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Library of Congress Cataloging i- Publication Data Cie nearopyhcog ited by Kenneth M. Ticinlsbatiogaphicl referees ond nde ISBN G75--105981871 1. Newopmychitry. 2. Clink meuropchology I. Hellman, Kenneth M (Keaneth Marin), 199 editor tales, Ear, 1983-edtr IDNLMG 1 Nemons Stem Diessesdagrss 2. Neuobehavtoral Manifestations 3. Deli, Dement Armes Cognitive Dorersaiaguons 4. Neurpeyhology—mthods, WE. 940] wn, Edward Valenstein, — Filth Edition, C3414 2011 6165—ded2 2010046443 987654521 Printed in USA. con acid-free paperContents 6A 9. Contributors, xiii Introduction, 3 Kenneth M, Heilman and Edward Valenstein Syndromes, 22 David Caplan antics, 42 idall Phonology, Si Stephen E. Nadeau and Diane L. Ke Syntactic Aspects of Language Disorders, 86 David Caplan Acquired Dyslexia, 115 H. Branch Coslett Lauren Ullrich and David P. Roeltgen Disorders of Visual-Spatial Perception and Cognition, 152 Martha J. Farah and Russell A Epstein Acaleulia and Disturbances of the Body Schema, 169 Natalie L, Denburg and Daniel Tranel Anosognosia, 198 John C. Adair and Anna M. Barrett xi4 empirical evidence, and phrenology soon was reduced to the status of a pseudoscience. When phrenology fell into disrepute, many of Gall’s original contributions were blighted. His teach- ings, however, can be considered the founda- tion of modern neuropsychology. Noting that students with good verbal memory had prominent eyes, Gall suggested that memory for words was situated in the frontal lobes. He studied two patients who had lost their memory for words and attributed their disorder to frontal lobe lesions. In 1825, Bouillard wrote that he also believed cerebral function to be localized. He demonstrated that discrete lesions could produce paralysis in one limb and not others and cited this as proof of localized function. He also believed that the anterior (frontal) lobe was the center of speech He observed that the tongue had many fune- tions other than speech and that one function could be disordered (e.g., speech) while others remained intact (¢.g., mastication). This obser nggested to him that an effector ca have more than one center that controls its actions (Bouillard, 1825). In 1861, Paul Broca heard Bouilland’s pupil Auburtin speak about the import anterior lobe in speech. Broca had « hospital patient who was being treated for gangrene This patient had a prior stroke that had resulted in a right hemiplegia, together with loss of speech and writing. The patient was able to understand spe one word: “ mortem inspection of the brain revealed a cavity filled with fluid on the lateral aspect of the left hemisphere. When the fluid w drained, there could be seen a karge left he sphere lesion that included the first temporal gyrus, insula, corpus striatum, and frontal lobe, including the second and third frontal convolu- tions as well as the inferior portion of the verse convolution. In 1861, Broca saw another & ce of th h but could articulate only s patient who had lost the power of speech and writing but could comprehend spoken language. Autopsy again revealed aleft hemisphere lesion involving the second and third frontal convolu- tions. Broca later saw eight patients who suf- fered a loss of speech, which he called aphemia, but which Troussean later called aphasia CLINICAL NEUROPSYCHOLOGY All eight had left hemisphere lesions. This was the first demonstration of left hemisphere dominance for language (Broca, 1865), and it pro- vided strong evidence to support Gall’s hypoth esis of brain modularity. Broca’s observations produced great excite ment in the medical world. Despite his clear demonstration of left hemisphere dominance, medical opinion appeared to split into two camps, one favoring the view that different functions are exercised by the various portions of the cerebral hemisphere and the other denying that psychic finetions are or can be localized. Following. Broca’s initial observations, a flurry of activity occurred. In 1868, Hughlings Jackson noted that there were two types of aphasie patients—fluent and nonfluent—and in 1869, Bastian argued that there were patients who had deficits not only in the articulation of words but also in their memory for words. Bastian also postulated the presence of a visual and auditory word center and a kinesthetic center for the hand and the tongue, He proposed that these centers were connected and that information, such as lan- guage, was processed by the brain in different sways by cach of these centers. Lesions in these centers would thus produce distinct syndromes, depending upon which aspect of the processing was disturbed. Bastian thus viewed the brain as a processor. He was the first to describe word. deafness and word blindness (Bastian, 1869). In 1874, Wernicke published his famous Der Aphasische Symptomenkomplex (Wernicke, 1874). He was familiar with Meynert’s work, which demonstrated that sensory systems project to the posterior portions of the hemispheres, whereas the anterior portions appear to be effere nicke noted that lesions of the posterior portion of the superior temporal region produced an aphasia in which compre- hension was poor. He thought that this andi- tory center contained sound images of words, whereas Broca’s area contained images for the movements need to produce words. He also thought that these areas were connected by a commissure, or White matter tract, and that a lesion of this commissure would disconnect the area for sound images from the area for images of movement, resulting in a language dis bance called conduction aphasia, in which urINTRODUCTION comprehension was intact, speech was fluent, but repetition was impaired Wernicke’s scheme could account for motor conduction, and sensory aphasia with poor rep- tition. Lichtheim (1885), however, described ents who were nonfluent but repeated nor id sensory aphasics who could not com- prehend but could repeat words. Elaborating ‘on Wernicke’s ideas, he devised a complex scheme to explain the mechanism underlying seven types of speech and kanguage disorders. Bastian, Wernicke, and Lichtheimm demonstrated that complex beh: modular components. They also developed information processing models showing how these components interacted to produce com- plex behaviors such as speech, These models have had heuristic and clinical value. Anatomical structure constrains functions Detailed anatomical studies of the cerebral cortex revealed subtle regional differences the pattern of cellular organization, and 1909, Brodmann published the results o! tomic studies defining eytoarchitectonic regions in the cortex of humans and other species, That different areas of the cortex had different archi- tecture supported the postulate that the brain is organized in a modular fashion. When local- izing funct rent investigators still refer to Brodmann’s areas (Fi 1-1). Following World War I, the localizationist- nformation processing approach was abandoned in favor of a holistic approach. Many factors probably underlie this change. The localiza tionist theory was built on the foundation laid by Gall; thus, when phrenology was discredited, other localizationist theories became suspect Lashley (1938), using experimental methods opposed to the case reports used by the classical neurologists), reported that engram were not localized in the brain in modules, but rather appeared to be diffusely represented From these observations, he proposed a theory of mass action: The behavioral result of a lesion depends more on the amount of bra than on the location of the lesion. Head (1926) studied the linguistic performance of patients with aphasia and was not satisfied with the clas- sical ncurologists’ attempts to deduce schemas from clinical observations. Discussing one of iors can be fractionated into n removed 5 ‘No better anner in Wernicke’s ease reports, he wrot example could be chosen of the which the writers of this period were compelled to lop and twist their cases to fit the Procrus- tean bed of their hypothetical conceptions.” Although Preud studied the relationships between the br early in his jer provided the scientific world with expkanations of behavior based on psycho- dynamic relationships. The Gestalt psycholo- gists abandoned localization in favor of the holistic approach, Social and political influences were perhaps more important in changing neuropsycho- logical thought than were newer scientific theories. The continental European scientific community was strongly influenced by Kant’s Critique of Pure Reason, which held that, even thongh knowledge cannot transcend experience, it is nevertheless in part a priori. According to Kant, the outer world provides only the matter of sensation, whereas the mental apparatus (the brain) orders this matter and supplies the concepts by means of which we understand experience. After World War I, the continental European influence on science waned, while the influence of English-speaking countries blossomed. The American and English political and social systems were strongly influenced by John Locke, « 17th-century liberal philoso~ pher who, unlike Kant, believed that beh: and ideas were not innate but rather derived from experience (the concept of the mind as a “tabula rasa”), If brain organization is. pri- y dependent on experience (nurture), there was little reason to look at the structure and organization of the brain (nature) in order to understand behavior, This “black box” approach reached its zenith in the 1950s, with the work of the behaviorists such as B. F. Skinner, who focused on how “nurture” controlled behavior. In the second half of the 20th century, there has been a reawakening of interest in brain~ behavior relationships. Many developments contributed to this renaissance. The classical neurologists were rediscovered and their find ings replicated. Electronic technology provided. researchers with new instruments for observ- ing physiological processes. New statistical and behavi arcer, he ior marCLINICAL NEUROPSYCHOLOGY Figure 1-1. Brodmann’s cytourchitectural ibtle differences i pof the h the basis of contical cell structure and. 45 and Wernicke's area to the posterior part of ar procedures enabled investigators to distinguish random results from significant behavior. New behavioral paradigms, suck ing and lateral visual half-field viewing, permit ted psychologists to explore brain mechani in normal individuals, as well as in patients with brain injury. Anatomical studies using new stain ing methods permitted more detailed mapping of connections, and advances in neurochemi try and neuropharmacology ushered in a new dichotic listes sare defined on ughly to areas 44 and san, 1909). The different ar a. Broca's area corresponds van brain (Brod organizat form of neuropsychology; one in which, in addition to studying behavioral-structural rela- tionships, investigators can study beh chemical relationships. Recently, new forms of functional imaging, which will be discussed in more detail below, have allowed cognitive neuroscientists to map some correlates of brain activity during specific behaviors in both normal and brain-injured subjectsINTRODUCTION METHODS AND CONCEPTS: The attempt to relate behavior to the brain rests on the assumptions that all behavior is mediated by physical processes and that the complex behavior of higher animals depends upon physical processes in the central nervous system. Changes in complex behavior must therefore be associated with changes in the physical state of the brain. Conversely, changes in the physical state of the brain (such as those associated with brain damage) can alter behav- ior. The organization of the nervous system, which is to. large extent determined by genet ies, but which can also be modified by experi- ence, sets limits on what can be perceived and. learned. This organization also determines to a great extent the nature of the behavioral changes that occur in response to brain injury. The understanding of brain-hehavior rela- tionships is aided most by the study of bel iors that can be clearly defined and that are likely to be related to brain processes that ean be directly or indirectly observed. Behaviors that can be selectively affected by focal brain lesions or by specific pharmacological agents are therefore most often chosen for neurop- wv sychological study. Conversely, behaviors that are difficult to define or that appear unlikely to be correlated with observable anatomical, ,orchemieal processes in the brain ndidates for study. As techniques for studying the brain improve, more forms of behavior are becoming amenable to study. Although early in his eareer Sigmund Freud engaged in behavioral neurology research and even coined the term agnosia for patients who had sensory recognition disorders, in his later work he used psychodynamic theory to explain human behavior. Psychodynamic explanations of behavior may be of considerable clin ity in the evaluation and treatment of certain behavioral disorders, but until some correla tion with underlying brain processes is dem strated, they will not help neuropsychologists understand brain-behavior relationships. Fur- thermore, psychodynam damaged patients must be examined critically, so that the emotional res- explanations of the ponse to the injury can be distinguished from emotional changes caused by the brain damage 7 Depression, for example, can be seen in brain- damaged persons, such as patients with hemi- spheric stroke. The obvious psychodynamic explanation is that depression is a “normal” reaction to the loss of function resulting from the brain injury. Evidence that depression correlates less with the severity of functional loss than with the site of the brain lesion, how- ever, suggests that, in some patients, depres- sion may be a direct result of the brain injury and that, in such cases, the psychodynamic explanation may be irrelevant, Sim apply to the better-documented associ apathy with lesions in the frontal lobes and denial of illness with lesions in the right hemisphere. There are many valid approaches to th study of brain-behavior relationships, and no morally and intellectually sound approach should be neglected. We will briefly consider the major approaches, emphasizing those that have been used to greatest advantage. ar caveats ns of INTROSPECTION At times, patients’ observations of their own mental state may be not only helpful but nece sary. How else ean one learn of halluci emotional experiences? It is conceivable that people’s insights into their own mental pro- cesses may be of importance in delineating brain mechanisms. For example, persons with “pho- tographic” memory not surprisingly report that they rely on visual rather than verbal memory, and experiments suggest that visual memory has a greater capacity than verbal memory. Patients may have similarly useful insights, s would do well to hi refully to what their patients say. This does not mean, however, that clinicians and researchers must fully aceept these explanations. Even in normal persons, introspection is not ahvays. valid. In brai damaged patients, it may be even less reliable. This is particularly true when the language cen- ters have been disconnected from the region of the brain that processes the information the patient is asked about (Geschwind, 1965). For aple, sensory information from the left hand projects to the right hemisphere, and thus blind- folded patients with a callosal lesion (separating the left language-dominant hemisphere from tions or and clin exathe right hemisphere) eannot correctly name an object placed in their left hand. Curiously, such patients usually do not say that they cannot name the object, nor do they explain that their left hand can feel it but they cannot find the right word. Instead, in nearly every such ease recorded, the patient confabulate: name. It is clear that, in this situation, the patient's langage area, which is providing the spoken “insight.” cannot even appreciate the presence of a deficit (until it is later brought to its at let alone explain the nature of the difficulty. In other situations, itis apparent that patients make incorrect. assumptions about their deficits. Patients with pure word deafness (who cannot understand spoken language but nevertheless can speak well and ean hear) often assume that people are deliberately being obscure; the result of this introspection is paranoia, Thus, although a patient's introspection at times ean provide useful clues for the clinician, this information must always be analyzed critically and used with « ation THE BLACK-BOX APPROACH Behavior can be studied without any knowl edge of the nervous system. Just as the electrical engineer can study the function of an electronic apparatus withont taking it apart (by apph s and studying the outputs the brain can be approached and studied as a “black box.” The object of the black-box approach is to determine laws of behavior. These laws can then be used to predict behavior, whieh is one expressed aim of the study of psychology. To the extent that laws of behavior are determined by the “hardwiring” of the brain, the black-box approach also yields information about brain function, In this regard, the systen atic study of any behavior or set of behaviors is relevant to the study of brain function. Psy- chology, linguistics, sociology, aesthetics, and related disciplines may all reveal a priori prin- ciples of behavior. The study of linguistics, for example, has revealed a structure common, to all languages (Chomsky, 1967). Since there is no logical constraint that gives language this structure, and since its generality makes environmental influences unlik an assume that the basic structure o one language is CLINICAL NEUROPSYCHOLOGY hardwired in the brain. Thus, observations of behavior can constrain theories of brain fune- tion without any reference to brain anatomy, chemistry, or physiology (see, for example, Caramazza, 1992). black-box approach yields useful tion, such informa informatic brain fn tion is limited because the brain itself is not studied. The study of neuropsychology reflects its origins in 19th-century medical science chemistry, and physiology as relevant variables: purely cognitive studies are but a part of this endeavor. BRAIN LESION-ABLATION PARADIGMS Focal brain lesions change behavior in specific ways. Studies correlating these behavioral changes with the sites of lesions yield informa- tion that can be used to predict, from a given behavioral disturbance, the site of the lesions and vice versa. Such information has great clinical utility. It is another matter, however, to try to deduce from the behavioral effects of an abla- tive lesion the normal mechanisms of brain function mediated by the specific area that is damaged. As Hughlings Jackson pointed out the abnormal behavior ry ago, observed after a brain lesion reflects two fune- tional changes caused by this damage: the loss of the functions mediated by the damaged portion of the brain, and the functioning of the remaining brain tissue after this loss. This remaining brain may react adversely t compensate for, the loss of function caused by the lesion, and thus either add to or minimize the behavioral deficit. Acute lesions often dis- turb function in other brain areas (termed or diaschisis), these metabolic and physiological changes may not be detectable by neuropatho- logical methods and may thus contribute to an overestimate of the function of the lesioned area. Lesions may also. produce changes in behavior by releasing other brain areas from facilitation or inhibition. Thus, it may be diffi cult to distinguish behavioral effects caused by an interruption of processing normally occurring in the damaged area from effects due to less specific alterations of function in eas of the brain other aINTRODUCTION Possible nonspecific effects ofa lesion, includ ing mass action effects and reaetions to disabil- ity or discomfort, ean be excluded as_major determinants of abnormal behavior by the use of “control” lesions. If lesions of comparable size in other brain similar reas do not produce behavioral effects, one cannot ascribe these effects to nonspecific causes. It is especially elegant to be able to demonstrate that such a control lesion has a different behavioral effect. This has been termed double-dissociation lesion A produces behavioral change a but not b, whereas lesion B produces behavioral change b but not « (Teuber, 1955). Once nonspecific effects have been excluded, fone must take into account the various ways in which a lesion may specifically affect behavior If a lesion in a particular region results in the loss of a behavior, one must not simply ascribe to that region the normal function of perform- 1g that behavior. The frst step toward making @ meaningful statement about brain-behavior relationships is a scrupulous analysis of the behavior in question, For example, ifa lesion in a particular area of the brain interferes with writing, it does not mean that the area is the “writing center” of the brain. Writing is a com- plex process comprising several different com- ponents, each of which may be programmed by a different arca of the brain, Components include sensorimotor control of the limb, pro- gramming of movements necessary for writing, intact language function, mental alertness, and so on, One must study every aspect of behavior that is directly rekited to the task of writing and define as closely as possible which aspects of the process of writing are disturbed. It may then be possible to make a correlation between the dam- aged portion of the brain and the component of the writing process that has been disrupted. Itis important to distinguish between lesions that destroy areas of the brain that store spe- cific forms of information (representations) and lesions that disconnect such areas from one another, disrupting processes that require coordination and intercommunication bet- ween two or more such areas (Geschwind, 1965). When a person is writing, for example, coordination must exist between areas that contain representations of how words are spelled nd areas important in programming 9 the movements needed to write letters. Lesions that disconnect these areas produce agraphia, even though there may be no other language or motor deficit. A lesion in the corpus callosum, for example, may disconnect the language areas in the left hemisphere from the right hemi- sphere motor area, thus producing agraphia in the left hand. Significant advances have been made in lesion localization. Until about four decades ago, the anatomic localization of a human brain injury relied primarily on postmortem ¢ nation. With the advent of computed to graphy (CT) and magnetic resonance imaging, (MRD, it became possible to localize brain lesions in live people. More recently, morpho- metric programs (Sowell et al., 2002) have enabled clinicians and investigators to def the degree and distribution of cortical atrophy in degenerative disorders, extending the local- ization of function to disorders not traditionally thought of as causing focal lesions, Advances have also been made in the localization of wl te matter tract lesions. The function of specific cortical mined in part by its cytoarchitecture, but principally by its input and output—its connections, Pioneers such as Liepmann and Maas (1907) and Dejerine (1892) recognized that injur pathways that connect cortical modules ean result in specific behavioral abnormalities. Geschwind’s (1965) classic paper on discon- nection syndromes revived interest in the syn- dromes described by the ¢ pointing out the extent of white m standing in detail the anatomy of brain connec- tions. Standard CT and MR imaging allows investigators to see white matter damage, but diffusion tensor imaging (DTI) tractography can visualize intact and damaged white matter pathways (Filler, 2009). Partial recovery of function can be attributed to factors such as resolution of edema, increase in blood supply, recovery from ischemia, and resolution of diaschisis. In addition, the brai not a static organ. It is constantly reorgani itself, establishing and strengthening conne: tions, as well as pruning underutilized con- nections. This brain plasticity is most evident in the developing brain, but continua eas is del to white matter s at a slower10 pace into adult years, persisting even into old age. Brain reorganization can lead to partial or complete recovery from the behavioral effects of brain injury. Therefore, failing to find a deficit in a particular behavior after a brain injury does not prove that the injured portion of the brain does not normally subserve that behavior, par- ticular if time for recovery has elapsed. Brai plasticity especially complicates the study of behavioral disorders in the developing brain. cither before or after birth. Another difficulty in using the ablative para- digm to learn abont brain organization is that natural lesions, such as strokes or tumors, do. not necessarily respect finctional neuroanatom- ical boundaries. Ischemic strokes occur within the distribution of particular vessels, and these vessels often provide blood to multiple ana- tomic areas. The association of two behavioral deficits may therefore result not from a fune- tional relationship, but rather from the fact that two brain regions with little anatomical or physiological relation are supplied by th same vessel. For example, the associ verbal episodic memory disturbance with pure word blindness (alexia without agraphia) merely indicates that the mesial temporal lobe, the ‘occipital lobe, and the splenium of the corpus callosum are all in the distribution of the pos- terior cerebral artery, Experimental lesions mals can avoid this problem; however, even within a specific anatomical region man systems may be operating, sometimes with contrasting behavioral functions. Despite all these problems, the study of brain ablations in humans and animals has yielded more information about brain-behavior relationships than any other approach, and it has been given renewed impetus by the recent development of powerful methods of neur: anatomic structural imaging, Lesions as small as 2-3 mm in diameter can be detected by modern x-ray CT. Magnetic resonance imag- ing scanning gives information about brain structure and blood flow, and can also provide: infor about metabolie activity ion of a in an BRAIN STIMULATION PARADIGMS Brain stimulation has been used to map © the brain and to elicit changes in behavior. One attractive aspect of this method nections CLINICAL NEUROPSYCHOLOGY has been that stimulation, as opposed to abla~ tion, is reversible. (Reversible methods of abla- tion, such as cooling, have also been used to study brain-behavior relationships.) The addi- tional claim that stimulation is more physiologic stion; It is highly unlikely that gross electrical stimulation of the brain repro= duces any normally occurring physiological state, The stimulation techniques that are usu- ally employed cannot selectively affect only one class of neurons. Furthermore, stimulation disrupts ongoing activity, frequently inhibit- ing it in a way that resembles the effects of ablation, Cortical stimulation is often used prior to ablative surgery to remove an epileptic focus or to treat brain tumors, to map the functional properties of brain regions in the operative field, If stimulation of a cortical area produces cognitive dysfunction, such as deficits in speech ‘or memory, the surgeon will try to minimize damage to these regions, In 1985, Anthony Barker used a magnetic coil held over the scalp to induce currents in motor cortex, resulting in activation of the region of cortex under the coil, with resulting contraction of the muscles controlled by this cortex (Barker, Jalinous, and Freeston, 1985). Subsequently, it was found that slow rates of repetitive transeranial magnetic stimulation (TMS) inactivate underlying cortex. Repetitive transcranial magnetic stimulation has been used to mimic ablative lesions to learn about the functions of specific portions of the cerebral cortex. Repetitive transcranial magnetic stimu- lation has also been used to treat neurobehav- ioral disorders. For example, rTMS over the lateral portion of the left frontal lobe has been used to treat depressed patients who could not be successfully treated with medications, and TTMS of the left hemisphere has been used to treat neglect from right hemisphere strokes. It was posited that the ipsilesional (rightward) attentional bias seen in these patients might be caused by disinhibition of the left hemisphere, resulting from damage to the right hemisphe Left hemisphere inactivation treatment with TMS has been reported to reduce the severity of neglect by reducing this asymmetrical hemi- spheric activation (Koch et al., 2008) For the past 10 years or so, phys been placing indwelling electrodes in the brain is open to q ns haveINTRODUCTION and attaching stimulators for chronic deep brain stimulation to treat certain neurological and psychiatric conditions. Parki dystonia, and tremor have been treated with electrodes placed in the globus pallidus intern: lous, and the thalamus, In m disease, many of these patients, there is a remission of motor symptoms, but stimulation of deep brai structures also has behavioral effects. Deep brain stimulation is also beginning to be used to treat people with psychiatric disorders. For ple, stimulation of the ventral me ssfully treat depression (Mayberg, 2009), and stimulation of the nucleus accumbens/anterior limb of the internal capsule has been used to treat obsessive-compubsive disorder (Goodman et al, 2010). The cognitive effects of deep brain stim- ulation are also beginning to be explored. front: lobe has been used to succ NEUROCHEMICAL MANIPULATIONS immunological methods fied groups of neurons in the central nervous system that use specific neurotrans- mitters. The number of neurotransmitters iden- tified continues to increase, and one neuron may express more than one neurotransmitter. The anatomy of major neurotransmitter path- ways has been elucidated, and the molecular mechanisms by which some neurotransmitters, function is now known is some detail. Drugs given systemically or applied to specific ana- tomic areas may stimulate, inhibit, or block par ticnlar neurotransmitters, There are also drugs that will selective destroy neurons containing specific neurotransmitters, and genetic meth- ods are available to produce animals that lack specific substances, Positron emission tomog- raphy (PET) studies can image specific ne rotransmitters, such as dopamine, in hum: Using these and other techniques, itis possible to correlate the behavioral effects of pharma- ological agents with dysfunction in anatomical areas defined by chemical criteria. Neurochemical have iden ELECTROPHYSIOLOGICAL STUDIES The Electroencephalogram Electrophysiological studies of human beha have been attempted during brain surgery, and ior " depth electrode recording may be justified in the evaluation of a few patients (usually in prep- aration for epilepsy surgery), but most studies rely on the surface-recorded electroencephalo- gram (EEG). The raw EEG, however, demon- strates changes in amplitude and frequeney that are generally nonspecific and poorly localizing Computer analysis of EEG frequency and ampli- tude (power spectra) in different behavioral situ- ations (and from different brain regions) has ed correlations between EEG activ- avior, but only for ce! ior (such as arousal) or for broad a elds (e.g., between hemispheres), The use of computer averaging has increased our ability to detect electrical events that are time-locked to stimuli or responses. Thus, cortical evoked potentials to visual, auditory, and somesthetic stimuli have been recorded, as have potentials that precede muscle activation. Certain potentials appear to correlate with expectancy (the contin- ‘gent negative variation and the P300 potential), That potentials can be “evoked” by purely mental events is demonstrated by the recording of potentials time-linked to the nonoccurrence of expected stimuli. Computer algorithms have been developed to trace the spatial and temporal spread of electrical activity associated with spe- cific single events, or with ongoing behaviors, and to assess the coherence of activity from dif- ferent brain regions. Changes in magnetic fields can also be measured, Although magnetoenceph- alography (MEG) requires much more elabo- rate equipment than EEG, it is less affected by inter demons ity and be pects of ator D, als generated at a greater depth, The principal advantage of these physiologic techniques is their temporal resolution, measured in millisec- onds. With more powerful computer analysis, the spa resolution of these physiological 1g, with MEG capable of resolving the source of an event within several millimeters to about 2 em. measures is Single-unit Recording Discrete activity of individual neurons ean be recorded by inserting microelectrodes into the brain. Obvionsly, this is largely limited to animal experiments. Much has been learned (and remains to be learned) fror this technique in alert, responding animals. the use of12 Responses to well-controlled stimuli ean be recorded with precision and analyzed quantita- tively. Interpretation of single-unit recording presents its own difficulties. The brain activity related to a behavioral event may oceur simulta- neously in many cells spatially dispersed over a Recording from only one cell may not yield a meaningful pattern, but itis now possible to record from arrays of neurons. In addition, single-unit recording may be difficult relation to complex behaviors. considerable ar to analyze FUNCTIONAL NEUROIMAGING In addition to the electrical and magnetie brain mapping just discussed, the most exciting development in recent years has been the advent of powerful techniques for imaging changes in brain funetion in the intact organism, Currently, three major forms of brain imaging are used: positron emission tomography (PET), single-photon emission computed tomography (SPECT), and functional MRI (fMRI). Eacl these uses a different technique, and each has both positive and negative aspects. Unfortunately, these three imaging tech- niques do not have the temporal resolution of clectrophysiologic methods, which are measured in milliseconds; however, PET and especially IMRT have much better spatial resolution, and IMAI studies have temporal resolutions of close to 1 second. These three techniques will be very briefly described here (for additional informa- sau & Crosson, 1995; D’Esposito 2000), Single-photon emission computed tomograe phy studies employing hexamethyl-propylene- amine-oxime (HMPAO) as the radioactive ligand indirectly measure changes in blood flow. The ligand binds to vascular endothelial membranes over a period of about 2 minutes, and has a half-life of 6 hours, so the behavioral task can be performed outside the scanner and the sub- ject scanned afterward, a distinet advantage ‘over (MRI studies. The spatial resolution of s technique is about 6-7 mm, and the t poral resolution, 34 minutes. The dose of radioactivity limits the number of studies that can be done to about three a year. Positron of ission tomography studies using racers (such as H, "O) CLINICAL NEUROPSYCHOLOGY provide measures of absolute blood flow. The short half-life (about 2 minutes) allows for rela- tively brief behavioral trials, and the low radia- tion exposure enables multiple trials in one sitting, Because of its short half-life, the tracer must be manufa d close to the experiment, a very costly constraint, Also, the experiment must be performed within the the scanner environment is not as constrained or noisy as with [MRI (see below). Positron emission tomography blood flow studies have a temporal resolution of about 2. minutes, 4 to 16 mm. Because data must be acquired over more than 10 seconds, PET studies usually use blocked trials, and responses to a single event are difficult to discern Positron emission tomography studies using fluoredeoxyglucose ('*F or FDG) are a more direct measure of brain metabolic activity. FDG is taken up into the brain by the same transport- ers that take up glucose, but then is metabo- lized slowly, so that it marks areas of greater ivity for several hours. As with ~anner; however, and a sj resolution of fron metabolic SPECT, the task can be performed outside the scanner, so there are therefore few constraints on the type of behavior that can be studied The uptake of FDG takes 30-40 minutes, so temporal resolution is very poor Functional MRI is faster than PET, and is capable of measuring activity generated by a single behavioral event, so that studies are not restricted to blocked trials. The temporal resolu- tion is as little as 1 second. Functional MRI also. much better spatial resolution, as little as Timm, The need to acquire data during the task, however, phices constraints on the kind of behavior that can be studied. The subject is con- fined in a very noisy MRI machine, and move- ment, speech, and electromagnetic signals can seriously interfere with the quality of the image. Functional imaging studies of cerebral blood flow assume that a local change in blood flow (that results in a change in measured signal) is related to changes in synaptic activity, and changes in synaptic activity are responsible for specific changes in behavior, Even in the absence of stimuli, the brain is active. Thus, to determine how a behavior influences brain activity, one must subtract irrelevant back- ground signals. Beea e resting activityINTRODUCTION uncontrolled, investigators often use control tasks that resemble the study task in all but a single variable, which then becomes the behay- ior that is studied. There are many methodological and theo- retic problems with {MRIL At the most funda- mental level, the exact means by which the IMRI signal is generated is not entirely under stood. The blood oxygen level dependent (BOLD) method used in {MRI studies assumes. that blood oxygen levels, reflected by the ratio of oxyhemoglobin to. deoxyhemoglobin, are related to synaptic activity in the brain, Synaptic rgy, which consumes oxygen and increases the relative concentration of deoxyhemoglobin to oxyhemoglobin; but within a couple of seconds, a reactive increase in blood flow overeompensates, and the proportion of oxyhemoglobin actually increases over base- line. It is very difficult to detect the initial dip in oxygen levels, and the BOLD technique has relied upon the reactive increase in blood flow and oxyhemoglobin levels, Single-photon emission computed tomo- graphy, PET, and (MRI have all demonstrated reproducible blood flow changes in primary sensory areas in response to stimuli of the appropriate modality. These responses are an order of magnitude larger than behavior-related blood flow changes in association cortex, espe~ cially in polymodal and supramodal cortex. One reason is that primary sensory cortex is relatively quict in the absence of the appropriate sensory stimulus, whereas supramodal cortex is not so dependent uponexternalstimulation. Therefore, when the control activity is subtracted from the task-related activity, much more of the signal is lost in high-order cortex than in primary sen- sory cortex. Interpretation of observed may be problematic. It is usual to expect tf area that mediates a behavior will become more active and will have greater blood flow with that behavior; however, it is possible that a change pattern of activity could mediate a behavie without an increase, or perhaps even with an overall decrease, in activity. It has been reasoned that a brain region that is adept at a behavior will be less activated than when involved in a behavior at which it is less adept. If this is true, almost any functional imaging result can have interpretations: ncreased two oppo 13 activation during an experimental task versus a control task might be interpreted as evidence that the activated region is critical to perfor- mance of this task, oF it may be interpreted as demonstrating that this region of the brai not accustomed to performing this activity, In addition, many neurons in the cerebral cortex are inhibitory. During a specific bchavior, areas of the brain that might interfere with imple- menting this behavior must be inhibited. Thus, functional imaging might not be able to distin- nges are rekated assemblies that are 1 observed ch guish whe! to the neuron the behavior or to the neurons that are inhibit= ing other neuronal assemblies. Based on these dichotomies, the interpretation of functional images is often problematic and must be eon firmed by convergent evidence using other tech- niques, such as ablation-lesion studies Although in behavioral studies resting activ- ity typically is subtracted from activity during the task, resting patterns of activity have been studied in normal and in disease states, defin- of activity, in ing a so-called “default mode” which certain areas are relatively more active than other brain areas during rest with eyes closed (Raichle et al., 2001), The significance of various default networks and their relation- ship to states of consciousness and disease states is currently an active area for research (Boly et al., 2008). COMPUTATIONAL MODELS Donald Hebb (1949) stated that, “Neurons that fire together wire together,” meaning that the strength of connections between nettrons is gow cerned by their firing patterns. This idea has led to the attempt to model brain function in terms of computer function. The typical, serially orga- nized computer has not fared well as a model for brain function, but computers that use mul- tiple parallel processors arranged in a network (parallel distributed processors, or PDP net- works) have interesting brain-like properties These include the ability, without further pro- ming, to “learn” associations between coin- cident stimuli, to behave as if“rules” are leaned despite being exposed only to data, and to con- tinue to function in the face of damage to a portion of the network (“graceful degradation”)4 (Rumelhart & McClelland, 1986). Properties of PDP networks are now often invoked to help explain the nature of neuropsychologieal deficits occasioned by brain injury, such as interlan- guage differences in error rates in patients with ssi. Although the brain is highly interconnected, it does not function as a single network, but rather as a collection of many overlapping and interconnecting “modular” networks, each having a specific funetion. The funetion of a module depends upon its connections. One can therefore see that network theory can easily be reconciled with the traditional methods of localization of brain function discussed above apl ANIMAL VERSUS HUMAN EXPERIMENTATION The study of brain-behavior relationships has long relied on experimental research using animals, which allowed investigators to use techniques such as precise anatomic ablati istological mapping of brain connections, and physiological recordings of behaving subjects that are either not applicable to humans or can be applied only with great difficulty. Despite major differences in anatomy between even the subhuman primates and humans (Figure 1-2), much of this basic research is of direct relevance to human neurobiology Behavioral studies in animals have yielded a great deal of information, but the applicability of this information to the study of complex human behavior is not always clear. In 1950, nothing in the literature on temporal lobe lesions in animals would have led to the predic- tion that bilateral temporal lobectomy in humans would result in permanent impairment of episodic memory. Even after the association of medial temporal lobe damage in humans with amnesia had been well established, it took 20 years to develop new testing paradigms that could demonstrate episodic memory impair- ments in animals with bitemporal ablations (Mishkin, 1978), Conversely, the applicability of behavioral deficits in animals (and esp nonhuman primates) to syndromes in cially CLINICAL NEUROPSYCHOLOGY humans has also recently been systematically investigated, and some parallels are discernible (Oscar-Berman et al., 1982). Studies of the limbic system and hypothalamus in animals have contributed important information about the relevance of th ‘uctures to emotional the emotional content of however, avior is difficult to study in animals that cannot report how they feel. Most obviously, animals cannot be used to study behavior that, an, such as kinguage, Studies ion im ani is uniquely by of ne relate to some aspects of speech in humans, but they do not elucidate the neural mech nisms underlying language. Studies of linguistic behavior in nonhuman primates ate controver- sial, and their relevance to the study of language in humans rem CONCEPTUAL ANALYSIS Many believe that science proceeds by way of careful observation, followed by analysis, which leads to the formation of hypotheses on the basis of the observed data (a posteriori hypothesis). In fact, meaningful observations frequently cannot be made without some sort priori hypothesis. How else which observations to make? An observation can be significant only in terms of a conceptual fi ofa an one decide nework. Some investigators are loathe to put either a priori or a posteriori hypotheses in print, feel- ing that they are too tentative, Often encour- aged by journal reviewers and editors, they report observations with a minimum of inter- pretation. This may be unfortunate because tentative hypotheses are the seeds of further observations and hypotheses. Other invest tors speculate extensively on the basis of only a few observations. These speculations may lead to clearly stated hypotheses that generate fur- ther observations, but there is a risk that obser- vations may be honestly and inadvertently distorted to fit the hypotheses. For example, investigators always discard “irrelevant” infor- mation either int ationally or not; however, investigator with an alternative hypothesis mayINTRODUCTION ae ead ea aa (splenium) Figure 1-4. Magnetic resonance imaging of the cerebral hemispheres, axial section through the thalamus and basal gangh structures ate indicated by labels on the left side of the diagr nuclear structures appear «larker than white matter structu ‘The portions of frontal and parietal lobes that fold over the connect gray matter structures. The right and left cerebral hemisph: » connected by the cerebral commissures, the largest of which is the corpus callosum, Neurons are also found subcortical nuclei, as seen in Figure 1-4. They include the caudate and putamen (together referred to as the striatum), the thalamus, and white matter (conneeting) structures inchid- ing the internal and external capsules and the corpus callosum. The phylogenetically oldest regions of the cerebral cortex form a ring ot limbus around the brainstem and diencephalon (which includes. the striatum nd hypothalamus), and were designated as the grand lobe limbique by Paul Broca (see Figure 1-5). These regions, which include the hippocampal cortex, the cingulate and retrosplenial cortex, the orbitof- rontal cortex, and the have prominent connections with the hypot amu, which controls endocrine and autonomic functions related to our internal milien. Fune- tionally, they are related to autonomic and thalamus, nterior insular corte Principal gray matter (nuclear) structures are indicated om the right side of the 7 ar Putamen cortex insular cortex wd n: white matter ted images, cerebral cortex and other ribbon of cerebral cortex is easily distinguished. and parietal opercula, and also, somewhat less tuitively, to memory (see Chapters 15 and 16). The cortex of some limbic structures, such as the hippocampus, has fewer layers than adjacent six-layered neocortex. Each hemisphere is divided into four lobes: frontal, parictal, temporal, and occipital (Figure 1-6). The frontal lobe is separated from the parietal lobe by the central sulcus. Fuster emotional behavior suggests that the anterior-posterior division of the cerebral hemispheres by the central sulcus is analogous to the division of the neural tube (and spinal cord) into posterior (dorsal) and anterior (ventral) halves, case, sensory input is to the posterior (dorsal) divisions, and motor output is from the anterior (ventral) divisions. Thus, visual, auditory, and somatosensory input to the cerebral cortex is such that, in each to prim in the occipital, temporal, and parietal lobes, respe the primary motor cortex is in the frontal lobe (see Figure 1-7). Primary coi rounded by first-order association cortices that ry ares ices are sur-20 CLINICAL NEUROPSYCHOLOGY SOMATOSENSORY MOTOR (pre-central gyrus) Figure 1-7. Primary cortical motor and sensory areas ate sphere. Primary a (post-central gyrus) AUDITORY (Hesch's gyrus) VISUAL SOMATOSENSORY VISUAL (on ccalearine fissure) Jicated on lateral and medial views of the cerebral hemi- ory area (Heschl’s gyrus) ison the superior surface ofthe superior temporal gyrus, ried in the Sylvian fissure: although indicated by a small area of shading on the lateral (upper) view, i is not visible unless the Sylvian fissure is pried open. Similarly, the areas indicated for motor, sensory, andl visual cortex do not depict large areas of cortex depths of the sie. REFERENCES Barker, A. T., Jalinous, R., & Freeston, 1 L. (May 1985). Non-invasive magnetic stimulation of human motor cortex. The Lancet, 1(8437), 1106-1107. Bastian, H. C. (1869). On the various forms of loss of speech in cerebral disease. British Foreign Medlico-Surgical Review, 43, 70492. Boly, M., Phillips, ©, Tshibanda, —L., Vanhaudenhuyse, A., Schabus, M., Dang- ‘Vu, T. T., et al. (2008). Intrinsic brain activity in altered states of consciousness: How conscious is the default mode of brain function? Annals of the New York Academy of Science, 1129, 119-129, Bouilland, J. B. (1825). Récherches cliniques propres a démontier que la perte de la parole correspond a la Iésion de lobules anterieurs duu cervean, et & confirmer Vopinion de M. Gall surle siege de Torgane du langage articulé, Archives of General Medicine, 8, 25-45. Broca, P, (1865). Sur la faculté du langage artieulé, Bulletin Societe Anthropologie Paris, 6, 337-393, Brodmann, K, (1909). Vergleichende Lokalisa- ionslehre der Grosshirnrinde in ihren Prinzipien dargestellt auf Grund des Zellenbaues. Leipzig: Johann Ambrosius Barth Verlag. Caramazza, A. (1992). Is cognitive neuropsychology possible? Journal of Cognitive Neuroscience, 4: 80-95,INTRODUCTION Chomsky, N, (1967), The general properties of language. In C,H. Millikan & F. L. Dailey (Eds), Brain mechanisms underlying speech and language. New York: Grune and Staton. Dejerine, J. (1892). Ci pathologique et clinique des differentes varietes de cecite verhale. Compte rendu des seances de la societe de biologie 4, 61-90. Esposito, M. (2000). Functional neuroimaging in cognition. Seminars in Neurology, 20, 487-498. Filler, A. (2009). Magnetic resonance nemography and diffusion tensor imaging: Origins, history, and clinical impact of the first 50,000 cases with an assessment of efficacy and utility ina prospec- tive 5000-patient study gronp. Neurosurgery, 5(4 Suppl), 29-43. Geschwind, N. (1965). Disconnexion syndrome animals and men. I and II. Brain, 88, 237-294, 585-644, Goodman, W. K., Greenberg, B. D., Ricciuti, N., Bauer, R., Ward, H., Shapira, N.A.,et al (2010). Deep brain stimulation for intractable obsessive compulsive disorder: Pilot study using a blinded, staggered-onset design. Biological Psychiatry, 67, 535-542. Head, H. (1926). Aphasia and kindred disorders of speech. Cambridge: Cambridge University Press. Hebb, D.O. (1949). The organization of behavior New York: Wiley. ‘bution a etude anatomo- Koch, G., Oliveri, M., Cheer, B., Ruge, D., Lo Gerfo, E., Salemo, $., et al, (2008). Hyperexcitability of parietal-motor functional connections in the intact left-hemisphere of patients with neglect. Brain, 131, 3147-3155, Lashley, K. S. (1938). Factors limiting recovery after central nervous lesions. Journal of Nervous and Mental Disorders, 888, 733-755. Lichtheim, L. (1885). On aphasia. 433-454. Liepmann, H., & Mass, , (1907), Fall von links seitiger Agraphie und Apraxie bei rechsseitiger Lahmung. Z. Psychol. Neurol., 10, 214297. Mayberg, H. S. (2009) ted clectrode-based modulation of nemral circuits for depression Journal of Clinical Investigation, 119, 717-725. Brain, 7, a Mazziotta, J. C. (2000). Imaging: Window on the brain, Archives of Neurology, 57, 1413-1421. Mishkin, M. (1978). Memory in monkeys severely impaired by combined but not by separate jgdala and hippocampus. Nature, 973, 297-298. Nadeau, S. E,, & Crosson, B. (1995), A guide to the funetios ging, of cognitive processes. Neuropsychiatry, Neuropsychology, and Behav- ioral Neurology, 8, 143-162. Nienwenhuys, R., Voogd, J., & van Huijzen C (2008). ‘The human central nercous system. Berlin: Springer-Verlag Osear-Berman, M., —Zola-Morgan, M. Oberg. R. G. E., & Bonner, R. T. (1982). Comparative nenropsychology and Korsakoff's syndrome syed response, delayed alter- nationand DRL performance. Neuropsychologia, 20, 187-202 chle, M. E., MacLoed, A. M., Powers, W. J., Gusnard, D. A., & Shulman, (2001). A default mode of brain function. Proceedings of the National Academy of Science, US.A,, 98, 626-682, Rumelhatt, D. E., McClelland, J. L., & the PDP Research Group (1986). Parallel distributed processing, Explorations in the microstructure of cognition. Cambridge, MA: MIT Press Sowell, E.R. Thompson, P. M., Rex, D., Kornsand, D., Tessner, K. D., Jernigan, T. L., & Toga, A. W. (2002). Mapping suleal pattern asymmetry and local cortical surface gray matter distribution in vivo: maturation in_perisylvian cortices. Cerebral Cortex, 12, 1 Teuber, H. L. (1955). Physiological psychology. Annual Review of Psychology, 6, 267-296. Ungereider, L. G., &e Mishkin, M. (1982). Two corti- cal visual systems. In D. J. Ingle, M. A. Goodale, & R. J. W. Mansfield (Eds.), Analysis of visual behav- ior, pp. 594-986, Cambridge, MA: MIT Press. Wericke, GC. (1874). Des Aphasische Symptom- ‘enkomplex. Breslau: Cobn and Weigart.APHASIC SYNDROMES Both symptoms and syndromes are linked to taxonomic frameworks in which phei are related to one another. As understanding of a set of phenomena increases, the taxonomies to which symptoms and syndromes are related ily determined by the mech that produce and relate’ the symptoms Syndromes become more informative, and more valuable scientifically and clinically, as they can be related to more principled taxonomies Turning to aphasie syndromes with these considerations in mind, the challenge for neu- rologists, psychologists, and speech-language pathologists is to determine what aphasie symp= nena toms are, what their co-occurrence patterns are, and to develop explanations for their oce- ce. In this chapter, I briefly review approaches to these questions, and outline questions and challenges that remain. urrence and co-oceurret CLASSICAL CLINICAL APHASIC SYNDROMES Aphasie syndromes were first described ove 150 years ago (Broca, 1861; Wernicke, 1 Lichtheim, 1885). The approach to aphasia developed during this period continues to influence the field in two ways: the aphasic disorders identified at that time, which have been called syndromes, are still commonly referred to in both clinical and research work; and the principles enunciated in the early research remain basic to aphasiology. It is therefore appropriate and useful to begin a ‘ic syndromes with those papers Broca (1861) described a patient, Leborgne, with a severe speech output disturbance. Leb- orgne’s speech was limited to the monosyllable “tan.” In contrast, Broca described as normal \dersta Leborgne’s ability to u guage, express himself through gestures and facial expressions, and understand nonverbal communication. Broca claimed that Leborgne had ost “the faculty of articulate spee: Broca related this impairment to damaged nenral tissue; Leborgne’s brain contained a lesion whose center was in the posterior portion of the inferior frontal convolution of the left 23 hemisphere. The lesion extended posteriorly into the parietal lobe. Broca related the most severe part of the lesion to the expressive lan- guage impairment. This area became known as “Broca’s area.” Broca argued that this was the neural site of the mech solved in speech production, In 1874, Wernicke described a patient with a speech disturbance that was very different from that seen in Leborgne. Wernicke’s patient was fluent, but her speech contained words with sound errors, other errors of word forms, and words that were semantically inappro- priate. Also unlike Leborgne, Wernicke’s patient did not understand spoken language. Wernicke related the (vo impairments—the one of speech production and the one of com- y arguing that the patient had sustained damage to “the storehouse of andi- tory word forms.” Under these conditions, speech would be expected to contain the types prehension of errors that were seen in this ease, and com- prehension would be affected. Establishing the location of the lesion in this case was more problematic. Wernicke did not have the oppor- tunity to perform an autopsy on his ease However, he did examine the brain of a second patient whose language had been deseribed prior to her death by her physician in terms that made Wemicke think that she had had a set of symptoms that were the same as those he had seen in his case, The lesion in this second patient occupied the posterior portion of the first temporal gyrus, also on the left Wernicke sugyested that this region, which came to be known as “Wernicke’s area,” was the locus of the “storehouse of auditory word forms.” Wemicke’s paper was the first to deseribe an aphasic syndrome, in the sense of a constel- lation of symptoms, He had found two defi- cits—fluent paraphasie speech and_ poor auditory comprehension—and he related therm both to a single functional abnormality: mal representations of the sound patterns of words. He further related this abnormality to the location of the lesion he thought produced this deficit. The lesion he thought was respon sible for the deficit was in the area of the brain adjacent to the primary auditory cortex (Heschl’s gyrus). Basing his ideas on those of bnor-24 his teacher, Meynert, Wernicke argued that a lesion in this location would affect the long- term storage of the sounds of words because the areas of cortex just adjacent to the primary anditory cortex supported higher-order audi- tory processing, including processing of audi- tory input as language. Wernicke pointed ont that the syndrome he had described was the direct perceptual counterpart to the syndrome that Broca had described, in which a lesion adjacent to the motor cortex produced an impairment of motor speech. Broca and Wern fundamental principles that underlie the cal aphasic syndromes ‘ke thus enunciated three * Language processors are localized (Broca, 1861). * Diverse language symptoms can be due to an underlying deficit in a single language processor (Wernicke, 1874). + Language processors are localized in brain regions because of the relationship of the processor to sensory or motor funetions (Wemicke, 1874). A decade later, Lichtheim (1885) applied these principles to a wider range of symptoms. Lichtheim recognized seven syndromes affect- ing spoken language: * Broca’s aphasia, a severe expressive lan- guage disturbance reducing the fluency of speech in all tasks (repetition and read- ing, as well as speaking) and affect elements of language, such as grammal cal words and morphological endings, without an equally severe disturbance of auditory comprehension © Wernicke’s aphasia, the combination of fluent speech with erroneous choices of the sounds of words (phonemic parapha- sias) and an anditory comprehension disturbance © Pure motor speech disorders—anarthria, dysarthria, and apraxia of speech—output speech disorders due to motor disorders, in which speech is misarticulated but comprehension is preserved * Pure word deafness, a which the patient does not recognize disorder in CLINICAL NEUROPSYCHOLOGY spoken words, but spontaneous speech is normal * Transcortical motor aphasia, in which spontaneous specch is reduced but repeti- tion is intact * Transcortical sensory aphasia, in which a comprehension disturbance exists with- out a disturbance of petition + Conduction aphasia, a disturbance in spontaneous speech and repetition consisting of fluent paraphasic speech, without a disturbance in anditory comprehension These syndromes are listed in Table 2-1 Lichtheim argued that these syndromes followed lesions in those regions of the brain depicted in schematic form on a diagram he published in his paper, reproduced here as Figure 2-1. To understand Lichtheim’s view of the relation of lesion locations to the syndromes we need to note that Lichtheim made the assumption that the meaning of words resided in the superior portion of the parietal lobe {indicated "C,” for “concepts,” in Figure 2-1), and that he assumed that, in speech production, word meanings activated both word sounds in Wernicke’s area and the motor speech plan- ning mechanism in Broca’s area; hence, the two arrows originating in the concept center, , in Figure 2-1. With this background, the relationship of the seven syndromes to lesion sites is quite straightforward. Broca’s aphasia, which affects expressive language alone, is du Broca’s area, the center for motor speech plan- ning adjacent to the motor strip. Wernicke’s aphasia follows lesions in Wernicke’s area that disturb the representations of word sounds, as we have seen, Pure motor speech disorders arise from lesions interrupting the motor path ways from the cortex to the brainstem nuclei that control the articulatory system, These disorders differ from Broca’s aphasic because they are not linguistie; th itself, not the planning of speech. Pure word deafness affects the transmission of sound input into Wemnicke’s area. It therefore dis- rupts word recognition but not speech, since words themselves are intact and accessible for speech production purposes, Tr to lesions in y affect articulation nscorticalAPHASIC SYNDROMES 27 Figure 2-2. The version of the classical modlel developed by Geschvvind (1982). The major addition is that the concept center is eliminated and the inferior parietal lobe is identified as the locas of associations between word forms and sensory properties AN ASSESSMENT OF THE ‘CLASSICAL SYNDROMES As noted above, to assess these syndromes, we must consider how they describe aphasie symp= toms, how the symptoms they identify are grouped, and the basis for any such grouping, With respect to the first of these topies, the classic syndromes have identified the domain of symptoms that form the basis for syndromes. These consist, first and foremost, of the relative preservation of patients’ performances in the usual tasks of hang king, under- readin nd standing spoken languaj writing). Although this might seem like ous set of phenomena upon which to descriptions of aphasia, this focus contrasts with other appr aphasia, Jackson, Head, Goldstein, and other hes to the description of pion phasiology concentrated on the conditions under which language is used. In a famous paper, Hughlings Jackson described « patient, a carpenter, who was mute, but who mustered up the capacity to say “Master's” in response to his son’s question about wh his tools were. Jackson's poignant comments convey his emphasis on the conditions that provoke speech, rather than on the form of the speech itself The father had left work; would never return to it: (the was anvay from home; his son was on a visit question was directly put to the patient, Anyon saw the abject poverty the poor man’s family lived in would admit that these tools were of immense » them, Hence we have to consider as regards J other accasional utterances the strength of sta Jackson, 1878, p. LSI) the accompanying emotion (1948 about jents—both those with and those Goldstein asia—were capable of abstracting away from the immediaey of a situation to eon sider longer-term goals, a capacity he called the ability to assume “the abstract attitude, Both Jackson and Goldstein songht a descrip- tion of hangnage use as a function of motiva- tional and intellectual states, and tried to describe aphasie disturbances of kinguage in wctors that drive kn relationship to the guage production and make for depth of eomprehen- sion. T ing | more humanly relevant than a description of sis surely a vital aspect of understand- nents. In many ways, it is nage impait28 language impairments in terms of which phonemes are produced in spontaneous speech or repetition, Unfortunately, it is a very intrac- table goal. Wernicke, Lichtheim, Geschwind and those researchers who conceived and developed the framework of the class syndromes focused aphasiology on everyday language use, abstracting away from suc considerations. To date, this has proven a wise choice Second, the description of symptoms in classical aphasic syndromes inchides linguistic and psycholinguistic descriptions of language For instance, Benson and Geschwind (1971) deseribe Broca’s aphasia as follows: The language output of Broca’s aphasia can be described as nonfluent. Itis sparse, dysprosodic, and, auticulated; itis made up of very short phrases poorly and it is produced with effort, particularly im init tion of speech. The output consists primarily of substantive words, ie., nouns, action verbs, or sig- nificant modifiers, The pattern of short phrases lack- ing prepositions is often termed “telegraphic speech”... Comprehension of spoken language is much better than speech but varies, being com- pletely normal in some cases and moderately dis- turbed in others. (p. 7) These linguistic and psycholinguistic fea- tures are important, because characterizin speech as abnormal is not sufficient to discrin inate one classic syndro ne from another; as we have seen, speech is abnormal in both Broca’s and Wernicke’s aphasia, but in different ways Moreover, given that aphasia is a disturbance of language and its processing, it is obviously desirable to include descriptions of affected Jangnage elements and psycholinguistic opera- tions in the data that determine aphasic syndromes The classic approach thus established the basic phenomena that are relevant to aphasie syndromes. It encountered serious problems in taking the next steps required by a sue- cessful taxonomy: characterizing the symp- toms fully and_ systematically co-occurrence of symptoms, and accoun for the symptoms and their co-occurrence mechanistically. The first major failing of the categorization of the classical syndromes is the limited, CLINICAL NEUROPSYCHOLOGY unsystematie, and atheoretic description pro- vided by its advocates of linguistic representa- tions and psycholinguistic operations that are affected in aphasia, As an example, the abnor- malities listed as characteristic of Broca’s aphasia by Benson and Geschwind constitute a set of unrelated disturbances affecting spe each likely due to disturbances of different operations. The symptoms of “dysprosodic” speech, “poorly articulated” speech, and “short phrases lacking prepositions” are likely to reflect disturbances in the assignment of pros- ody, specifying the articulatory gestures for phonemes, and construction of syntactic forms, respectively. These descriptions are too gen- eral: those with Broca’s aphasia m variety of disturbances affecting each of these aspects of speech planning and production. have a “Poorly artic peech can be dysarthrie or apraxic (each of these been farther subdivided); * speech can take a wide variety forms, not simply be lacking in prepositions. These descriptions are also incomplete: those with Broca’s aphasia fre- quently have some short bursts of fluent speech with substitution of grammatical elements (paragrammatism), not just omission of these elements (de Bleser, 1987). By ignoring these limitations in the deserip- tions of aphasie symptoms, the pattern of association of the symptoms that are specified in the syndromes is not established. Cluster analysis has yielded different results, depend- ing on what aphasia test was used (Metter et al., 1984) and the time at which patients were tested (Kertesz & Phipps, 1980). Goodglass and Kaplan (1972, 1982) argued that the p tern of positive and negative weights of tests on factors in a factor analysis of over 250 apha- sics tested using the first edition of the Boston Diagnostic Aphasia Examination provided support for the classical syndromes. For instance, they considered a factor on which production of the ontput features associated with Wernicke’s aphasia loaded highly posi- tively and comprehension loaded highly negatively to be one that captured disorders ted with Wernicke’s aphasia. If it is rea- sonable to interpret this factor in this way {alternate analyses are always possible, and alternate ways of doing factor analysis mayAPHASIC SYNDROMES 1d different results), the implication is that every patient is a Wernicke’s aphasic to some extent, This is an interesting possibility, quite different from the classical view that patients as a whole fall into one syndrome or another: The presence of a “Wemicke factor every patient could result from lesions affecting the ent degrees in different patients. This hypoth- esis could be tested by correlating patients’ factor in Wernicke’s , but these analyses have not been done. to determine whether the that causes Wernicke’s aphasia to differ- ores with lesion. si Another way symptoms described in the classical syndromes co-oceur frequently is to refer to clinical expe~ rience. If the symptoms frequently co-oceur, classification of most patients into the clinical syndromes should be relatively easy. In fact, it not, It is widely appreciated in clinical cireles that the classic syndromes do not apply well to many slowly developing diseases, such as by tumors or Alzheimer disease; to. multifocal dis or in the: s, such as closed head injur acute phase of focal disease, such as stroke. Even in the clinical setting, where they can be applied with some success, studies of the chronic phase of single-focal, rapidly deve- loping lesions such as strokes have shown widespread disagreements as to a patient’s classification (Holland et al,, 1986) and/or that clinicians identify a large number of “unclassifiable” cases (Lecours, Lhermitte, & Bryans, 1983. An unclassifiable case is repre- sented by the patient shown in Figure 2-3, whose scores on the Boston Diagnostic Aphasia Examination do not fit the criteria set out by Goodglass and Kaplan (1972, 1982) for any, syndrome, Despite the widespread nse of these syndromes in clinical reports, it is truly unc whether more than a small percentage of patients with language disorders actually fit the criteria for these syndromes. If the classic syndromes do not divide patients into identifiable groups, and there is little evidence that patterns of performance on aphasia tests produce factors that spond to the syndromes, one might think to abandon the classification for lack of evidence. However, many clinicians argue that the classic to provide important the location of mixed” or Len syndromes continue information about lesions. 29 In addition, the relation of the syndromes to lesion locations continues to be viewed as pro- viding an explanation for the syndromes, based upon the principles enunciated by Wernicke that relate perceptual processing to unimodal sensory association cortex and motor planning, to unimodal motor association cortex. I will dis cuss the second of these topics below With respect to the first, a number of com- puted tomography (CT) and magnetic reso- ing (MRI) studies have confirmed a general relationship between the major syn- dromes and lesion locations. Broca’s aphasia is associated with anterior lesions; W ke's aphasia is associated with posterior lesions centered in the temporal-parietal juncture (Hayward et al., 1977; Kertesz, 1979; Naeser, 1989; Naeser & Hayward, 1978). Pure motor deficits of speech are associated with subcorti- cal lesions (Alexander et al., 1987; Naeser et al., 1989, Schiff et al, 1983). Pure word deafness is associated with lesions in the auditory asso- ice i ciation areas and surrounding white matter tracts, often bilaterally (Auerbach et al, 1982; Coslett, et al.,1984; Denes et al., | Metz- Lutz, & Dahl, 1984). Transcortical motor and transcortical sensory aphasia are associated with watershed infarcts between the anterior and middle cerebral arteries (transcortical motor aphasia; Freedman et al., 1984) and middle and posterior cerebral arteries (trans cortical sensory aphasia; Kertesz et al., 1982). Conduction aphasia is associated with smaller lesions that appear to often affect the arcuate fasciculus (Damasio & Damasio, 1980 However, a closer look reveals many limi- tations of these correlations. Just as the co- occurrence of symptoms into syndromes is unreliable in many types of diseases, so too is the correlation of syndromes with lesions in many (perhaps most) neurological diseases The studies cited above deal overwhelmingly with chronic stroke patients. As with the co- occurrence of symptoms, even here, at least 15% of patients have lesions that are not pre- dictable from their s) es (Basso et al, 1985), and some researchers think this number is much higher—as high as 40% or more, depending on what counts as an exception to the rule (de Bleser, 1988). The relationship between lesion location and syndrome is more32 provided by these syndromes in clinical reports. In research studies, they continuc to exert two types of influence One is an effort to relate more specific symp- toms to the classical syndromes. For instance, Grodzinsky (2000) has argued that certain dis- orders affecting syntactically based sentence comprehension are only found in Broca’s apha- sia; Blumstein et al. (1982) have suggested that Broca’s aphasia is associated with abnormali- ties in “automatic” but not “controlled” seman= tic processing, A great deal of controversy surrounds such claims (see Chapter 4. for discussion of Grodzinsky’s claims). If th correct, they apply to a very small number of y are symptoms, and there is no explanation for their occurrence in a particular syndrome. Any such co-occurrences are not a basis for retaining the sie syndromes. A second way in which the classical syn- dromes influence contemporary research is throngh their effect on efforts to characterize newly explored language disorders. An exam- ple is the fledgling taxonomy of primary pro- gressive aphasia (PPA). Primary progressive aphasia was first described by Mesulan (1982) as a dementing disease whose primary initial symptom was aphasia. For well over a decade, efforts to subdivide PPA languished, but in ent years a series of clinical-radiological studies have led to partitioning of PPA. Gor Tempini et al. (2003) distinguished between nonfluent PPA (“nonfluent speech output, ‘labored articulation,” agrammatism, difficulty with comprehension of complex syntactic strnetures, word-finding deficits, and preserved single-word comprehension”), logopenie pro- gressive PPA (“slow rate, grammatically simple but correct [speech], and... frequent word- finding pauses”) and semantic dementia (“fiuent, grammatical speech; confrontation naming deficits; semantic deficits for words and, initially less severely, for objects; surface dyslexia; and relatively spared syntactic com- prehension”) (all ci et al, 2003. pp 337-338). The similarities of nonfluent PPA to Broca’s aphasia, semantic dementia to tra sory aphasia, and of logopenic PPA to anomia or conduction aphasia are striking, and reflect the perva- sive influence of the classic syndromes, with re cortical CLINICAL NEUROPSYCHOLOGY their emph processing, The classic syndromes rest on a principle of neural organization that also continues to be influential—the idea that cognitive operations are localized where they are because of their relations to perceptual and motor processes, which has been retained as an explanatory principle (Mesulam 1990, 1998; for a variant view, see Damasio, 1989). The failure of the neuroanatomical model underlying the aphasic syndromes to predict lesion-deficit correla- tions or the localization of neurovascular or neurophysiological responses to language pe formances not been taken as evidence son fluency and single-word inst this principle, only against particular instantiations of it. For instance, the absence of evidence that the meanings of words are represented in the the results of both activation studies (M 1996) and the effects of pathology (Hodges et al., 1992) indicating that conerete nominal concepts are represented in the infe- rior temporal lobe have led researchers to abandon Geschwind’s hypothesis. that par etally based cross-modal associations underlie word meaning, but not the more general idea that word meanings are localized in areas of the brain that support particular perceptu: motor processes. In fact, the idea of a neuro logical basis for “embodied cognition” is enjo inga very product ¢ (Martin et al., 1996; Pulvermuller, 2003). Even language operations that do not fit into the model of functional neuroanatomy that underlies the classical syndromes—hecause they are not clearly either perceptual or motor—have been related to the brain through elaborate exten- sions of the basic principle. Constructing syn- tactic representations, for instance, is an abstract operation that bears a very distant relation to perceptual and motor processes, and the classical neuroanatomical model makes no predictions about where the neural tissue that supports these processes is localize However, in an extension of the model that incorporated Luria’s (1966) views regarding the role of the dorsolateral frontal lobe in cog nitive control, Fiebach and Schubotz (2006) suggested that syntactic analysis of sentences in comprehension is localized in Broca’s areaAPHASIC SYNDROMES because the lateral premotor area, including Broca’s at is involved in the detection of patterns in arbitrary dynamic, temporally extended perceptual events, which includes speech. I shall return to these claims below. The present point is that the principle underly- ing the to exert great intellectual influence in the domain of functional neuroanatomy theories, one, I would say, rivaling the impact of concepts such as neural nets (Arbib, 2002), functional connec- tivity (Seth, 2005), small worlds (Bassett & Bullmore, 2006), and oscillatory neurophysio- logical processes (UhIhass et al., 2008). Given the close connection between explanatory principles and syndromes discussed in the introduction to this chapter, the effect is to orce acceptance of the ¢ I syndromes (the “you are known by the company you keep principle) sical models conti te NEW APPROACHES Whatever the impact of the theoretical prinei- ples that underlie the classical syndromes, the empirical limitations of these syndromes, briefly reviewed above, require attention. In the past 30 years, these limitations have begun to be addressed. The most significant work has been the development of detailed models of many aphasic abnormalities, ranging from speech planning (Dell et al., 1997) through syntactically based comprehension (see Chap- ter 4), semantic representations (Garamazza & Mahon, 2003), alexia (Coltheart, 2006), and others. It is well beyond the scope of this chap- ter to review all this work, but a brief introduc- tion to linguistics and psycholinguistics may allow readers who are unfamiliar with these fields to see the possible scope of work along these lines, The language code conneets particular types of representations to particular aspects of meaning. Words connect phonological units with items, actions, properties, and logical con- nections. Word formation forms words from existing words. Sentences relate words in hier- archical syntactic structures to each other to determine semantic relationships between them, such as who is accomplishing or receiving 33 an ion. Discourse relates s express temporal order, causation, inference and other semantic values. Table 2-3 attempts to systematically describe the levels of the lin- guistic representations that are basic to language at the word les 2-4 and 2-5 and Figures 24 and 2-5 present models of how these forms are processed. Tables 2-3 through 2-5 and Figures 2-4 and are highly simplified, but they suggest of what language and the language processing system consist. ‘As seen in these tables and figures, there are many levels of detail at which one can describe language and language processing Depending on the level of detail at which lan- guage impairments are described, there may he hundreds of independent language process- ing impairments. For instance, we may recog- nize a disturbance of converting the sound waveform into linguistically relevant units of sound—acoustic-to-phonemic conversion—or recognize disturbances affecting the to recognize subsets of phonemes, such as vowels, consonants, stop consonants, frica tives, nasals, and the like (Saffran et al., 1976). For many clinical purposes, an adequate way to approach aphasie impairments is at the level of detail that identifies language process- ing impairments in terms of sets of related operations responsible for activating the major forms of the language code and their associ- ated meanings in the usual language tasks of omprehending auditorily presented language, writing, and reading. These levels of the language code are listed in Table 2-3. However, for many research purposes, and for some clinical purposes, a more detailed deserip- tion of linguistic representations and opera tions is needed. A psycholinguistic approach to aphasia would describe aphasic symptoms as disorders of spe- cific psycholinguistic operations that have, as aconsequence, the failure to normally activate specific linguistic representations in particular tasks. Two obvious ways to identify syndromes within this framework are as individual symp- toms that are due to impairments of indi- vidual operations and as sets of symptoms that arise from a single impaired operation. With respect to the first type of syndrome, as noted, senten to ind sentence level,