobes bilaterally. Trained tasks activated the hippocampi much less but has been identified in the encoding or formation of episodic memory. did activate the right infero-occipitotemporal region. This finding cor- Although the hippocampus and all of its subregions are critical to the relates with human studies indicating that overlearned memories grad- encoding of information, it is highly connected (both structurally and ually become less dependent on the hippocampus. Rugg and colleagues functionally) to the amygdala, entorhinal cortex, perirhinal cortex, (1997) also found greater activation of the left medial temporal cortex temporal pole, insula, ventromedial prefrontal cortex, anterior and in tasks in which the subject remembered words by “deep encoding” posterior cingulate, precuneus, and inferior parietal cortex (Kier et al., of their meaning compared with simpler “shallow” encoding of the 2004; Poppenk and Moscovitch, 2011), which have all been implicated specific word. Other studies have shown that the deeper the encoding in the role of episodic memory. When sensory information is processed of a word’s meaning, the better the subject remembers it (Schacter, by specific sensory cortices (e.g., the occipital lobe for visual informa- 1996). Finally, the amygdala appears necessary for affective aspects of tion), prefrontal regions attend and select important information to memory items, such as recall of fear associated with a specific stimulus be encoded into memory. To-be-remembered information passes (Knight et al., 2009). through the entorhinal cortex and into the hippocampus through the Basic research on animals has begun to unravel the fundamental dentate gyrus (Rolls, 2007). The dentate gyrus acts as a “pattern separa- biochemical processes involved in memory. Bailey et al. (1996) have tor” creating unique memory representations as it passes information studied memory formation in the giant snail, Aplysia. Development of to hippocampal subregion CA3 (Yassa and Stark, 2011). Subregion long-term facilitation, a primitive form of memory, requires activation CA3 acts as its own autoassociation network whereby recurrent pro- of a gene called CREB (cyclic adenosine monophosphate response ele- jections onto itself work to store a memory representation temporarily ment-binding protein) in sensory neurons. This work formed the basis for later recall (Hunsaker and Kesner, 2013; for review see Rebola et al., of the Nobel Prize awarded to Eric Kandel, who has remained prolific 2017). in the field of memory (for review see Kandel, 2012). In this system According to early positron emission tomography (PET) work, sev- and also in similar studies on the fruit fly, Drosophila, gene activation eral brain regions show consistent activation in healthy subjects during and protein synthesis are necessary for memory formation. Injection memory retrieval. These brain regions include (1) the prefrontal cor- of protein-synthesis inhibitors into the hippocampus can prevent con- tex, especially on the right; (2) the hippocampus and adjacent medial solidation of memories (McGaugh, 2000). Although similar studies temporal regions; (3) the anterior cingulate cortex; (4) the posterior have not been performed in humans, it is likely that similar gene acti- midline regions of the cingulate, precuneate, and cuneate gyri; (5) vation and protein synthesis, perhaps beginning in the hippocampi but the inferior parietal cortex, especially on the right; and (6) the cere- proceeding through its neocortical connections, are necessary for the bellum, particularly on the left (Cabeza et al., 1997). A model for the transition from immediate working memory to longer-term storage of functions of these areas in memory is as follows: the prefrontal cortex memory (Bear, 1997). This field of research may hold promise for the appears to relate to attention, retrieval activation, and memory search; development of drugs to enhance memory storage. the hippocampi, particularly subregions CA3 and CA1, to conscious recollection of recently learned information; the cingulate cortex to Amnestic Syndrome the activation of memory and selection of a specific response; the pos- The amnestic syndrome (Box 7.1) refers to profound loss of recent terior midline regions to visual imagery; the parietal cortex to spatial or short-term episodic memory. These patients, most of whom have and memory awareness; and the cerebellum to voluntary self-initi- bilateral hippocampal damage, have normal immediate and working ated retrieval (Cabeza et al., 1997; Dickerson and Eichenbaum, 2010; memory span and largely normal ability to recall remote and semantic Wagner et al., 1998). In subjects asked to recognize previously pre- memories such as their childhood upbringing and education. Other sented pairs of associated words, the right prefrontal cortex, anterior cognitive or higher cortical functions may be completely intact (e.g., cingulate cortex, and inferior parietal region were the most activated. attention, executive functioning, language), which distinguishes When the subject had to recall the words, the basal ganglia and left cer- these patients from those with dementias such as Alzheimer disease. ebellum also became active. In similar studies using functional MRI, Procedural or motor memory (see “Other Types of Memory,” later Wagner and colleagues (1998) found that the left prefrontal region in this chapter) tends to remain preserved in patients with amnestic was predominantly involved when words were semantically encoded syndrome, who may be taught to perform a new motor skill such as in memory; the right frontal activations seen in the previous study mirror writing. When asked to perform the newly learned skill again, reflected nonverbal memory stimuli. Even in the hippocampus, words the patient will typically not recall knowing how to do it, but the elicited activation of the left hippocampus, objects evoked activation motor skill remains active, and the patient can easily demonstrate the @ @ @ D D D D @ D1 F CD @ 2C @ C C@ @ ). @ 4 C F  CHAPTER 7 Intellectual and Memory Impairments 63 Anterior thalamic BOX 7.1 Amnestic Syndrome Features nucleus Thalamocingulate Cingulate Impaired recent memory (anterograde, retrograde) tract gyrus Global amnesia Thalamus Spared procedural memory Prefrontal Preserved immediate memory cortex Preserved remote memory Fornix Intact general cognitive function Disorientation to time or place Confabulation skill. Other more variable features of the amnestic syndrome include potential disorientation to time and place. Furthermore, the amnestic Amygdala Mammillothalamic syndrome can include confabulation, or making up information the tract memory system does not supply. Amnestic patients live in an eter- Mammillary Parahippocampal nal present in which they can interact, speak intelligently, and reason body Hippocampal gyrus formation appropriately, but they do not remember anything about the interac- Fig. 7.2 Episodic Memory. The medial temporal lobes, including the tion a few minutes after it ends. An amnestic patient may complete an hippocampus and parahippocampus, form the core of the episodic IQ test within the normal or even above-normal range but not recall memory system. Other brain regions are also necessary for episodic taking the examination minutes later. These patients are condemned memory to function correctly. (Adapted from Budson, A.E., Price, B.H., to repeat the same experiences without learning from them. Memory 2005. Memory dysfunction. N Engl J Med 352, 692–699.) research owes a great debt to the patient H.M., who underwent bilat- eral medial temporal resection for intractable epilepsy and lost all short-term memory, surviving for more than 50 years in this amnestic state (Corkin, 2002, Dittrich and Patient, 2016; Squire, 2009; ). He was ablation of one hippocampus will not result in an amnestic syn- the experimental subject from whom much of our knowledge of the drome, although partial memory deficits still occur. Other common amnestic syndrome derives. causes of the amnestic syndrome involving bilateral medial temporal The registration of short-term episodic memory involves a con- lesions include bilateral strokes in the posterior cerebral artery terri- solidation period during which a blow to the head, as in a football tory, involving the hippocampus, and herpes simplex encephalitis, injury, can prevent memories from being stored or recalled. The rec- which has a predilection for the orbitofrontal and medial temporal ognition or recall of newly learned information appears to require the cortices. Gold and Squire (2006) described three new cases of the hippocampus. The site of storage of memories, as noted earlier, likely amnestic syndrome with detailed neurobehavioral testing in life and involves large areas of the neocortex specialized for specific cognitive neuropathology at autopsy. One had bilateral hippocampal damage, functions such as auditory or visual analysis. Once processed in the one had Wernicke-Korsakoff syndrome with damage in the mam- neocortex and stored for a long period of time, items can be recalled millary bodies and dorsomedial thalamus, and one had bilateral tha- even in the presence of hippocampal damage, as in the case of remote lamic infarctions. We will return to these other anatomical substrates or semantic memories. After an injury producing hippocampal dam- of memory later. age, a retrograde period of memory loss may extend back from min- Although the neuroanatomy of memory storage and retrieval has utes to years, and the subject cannot form new anterograde memories. been known for many years, numerous recent refinements have been As the ability to form new memories returns, the period of retrograde made. Fig. 7.2 shows a simplified diagram of the memory system in the amnesia shortens or “shrinks” (“shrinking retrograde amnesia”). After human brain. The hippocampus on each side projects via the fornix to a minor head injury, the permanent amnestic period may involve a few the septal areas, then to the mammillary bodies, which in turn project minutes of retrograde amnesia and a few hours or days of anterograde to the anterior nucleus of the thalamus and on to the cingulate gyrus amnesia. In experimental studies in which amnestic subjects are shown of the frontal lobe, which projects back to the hippocampus. This cir- famous people from past decades, a temporal gradient has been found cuit (Papez circuit) is critical for short-term memory registration and in which subjects have excellent memory for remote personages but retrieval. Disease processes that affect extrahippocampal parts of this recall progressively less from periods dating up to the recent past. circuit also cause amnesia. One well-studied example is the Wernicke- The neuroanatomy of the amnestic syndrome is one of the Korsakoff syndrome induced by thiamine deficiency, usually in the best-studied areas of cognitive neuropsychology. In animal mod- setting of alcoholism, with damage to the mammillary bodies and dor- els, bilateral lesions of the hippocampus, parahippocampal gyrus, somedial thalamic nuclei (Gold and Squire, 2006). A second clinical and entorhinal cortex produce profound amnesia (Squire and Zola, example is that of patients with ruptured aneurysms of the anterior 1996). Human patients undergoing temporal lobectomy for epilepsy communicating artery, which are associated with damage to the deep have shown very similar syndromes. In the early period of this sur- medial frontal areas such as the septal nuclei. These two amnestic gery, a few patients were deliberately subjected to bilateral medial syndromes are commonly associated with confabulation. The ante- temporal ablations, with disastrous results for memory, as seen in rior communicating artery aneurysm syndrome also involves frontal H.M. (Corkin, 2002; Squire, 2009). In other cases, unilateral tempo- executive dysfunction (Diamond et al., 1997). Traumatic brain injuries ral lobectomy caused severe amnesia. In one such case, published by commonly produce memory loss, probably because the most common the neurosurgeon Wilder Penfield late in his life, an autopsy many sites of damage are in the frontal and temporal lobes, but other deficits years after the surgery showed preexisting damage to the contralat- besides memory frequently occur. Of course, memory loss can be seen eral hippocampus. Patients currently receive extensive evaluation in several other neurological conditions, including brain tumors of the (e.g., the Wada intracarotid barbiturate infusion test) to ensure that thalamus or temporal lobes, white matter diseases such as multiple @ @ @ D D D D @ D1 F CD @ 2C @ C C@ @ ). @ 4 C F 64 PART I Common Neurological Problems sclerosis, and dementing diseases such as Alzheimer disease, which has TABLE 7.2 Types of Memory and Their a predilection for the entorhinal cortex, perirhinal cortex, hippocam- Localization pus, basal frontal nuclei, and neocortex (Braak and Braak, 1991). In these other disorders, memory loss is usually not as isolated a deficit as Types of Recent Memory Localization in the amnestic syndrome. Declarative (Explicit) Facts, events Medial temporal lobe Syndromes of Partial Memory Loss In contrast to the global amnesia seen in amnestic syndrome, Nondeclarative (Implicit) patients who have memory loss for selected classes of items have been Procedural skills Basal ganglia, frontal lobes described. For example, patients who undergo left temporal lobec- Classical conditioning Cerebellum (+ amygdala) tomy for intractable epilepsy usually have detectable impairment of Probabilistic classification learning Basal ganglia short-term verbal memory, whereas those undergoing right temporal Priming Neocortex resection have impairment only of nonverbal memory. Isolated sensory- specific memory loss syndromes have also been described, such as pure visual or tactile memory loss. Ross (1980) described two patients with bilateral occipital lesions that disconnected the visual cortex from OTHER TYPES OF MEMORY (NONDECLARATIVE OR the memory structures. These patients could draw a diagram of their IMPLICIT MEMORY) homes but could not learn new spatial layouts. Ross postulated that diagnosis of a selective visual recent memory deficit requires docu- A confusing array of memory classifications and terminology has mentation of normal visual perception, absence of aphasia sufficient to arisen, as shown in Table 7.2. Several aspects of memory do not impair testing, intact immediate visual memory, intact remote visual involve the conscious recall involved in the three temporal memory memory, and normal recent memory in other modalities. A similar stages. A simple example is motor memory, such as the ability to ride syndrome of isolated tactile memory loss has also been described. a bicycle, which is remarkably resistant to hippocampal damage. Such motor memories probably reside in the basal ganglia and cerebellum. Transient Amnesia In Squire and Zola’s (1996) classification, motor memories of this type Transient amnesia is a temporary version of the amnestic syndrome. are called procedural or implicit nondeclarative memories; note that all The most striking example of transient amnesia is the syndrome of three of the temporal stages of memory—working (immediate) mem- transient global amnesia, lasting from several to 24 hours (Kirshner, ory, episodic (short-term) memory, and semantic (long-term) mem- 2011, 2017). In this syndrome, an otherwise cognitively intact individ- ory—are declarative, explicit. ual suddenly loses memory for recent events, asks repetitive questions Another term for the class of memories for which subjects have about his or her environment, and sometimes confabulates. During no conscious awareness is implicit or nondeclarative memory (in con- the episode, the patient has both anterograde and retrograde amnesia, trast to the explicit, declarative memory of episodic events). Implicit as in the permanent amnestic syndrome. However, as recovery occurs, memories have in common storage and retrieval mechanisms that the retrograde portion “shrinks” to a short period, leaving a perma- do not involve the hippocampal system; perhaps for this reason, the nent gap in memory of the brief retrograde amnesia before the episode subject has no conscious knowledge of them. These procedural mem- and the period of no learning during the episode. The syndrome is ories involve “knowing how” rather than “knowing that.” Amnestic of unknown cause but can be closely imitated by disorders of known patients can learn new motor memories such as mirror drawing, which etiology such as partial complex seizures, migraine, and possibly tran- they can perform once started, although they have no recollection of sient ischemia of the hippocampus on one or both sides. Strupp and knowing the task. Motor learning likely involves the supplementary colleagues (1998) reported that 7 of 10 patients imaged during epi- motor cortex, basal ganglia, and cerebellum. Strokes in the territory sodes of transient global amnesia showed abnormal diffusion MRI of the recurrent artery of Heubner (affecting the caudate nucleus) can signal in the left hippocampus; 3 of these had bilateral hippocampal affect procedural memory (Mizuta and Motomura, 2006). Another abnormalities. Permanent infarctions were not found. More specifi- type of memory localized to the cerebellum is classical conditioning, in cally, the CA1 region within the hippocampus has been strongly impli- which an unconditioned stimulus becomes associated with a reward cated in transient global amnesia (for review see Bartsch & Deuschl, or punishment given when the conditioned stimulus is presented 2010) with many studies showing lesions using diffusion-weighted (Clark et al., 2002; Thompson and Kim, 1996). The conditioning itself MRI in the CA1 region in cases of transient global amnesia (TGA) clearly involves the cerebellum, but the emotional aspect of the reward (Bartsch et al., 2006; Lee et al., 2007; Yang et al., 2008). Other inves- or punishment stimulus may reside in the amygdala. Classical condi- tigators have found frontal lobe abnormalities by diffusion-weighted tioning can continue to function after bilateral hippocampal damage. MRI or PET. Gonzalez-Martinez and colleagues (2010) reported a case Squire and Zola (1996) outlined other types of nondeclarative memory in which a small left thalamic infarction found by diffusion-weighted that take place independent of the hippocampal system. Probabilistic MRI was associated with hypometabolism in the left thalamic region, classification learning (e.g., predicting the weather from a combina- seen on fluorodeoxyglucose (FDG) PET. These studies do not prove tion of cues that are regularly associated with sunny or rainy weather) an ischemic etiology for transient global amnesia; rather, they indicate is unaffected by hippocampal damage but impaired in diseases of the transient dysfunction in the hippocampus or its connections. The last basal ganglia such as Huntington and Parkinson diseases (Gluck et al., several patients with transient global amnesia observed at our hospi- 2002; Thompson and Kim, 1996). Learning artificial grammar can tal have had normal diffusion-weighted MRI studies, except for two also take place in the presence of amnestic syndrome, with functional patients who had incomplete recovery; these patients both had left imaging showing activation in the left parietal and occipital lobes medial temporal infarctions. Confusional migraine, partial epilepsy (Skosnik et al., 2002). In all these memory experiments, the subject (Bilo et al., 2009), drug intoxication, alcoholic “blackouts,” and minor has no awareness of how he or she is able to answer the questions. The head injuries can also produce transient amnesia. last form of nondeclarative memory is called priming, the presenta- tion of a stimulus associated with the word or idea to be remembered, @ @ @ D D D D @ D1 F CD @ 2C @ C C@ @ ). @ 4 C F  CHAPTER 7 Intellectual and Memory Impairments 65 which then aids in retrieval of the item (e.g., recalling the word doctor when nurse appears on a priming list). Priming appears to involve the neocortex (Levy et al., 2004; Thompson and Kim, 1996). Schacter and Buckner (1998) have shown that deliberate use of priming can help amnestic patients to compensate for their memory loss in everyday life. BEDSIDE TESTS OF MEMORY AND COGNITIVE FUNCTION The most important point to be made about bedside evaluations of cognition and memory is that they are an integral part of the neurolog- ical examination and a tool by which the neurologist localizes lesions affecting the higher cortical functions, just as the motor or cerebellar examinations localize neurological deficits. The most common error made by neurologists is to omit a systematic evaluation of mental func- tion in patients who seem “alert and oriented.” Deficits of memory, deficits in fund of knowledge, or focal deficits such as alexia, apraxia, agnosia, acalculia, or constructional impairment can be missed. Some patients have a “cocktail party” conversational pattern that belies such deficits; others become expert at deferring questions to a spouse or fam- ily member. Every neurologist has the task of deciding which patients need formal cognitive testing and whether to make up an individual test routine or to rely on one of the standard tests. Again, it is more important to make the assessment than to follow a specific format. The formal mental status examination should always include explicit testing of orientation including the date, place, and situation. Memory testing should include an immediate attention test, of which the most popular are forward digit span, serial-7 subtractions from 100, or “spell world backward.” Short-term memory should include recall of three to five unrelated words at 5 minutes followed by a recognition paradigm to elicit recall of unremembered words. Importantly, the patient must say all the words after presentation to make sure the items have been properly registered. At times, nonverbal short-term memory, such as Fig. 7.3 Spontaneous clock drawing and copying of a cross by a patient recalling the locations of three hidden coins or reproducing drawings, with a right parietal infarction. The patient had only mild hemiparesis can be useful to test, especially in the case of profound aphasia or ver- but dense left hemianopia and neglect of the left side of the body. The bal impairments. Remote memory can be tested by having the patient neglect of the left side of space is evident in both drawings. (Reprinted name children or siblings. Fund of information can be tested with with permission from Kirshner, H.S., 2002. Behavioral Neurology: Prac- recall of recent presidents or other political figures. For patients who tical Science of Mind and Brain, second ed. Butterworth-Heinemann, do not pay attention to politics, use of athletic stars or television celeb- Boston.) rities may be more appropriate. Language testing should include spon- taneous speech, naming, repetition, auditory comprehension, reading, left hemisphere language cortex in the frontal and temporal lobes, the and writing (the bedside language test is described in more detail in left parietal region (calculations, apraxia), and the right parietal lobe Chapter13). In our practice, we show patients more difficult nam- (visual-constructional tasks), or the frontal lobes (insight and judg- ing items such as the drawings from the National Institutes of Health ment, proverbs, similarities, Luria’s sequence test). (NIH) Stroke Scale or body parts such as the thumb or the palm of Several versions of formal bedside mental status testing have the hand. Praxis testing should include the use of both imaginary and been published, including Folstein’s Mini-Mental State Examination real (e.g., saw, hammer, pencil) objects. Both hands should be tested (MMSE), the Montreal Cognitive Assessment (MoCA) tool, Kokmen separately. Calculation tasks include the serial-7 subtraction test and Short Test of Mental Status, Saint Louis University Mental Status simple change-making problems. Visual-spatial-constructional tasks (SLUMS), and the Mini Cog (3-word recall and Clock Drawing Test). can include line bisection, copying a cube or intersecting pentagons or Perhaps the most widely used is the MMSE, consisting of 30 points: another design, or drawing a clock or a house (Fig. 7.3). Many neurol- 5 for orientation to time (year, season, month, date, and day), 5 for ogists supplement assessment of this domain with the clock-drawing orientation to place (state, county, town, hospital, and floor), 5 for test. Insight and judgment are generally best tested by assessing the attention (either serial 7s with 1 point for each of the first five subtrac- patient’s understanding of his own illness. Formal assessment includes tions or “spell world backward”), 3 for registration of three items, 3 for interpretation of proverbs (e.g., “Those who live in glass houses should recall of three items after 5 minutes, 2 for naming a pencil and a watch, not throw stones”) or abstraction (stating how an apple and an orange 1 for repeating “no ifs, ands, or buts,” 3 for following a three-stage are similar). Another bedside tool used to test frontal lobe process- command, 1 for following a printed command (“close your eyes”), 1 ing, or executive function, is the copying and continuation of Luria’s for writing a sentence, and 1 for copying a diagram of two intersecting test of alternating sequences (sequential squares and triangles; see Fig. pentagons. 7.1). A similar measure, also attributed to Luria, is the “fist/side/palm” The advantages of the MMSE are short time of administration and repetitive movement. With these tests, preliminary localization can be quantitation, useful in documentation for insurance benefits, such as made in the deep memory structures of the medial temporal lobes, the rehabilitative therapies or drug therapy, and for disability assessment. @ @ @ D D D D @ D1 F CD @ 2C @ C C@ @ ). @ 4 C F 66 PART I Common Neurological Problems Several disadvantages of the MMSE have been identified. First, the BOX 7.2 Bedside Mental Status normal range of scores depends on education. The low-normal cut- off is estimated by Crum and colleagues (1993) to be 19 for unedu- Examination cated people, 23 for graduates of elementary or junior high school, 27 Orientation (time, place, person, situation) for high school graduates, and 29 for college graduates. Second, age Memory (immediate, short term, long term) is also a factor. Third, even an abnormal score does not distinguish Fund of information a focal lesion from a more diffuse disorder such as an encephalopa- Speech and language thy or dementia. Fourth, the test is weighted toward orientation and Praxis language, and results can be normal in patients with right hemisphere Calculations or frontal lobe damage. Finally, the test is less sensitive to very early Visual-constructional abilities or subtle cognitive decline, such as within the mild cognitive impair- Abstract reasoning, sequential processes ment or prodromal phase of Alzheimer disease. To address these latter limitations, the MoCA was developed to assess more comprehensively multiple cognitive domains and provide more sensitivity to the iden- tification of mild cognitive impairment. Like the MMSE, the MoCA is patient’s recent memory, orientation, language function, affect or a 30-point test assessing executive functioning and abstraction, visu- mood, insight, and judgment. Affect and mood are best assessed in ospatial skills, language, attention, verbal recall, and orientation. The this fashion; if there is doubt, the clinician should consider how the SLUMS and Kokmen have similar designs. patient makes the clinician feel: a depressed patient often elicits sad- One answer to the dilemma of mental status testing is to use one of ness or depressed mood, whereas a manic patient makes the clinician the aforementioned assessment tools as a screening test and then sup- feel happy and amused. plement it with more focused tests. Box 7.2 lists the key elements of a In conclusion, this chapter considers the areas of neurology that mental status examination, whether the examiner chooses to adopt the most physicians find the most abstruse—namely, the higher cortical MMSE or one of the other bedside cognitive instruments, or to create functions, intellect, and memory. As stated at the outset, this area of an individual test battery. Several texts provide further detail on such a neurology can be treated as a series of specific functions to be analyzed battery. Although the mental status examination is the most neglected at the bedside and localized, just like other functions of the nervous area of the neurological examination, it generally requires only a few system. In fact, the rapidly increasing knowledge of cognitive neurosci- minutes, and its cost-effectiveness compares well with brain imaging ence and our vastly improved ability to image the brain both at rest and studies such as MRI or PET. during functional activities promise a new era of practical diagnosis of In addition to formal examination, an experienced clinician can higher cognitive disorders. learn much about the patient’s mental status by careful observa- tion during the history. Considerable insight can be gained into the The complete reference list is available online at https://expertconsult.inkling.com/. @ @ @ D D D D @ D1 F CD @ 2C @ C C@ @ ). @ 4 C F