Chapter 13 The contributions of neurophysiology to clinical neurology

Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 13

The contributions of neurophysiology to clinical neurology: an exercise in contemporary history GIOVANNI BERLUCCHI * Department of Neurological and Visual Sciences and National Neuroscience Institute, University of Verona, Verona, Italy

INTRODUCTION The emergence of a unified field of neuroscience in the last three decades of the 20th century has blurred, if not erased, the boundaries between the traditional disciplines dealing with the nervous system. Yet, well before the advent of neuroscience, two main reasons warranted the existence of a privileged connection between neurophysiology and clinical neurology. First, granted that the task of the neurophysiologist is that of understanding the normal working of the nervous system, it is a historical fact that normal nervous functions have often been inferred from disorderly functions. If in this vein neurophysiologists have undoubtedly learned much from experimental lesions in animals, it has been the clinical neurologists who have obtained first-hand information on the effects of pathology on the functioning of the most complex and interesting of all nervous systems, that of man. As a fortunate consequence of this division of labor, convergent evidence from lesion studies in animals by neurophysiologists and in humans by clinical neurologists has set our current knowledge about nervous functions on a firm comparative foundation. The special relations between physiological and clinical investigations on the nervous system have been aptly captured by the neurologist Gordon Holmes. In commenting on his own investigations of the visual cortex in man, he has written: This has required the collection of a large number of observations, for while the physiologist can rely on experiments which he can select and control, and can obtain from them more precise, sometimes critical and often measurable data, the clinician must depend on the analysis of observations which are rarely so simple or *

clear cut, and he is often unable to correlate them with the causal lesions responsible for them. The physiologist may be compared with the builder in ashlar or hewn stones which can easily be fitted together; the physician resembles the mason who has to use irregular rubble and therefore requires more time and labor to attain his end. But in some branches the “rubble” collected and put together by the clinician is essential, or can at least be complementary to the conclusions of the experimentalist. This is particularly so in the investigation of those functions of the brain which require the co-operation of a conscious subject who is able to communicate his experiences, as in the examination of sensory functions. (Holmes, 1944) The second reason for the existence of a special link between neurophysiology and clinical neurology is that their joint endeavors in the first half of the past century have given birth to clinical neurophysiology. This hybrid field of basic and clinical research has become independent from the parent disciplines and has developed in its own right. Clinical neurophysiology was recognized as an autonomous specialty with the foundation of the International Federation of Electroencephalography and Clinical Neurophysiology in 1947, and the launching in 1949 of its official publication organ, the journal Electroencephalography and Clinical Neurophysiology, known in short as the EEG Journal (Brazier and Cobb, 1979) and currently published with the title Clinical Neurophysiology. Herbert Jasper, the founder and first chief editor of the EEG Journal, was a pioneer of the application of neurophysiological methods to the study of neurological diseases (Andermann, 2000).

Correspondence to: Giovanni Berlucchi, Dipartimento di Scienze Neurologiche, e della Visione, Universita` di Verona, Strada Le Grazie 8, 37134 Verona, Italy. E-mail: [email protected], Tel: +39-045-8027141, Fax: +39-045-8027279.

170 G. BERLUCCHI For many years he collaborated with neurosurgeon Wilder unit, a choice which has been at the root of the concepPenfield at the Montreal Neurological Institute in studies tual and experimental advances of neuroscience up to combining electrical stimulations and recordings from this day. He conferred a physical reality to Marshall the brain of unanesthetized patients able to report their Hall’s concept of the reflex diastaltic arc in terms of subjective experiences (Penfield and Jasper, 1954). neuronal components and the synapses causing the uniThe present chapter reviews a number of historical directional march of impulses along reflex pathways contributions of neurophysiology to clinical neurology (Sherrington, 1897). He distinguished dedicated neuroin the 100 years that have elapsed since the publication nal pathways, such as those carrying exclusive inforof Sherrington’s The Integrative Action of the Nervous mation from a particular sensory receptor, from the System (1906), a book generally considered the neurofinal common path of the motoneurons, which allows physiologist’s bible. Most of those who made the coneach muscle potentially to be controlled by all sensory tributions called themselves physiologists rather than inputs, as well as by the will. With relatively simple neurophysiologists, because the latter term became behavioral observations following accurate peripheral popular only after Dusser de Barenne, Fulton, and Gerand central nervous lesions, he categorized many types ard founded the Journal of Neurophysiology in 1938 of reflex activities and inferred from the effects of (Jung, 1974). The term “neurology” is much older convergent allied and antagonistic reflex pathways that because it was introduced into the medical literature the output mechanisms of the nervous system are in the 17th century by Thomas Willis (Eadle, 2003). aimed at serving the singleness of action of the organThe phrase “clinical neurology” seems to have a more ism. He was the first to have a clear idea of the imporrecent origin, since it appears to have been first used tance of neuronal inhibition as a crucial component of in the United States in a textbook by Wechsler (1927) the normal working of the central nervous system and the title of an edited American translation (Sherrington, 1932). Sherrington’s investigation of the (Strecker and Meyers, 1924) of a German book by phenomenon and mechanisms of spinal shock after Curschmann (1924; see Steinberg, 2002). In Europe separation of the cord from the brain, and of decerethe term became popular after the publication of the brate rigidity after brainstem transections, did for many book Introduction to Clinical Neurology by Holmes years inspire clinical interpretations of disorders of mus(1946). cle tone and posture in man. For some neurophysiological contributions reviewed In 1875, in a major breakthrough in clinical neurolohere, the attribute “historical” is justified by their gengical testing, Erb and Westphal had independently diseral recognition as such by the scientific community, covered the knee extension response to percussion of while the choice of others has been dictated by their the patellar tendon, and had described its modifications actual or predictable impact on the advancement of neuin conditions such as tabes dorsalis and limb palsy roscience, as seen from the present author’s viewpoint. (Erb, 1875; Westphal, 1875; see Bonduelle, 2000; Louis, 2002). Initially this muscle response, christened knee THE FOUNDING FATHERS OF jerk by Gowers (1886), was wrongly attributed to a NEUROPHYSIOLOGY AND THE direct muscle reaction to percussion because of its very DEFINITIVE ESTABLISHMENT OF THE short latency. It was Sherrington who identified the NEURON THEORY knee jerk as a phasic enhancement of a tonic reflex maintaining the muscle tonus, because “severance of After Golgi and Cajal created neurohistology in the the afferent nerves of these muscles destroys their 19th century, Charles Scott Sherrington and Edgar tonus, and renders at the same time the knee jerk ineliDouglas Adrian acted as fathers to modern neurophycitable, just as also does the severance of their motor siology in the 20th century. They were jointly awarded nerves” (Sherrington, 1906). the Nobel prize in 1932 for their discoveries regarding Sherrington also showed that decerebrate rigidity in the functions of neurons. animals is a caricature of the normal muscle tonus. This provided an important clue to the understanding Sherrington and nervous integration of human spasticity as an abnormal reflex, though it Sherrington’s The Integrative Action of the Nervous now appears that an increased input from muscle spinSystem (1906) presented an elaboration of the concept dles is not as crucial for spasticity in primates as it is of reflex action, which was defined as the greatest sinfor decerebrate rigidity in cats and dogs. gle contribution of the physiologist to clinical neurolSherrington himself did not appear to take much interogy (Fulton, 1953). According to Granit (1966), est in clinical neurology. He hardly cited the ideas of his Sherrington’s fundamental merit was the choice of great contemporary neurologist Hughlings Jackson, and the neuron and its interconnections as his analytical apparently did not fully understand the work of his good

THE CONTRIBUTIONS OF NEUROPHYSIOLOGY TO CLINICAL NEUROLOGY neurologist friend Henry Head (Denny-Brown, 1957). Yet many of his neurophysiological discoveries were of major clinical relevance. The physiologist Angelo Mosso from the University of Turin was the first to see changes in brain blood flow through skull cracks in patients responding to sensory stimuli, doing mental arithmetic, and undergoing emotional experiences (Mosso, 1880). Shortly thereafter, Roy and Sherrington (1890) (Fig. 13.1) saw in animal experiments that the products of brain metabolism can cause variations of the caliber of cerebral arterioles. From this they inferred the existence of an intrinsic mechanism by which the blood supply to the brain can be varied locally in correspondence with local variations of functional activity. Many decades later the essential truth of this prescient intuition was fully acknowledged by physiological studies using radioactive measures based on inert gases, as developed by Sokoloff and Kety (1960) in the Physiology Department of the University of Pennsylvania, and first applied to the human cortex by Lassen and Ingvar (1961). These ground-breaking studies of the relations between cerebral blood flow and metabolism paved the way for the development of the modern brain imaging techniques, now a major tool for diagnosis in clinical neurology, as well as for

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research in all branches of neuroscience (Frackowiak, 1998; Raichle and Mintun, 2006). Further, following the localization of the motor cortex in the frontal lobes by Fritsch and Hitzig in dogs and by Ferrier in macaques (see Finger, 1994), Sherrington used more refined electrical stimulation techniques under asepsis to map the motor cortex in anthropoid primates (a gorilla, an orangutan, and two chimpanzees) whose brains are evolutionarily closer to that of man (Leyton and Sherrington, 1917). One of his former students, the famous neurosurgeon Penfield of the Montreal Neurological Institute, improved neurosurgical procedures by exploiting Sherrington’s precise cortical maps for constructing corresponding maps in the human brain (Penfield and Rasmussen, 1950). Finally, all fields of neuroscience benefited enormously from Sherrington’s ideas, which were transmitted and elaborated by many outstanding pupils who went on to pursue a career in physiology, including Magnus, Eccles, Bremer, Granit, Forbes, Fulton, and Camis (see Denny-Brown, 1957). Among other pupils of Sherrington who became clinicians, the most distinguished along with Penfield was the neurologist Denny-Brown, who trained with Sherrington as a PhD student and then worked in neurology at the National Hospital in London. He was then called to chair Harvard University’s Neurology Unit of Boston City Hospital in 1941, whereby he played a major role in the development of neurology in the United States (Vilensky et al., 2004).

Adrian and the single-neuron code

Fig. 13.1. Charles Roy and Charles Sherrington in front of the Department of Pathology of Cambridge University in 1893, 3 years after the publication of their joint paper on cerebral blood flow (from Granit, 1966).

Ivan Pavlov, the first neurophysiologist to be awarded a Nobel prize (in 1904, though for his work on the digestive system), is rightly regarded as a giant of physiology belonging in the same class as Sherrington. Yet his influence on neuroscience was not as great as that of Sherrington because he did not attempt to reduce his hypothetical mechanisms of the conditioned reflexes, such as, for example, cortical inhibition, to the neuronal level (Granit, 1982). Unlike Pavlov, Edgar Douglas Adrian also chose the neuron as his analytical unit, though with a different means from Sherrington’s (Adrian, 1935). As detailed in a following section, Adrian’s work has furnished the most important roots to the development of electroencephalography and electromyography, two major tools for investigation in both neurophysiology and clinical neurology, which eventually became the springboard for the take-off of clinical neurophysiology. By recording the electrical activity of single nerve fibers, he proved that the messages conveyed to the brain in each fiber from all sensory organs are trains of electrical impulses varying in frequency, but not in amplitude,

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with the intensity of the stimulus. Whether a sensation is tactile, auditory, visual, or other, depends on the sensory organ and the cortical area receiving the signals, not on the nature of the single signals, which are by themselves unvarying across sensory systems (Adrian, 1947a). Similarly, the commands sent by each motoneuron to the muscle fibers under its control, as well as the signaling between one group of neurons and another, are based on all-or-none action potentials coursing along individual nerve fibers (Adrian, 1947b). The work of Adrian and Moruzzi (1939; Fig. 13.2) extended to the cortex the notion that the rate and the temporal spacing of action potentials emitted by a single nerve fiber form a unitary code for neuronal communication, which presumably underlies all aspects of brain functioning, from sensation and movement to thought and action planning. Adrian’s conviction that impulses in nerve fibers represent the main language by which one neuron speaks to another continues to be the basic credo of neuroscientific thought, even if other secondary means of interneuronal communication, such as paracrine chemical signals, are also known to exist. For decades up to the present, action potentials have been recorded from countless single neurons and other excitable cells in most animal species including man, and a vast amount of current wisdom in all fields of neuroscience comes from the use of the technique originally championed by Adrian.

Adrian’s legacy and the contribution of single-neuron studies to the understanding of the brain One of the most profound empirical and conceptual contributions of neurophysiology to the notion of functional specialization in the brain is the demonstration that even single neurons are functionally specialized (e.g., Barlow, 1995). The search for single

Fig. 13.2. Edgar Adrian (left) and Giuseppe Moruzzi in 1953 during a visit to Tuscan villas.

neuron specialization in anesthetized and especially in freely behaving animals is based on Adrian’s concept that sequences of action potentials convey information about the evoking stimulus. Entirely new vistas on the general organization of the cerebral cortex have been furnished by Mountcastle’s (1957) discoveries on the receptive fields of single neurons in the somatosensory cortex; by those of Kuffler (1953) on the receptive fields of single neurons in the retina, and those of Hubel and Wiesel (2005) on the receptive fields of single visual cortical neurons; and by those of Evarts (1966) on the relations between single motor cortex neurons and specific muscles and movements. Hubel and Wiesel’s demonstration of how visual cortical neurons handle different attributes of the visual input, such as form, motion, and color, was especially fruitful for subsequent developments (Hubel and Wiesel, 2005). They found that a single cortical neuron can extract specific features of the visual stimulus, such as the orientation of a simple line segment of an object contour. This occurs because a subset of presynaptic neurons converging onto that neuron responds to adjacent light points along the line segment, and their responses are combined postsynaptically. If such convergence on single neurons in the early stages of the visual system can reconstruct a line from single light points, a further convergence from lower to higher stages of the cortical hierarchy might arguably turn relatively raw information into a meaningful picture; that is, to confer onto single neurons the capacity to respond selectively to whole entities of the natural visual environment. That such sophisticated neurons do indeed exist was first shown by the discovery of neurons selectively responsive to human and simian hands and faces in the inferior temporal cortex of macaques (Gross et al., 1972), later confirmed by Perrett et al., (1982). Evidence for the existence of similarly sophisticated neurons was then obtained in other sensory modalities as well as in motor regions of the brain, where neurons have been shown to fire in selective association with various aspects of movement production and control. A few selected examples indicate that, in the brains of experimental animals, there are neurons whose activity matches specific aspects of cognition and behavioral control of the entire animal. Single neuron activities can index how the animal pays attention to items or locations in its environment (e.g., Wurtz et al., 1982; Chelazzi et al., 1993), and how it memorizes information for later action control (Fuster and Jervey, 1982). The response threshold of sensory cortical neurons often coincides with the whole animal’s threshold for the behavioral detection of those stimuli (Shadlen and

THE CONTRIBUTIONS OF NEUROPHYSIOLOGY TO CLINICAL NEUROLOGY Newsome, 2001). Some hippocampus neurons in rats, called place units, fire when the animal is in specific locations of its familiar environment, so as to construct a neuronal hippocampal map of the outside space (O’Keefe and Nadel, 1978). Detailed features of behavioral associative learning become manifest in the activity of single neurons of the monkey cortex as the animal learns the task (Miyashita, 2004). Associative cortical areas of macaques contain neurons whose activity encodes the goals of viewed biological movements (Puce and Perrett, 2003), as well as other neurons which index precisely the animal’s intention to move the eyes or a limb (Andersen and Buneo, 2002). In the monkey premotor cortex, the so-called mirror neurons become active either during the performance of a specific movement or during the observation of the same movement made by another individual. This discovery has provided a strong argument for the use of single-neuron data for understanding the biological bases of imitation, action understanding and simulation, empathy, and even language evolution and development (Rizzolatti and Craighero, 2004). Finally, current explorations of human brain mechanisms underlying risky evaluations and decisions build on findings from single neuron studies in monkeys making choices based on previous experiences and future expectations (Glimcher, 2005). The lesson for clinical neurology from single neuron studies in behaving animals is that sensory, motor, and integrative functions of all degrees of complexity are potentially reflected at the single neuron level. Further, neurons linked to particular functions make up systems that are distributed in the brain, rather than being concentrated in circumscribed centers. Nevertheless, discrete lesions crucially placed within these distributed systems can impair functioning in selective ways, giving rise to specific patterns of impairment with preservation of other functions. This is particularly true in clinical neuropsychology, where modular theories of cognitive functioning can be tested against the putative removal of a “mental module” by a cerebral lesion. At present, functional localization in the nervous system appears to be alive and well in neurophysiology and clinical neurology alike (Mountcastle, 1998; Albright et al., 2000).

THE UPS AND DOWNS OF FUNCTIONAL LOCALIZATION IN THE NERVOUS SYSTEM IN THE 20TH CENTURY At the transition between the 19th and the 20th centuries, Flourens’ (1858) view of the cerebral cortex as a unitary substrate of a unitary intelligence was overturned by localizationist and connectionist conceptions.

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The cortex had come to be regarded as a mosaic of functionally specialized centers linked by discrete fiber connections, so that selective functional losses could occur upon direct damage to the centers or to their connections. Clinical neurologists including Broca, Wernicke, Liepmann, Lichtheim, Bianchi, Dejerine, and others, had been able to ascribe various specific psychological functions to specific regions and interconnections of cerebral cortex, particularly in the domains of language and voluntary motor control. Physiologists, such as Hitzig, Ferrier, Munk, SharpeySchafer, and others had supported the regional specialization of the cortex by describing selective effects of circumscribed lesions and electrical stimulation in experimental animals, although such effects were largely restricted to basic sensory and motor functions (see Finger, 1994).

Antilocalizationist tendencies in neurology and psychology This localizationist and connectionist view of the cortex came under severe attack when World War I furnished clinical neurologists with study material in the persons of young soldiers with missile wounds of the brain. Influential neurologists like Monakow, Head, Marie, Holmes, and Goldstein were already dissatisfied with the rather crude anatomical and behavioral analyses of the so-called brain cartographers and diagram-makers of the previous era. The new evidence convinced them that only elementary motor and sensory defects could be precisely related to specific sites of brain damage, as in the case of discrete, topographically-organized visual field losses resulting from different bullet trajectories within the occipital lobes (Holmes, 1944). Any attempt to localize language and other higher nervous functions in the brain came to be regarded as a futile exercise, and it was generally believed that disorders of such functions had better be imputed to diffuse alterations of brain organization (Boring, 1950; Finger, 1994). The neurologists’ aversion to localization of psychological functions in the brain was shared by holisticallyoriented physiological psychologists led by Lashley (1930), whose concepts of mass action and functional equipotentiality virtually resurrected Flourens’ notion of global cortical functioning. At the same time, selectivity of neural connections and specificity of functional representation were also questioned, if not completely dismissed, by radical functionalists who liked to depict the developing nervous system as a random, unstructured, and essentially equipotential network, to be molded and shaped into a functionally adaptive system by use, practice, and conditioning

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(Weiss, 1950). In a different vein, but again in sharp contrast with localization and connectionism, the Gestalt doctrine of psychoneural isomorphism equated brain activities underlying psychological functions with diffuse electrical fields spreading throughout the cortex as volume conductors, rather than with distinct patterns of nerve impulses in orthodox neuronal circuits (Kohler and Held, 1949). Finally, interest in brain–behavior relationships was discouraged by extreme behaviorists, who advocated the restriction of behavior analysis to directly observable input–output relationships of the whole organism, with total disregard for any independent neurophysiological evidence (Skinner, 1938).

Neurophysiology re-establishes the reality of functional localization However, a definite movement toward a return of brain localization and connectionism began to take place some time before the middle of the century, and neurophysiology was a protagonist in promoting it. It is then that the bases were laid for the presentday conviction that anatomical and physiological specificity and selectivity are the hallmarks of a cerebral organization in which there is no room for either mass action or functional equipotentiality (Mountcastle, 1998; Albright et al., 2000). As detailed below, combined neuroembryological and neurophysiological experiments showed that, well before birth, genes and developmental processes determine highly specific neural connections, which are then maintained and perfected by environmental influences. Cytoarchitectural and myeloarchitectural subdivisions of the cortex, as described by the early neuroanatomists, were given specific functional meaning by the neurophysiological demonstration that most of them contain orderly maps of the sensory or motor peripheries, as well as populations of neurons with quite distinctive physiological properties. An important neurophysiological distinction surfaced between neuronal systems conveying specific sensory or motor information, and deep brain systems with diffuse projections to the thalamus and cortex, which can modulate the activity of the entire nervous system in the sleep–wake cycle, as well as in attentional and motivational regulations. There are several of these diffusely projecting systems, each marked by a single transmitter specific for that system, and for its action on its cortical and subcortical targets. Better controlled lesion experiments in animals and more accurate analyses of neurological patients made it clear that, depending on its locus, focal brain damage can bring about unique combinations of impairments and spared psychological capabilities. Such patterns of

deficits allow reasonable inferences about the cerebral localization and organization of normal psychological processes. Brain stimulation in experimental animals, and particularly deep brain stimulation, proved suitable for evoking complex integrated behaviors. Species-specific behaviors evoked by deep brain stimulation in cats were documented in particular by the physiologist Walter Hess, who received the 1949 Nobel Prize for his discovery of the functional organization of the diencephalon in the coordination of the activities of the internal organs (Hess, 1964). The discovery by Berger of EEG effects over the entire cortex from sensory stimulation and changes in alertness (Berger 1929) prompted a search for regulatory systems that could cause such a diffuse reaction. Attention was focused on subcortical structures, and particularly on the hypothalamus and the brainstem. Lesion and stimulation experiments in animals had already pointed to a capacity of these structures to modulate total brain activity and to play a major role in instinctive and adaptive forms of general behavioral integration. The notion of the hypothalamus as a neuroendocrine center controlling the hypophysis and various hormonal activities (Ranson and Magoun, 1939) was emerging, along with the concept of specialized neurons secreting hormones rather than neurotransmitters (Scharrer, 1952, 1974). The finding of impaired vigilance and coma after hypothalamic lesions in experimental animals (Ranson and Magoun, 1939), and the lesion-EEG studies of Bremer (1936, 1974; Fig. 13.3), had suggested that waking requires an adequate cortical tone sustained by a continuous arrival of ascending facilitatory inputs at the cortex. Accordingly, the neurosurgeon Penfield had hypothesized that the involvement of functional areas of the cerebral cortex in common integrated action needs the coordinating action of a centrencephalic system, including those parts of the diencephalon and

Fig. 13.3. Horace Magoun (left) and Fre´de´ric Bremer at the first meeting of the International Brain Research Organization in Pisa (1961).

THE CONTRIBUTIONS OF NEUROPHYSIOLOGY TO CLINICAL NEUROLOGY brainstem which send symmetrical projections to the cortex of both hemispheres (Penfield, 1958). In a landmark neurophysiological discovery, Moruzzi and Magoun (1949) showed that electrical stimulation of the brainstem reticular formation produces an EEG reaction identical to the arousal reaction caused by natural sensory stimuli over the entire cerebral cortex and the thalamus. Initially a unitary arousal system lying in the brainstem reticular formation was thought to modulate the activity of the entire nervous system in the sleep–wake cycle, as well as in subtler modifications associated with different motivational states and levels of attentional control. Subsequently the notion of a brainstem arousal system as a functional unit was challenged on several grounds. Moruzzi (1972) showed that ascending brainstem influences can also induce sleep in an active way, and his midpontine pretrigeminal preparation in the cat provided a neurophysiopathological basis for understanding the preservation of consciousness in the so-called locked-in syndrome (Laureys et al., 2004). Chemical neuroanatomy (Dahlstrom and Fuxe, 1999) allowed the differentiation of multiple ascending systems (at least six) within the brainstem reticular core (Steriade and McCarley, 1990; Robbins and Everitt, 1996; Berlucchi, 1997; Steriade, 2001). Each of these systems is made up of relatively few neurons, all characterized by the same neurotransmitter (a biogenic amine or acetylcholine) specific to that system. The enormous branching of the axons of these few neurons ensures a widespread distribution of their projections in most of the diencephalon and telencephalon, and especially in the cerebral cortex, thus offering a structural counterpart to their putative regulatory and modulatory functions. An ascending modulation of cortical activities by diffusely projecting subcortical systems has been and continues to be a very influential concept in neurology for interpreting data from behavioral and clinical analyses, as well as from EEG, event-related potentials, and brain imaging studies. All current neuropsychological theories about attentional mechanisms, either intensive or extensive, or voluntary or reflexive, and their derangements in clinical neuropsychological syndromes, such as unilateral neglect, assign a major role to arousal systems and bottom-up subcortical influences upon the cortex. The chemically tagged ascending brainstem systems are also thought to be heavily involved in various memory and emotional mechanisms, including dependence on substances of abuse, as well as in normal and disturbed consciousness, and in the organic underpinnings of the major psychoses (Cools and Robbins, 2004). Selective activation of the dopaminergic system is thought to underlie the rewarding effects of brain stimulation,

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leading to self-stimulation in experimental animals, as serendipitously discovered by Olds and Milner (1954; see Olds, 1974; Milner, 1991). Currently, deep brain stimulation is utilized in clinical neurology mostly for the treatment of motor disorders and pain control, and in psychiatry for cases of obsessive compulsive disorder (Wichmann and DeLong, 2006).

NATURE AND NURTURE IN NEURONAL CONNECTIONS, THE REALITY OF DISCONNECTION SYNDROMES IN CLINICAL NEUROLOGY, THE CONCEPTUAL SHIFT FROM HEMISPHERIC DOMINANCE TO HEMISPHERIC SPECIALIZATION, AND THE EMERGENCE OF A NEUROSCIENCE OF CONSCIOUSNESS Many neurological diseases are caused at least partly by inherited or acquired genetic mutations, which alter the normal pattern of structural and functional organization of the brain. Examples include common diseases, such as Alzheimer’s disease, the major psychoses, and less common conditions, such as Huntington’s disease and other neurological conditions involving the degeneration of long connection tracts. Understanding of these disorders requires an understanding of how the neuronal organization of the system is put together during embryogenesis, and how the connections between neurons are maintained or modified during the life span. A further issue concerns the cogency and the clinical usefulness of the distinction between acquired neurological deficits that depend primarily on a loss of neuronal populations, and those that depend primarily on disconnections between otherwise functioning neuronal populations. These questions were addressed most effectively in the work of Roger Wolcott Sperry (Fig. 13.4).

Fig. 13.4. Torsten Wiesel, Roger Sperry, and David Hubel in Stockholm receiving the Nobel prize for Physiology or Medicine in 1981.

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Sperry, Hubel, and Wiesel and inborn neural connections and organizations Sperry considered himself a psychologist-cum-biologist rather than a neurophysiologist, possibly because he did not use the electrophysiological methods that characterized the neurophysiology of his time. Yet to the extent that his work re-established the reality of innate Sherringtonian circuits and solved the mystery of the functions of the corpus callosum, he should be recognized as an outstanding honorary neurophysiologist. His scientific career had begun in the 1930s, at a time when the work of two of his teachers, Paul Weiss and Karl Lashley, had built up an apparently substantial and convincing case against the classical Sherringtonian model of central nervous integration. In that frame of mind, Cajal’s neurotropic hypothesis, whereby central nervous organization was thought to come about by an orderly growth of selective neuronal interconnections during embryonic life (Cajal, 1909), had also been questioned, if not denied outright. Preference was accorded to the alternative notion that the developing nervous system starts out as an essentially random network, to be shaped into a functionally adaptive system by use and practice, and by elimination of inappropriate connections (Sperry, 1974). Undeterred by the fact that in the eyes of his teachers the connectionism of Sherrington and Cajal had become an example of simplistic and outmoded naı¨vete´, Sperry single-handedly proceeded to demolish the “blank slate” hypothesis of the developing nervous system. His ingenious and deceivingly simple experiments led him to conclude that the developing nervous system possesses a high degree of internal self-organization, prior to and independent of any environmental influences. His most eloquent results showed that in replicating original embryogenesis, central nerve regeneration in adult cold-blooded vertebrates rebuilds a preordained pattern of connections that persists even when forced by experimental manipulations to subserve completely maladaptive forms of behavior. Like Cajal’s chemotropic hypothesis, Sperry’s chemoaffinity hypothesis maintains that, early in development, the populations of nerve cells acquire and retain individual chemical identification tags, by which they can be recognized and distinguished from one another, such that lasting functional synaptic connections are established only between neurons that are selectively matched by inherent chemical affinities (Sperry, 1951, 1974; see Hunt and Cowan, 1990; Meyer, 1998). Although we now know that the formation of neuronal circuits may be more variable and functiondependent than Sperry was prepared to admit (Cline, 2003), the existence of a high degree of prenatal

organization of neuronal connections in the mammalian brain is best illustrated by the prenatal organization of the visual cortex (Hubel and Wiesel, 2005). In 1981, Sperry was awarded half the Nobel Prize for his discoveries concerning the functional specialization of the cerebral hemispheres, and Hubel and Wiesel received the other half for their discoveries concerning information processing in the visual system. The two different motivations fail to expose a strong conceptual link between the work of Hubel and Wiesel and that of Sperry (Berlucchi, 2006). In keeping with Sperry’s ideas, Hubel and Wiesel (2005) found that the complex wiring underlying the receptive field organization of visual cortical neurons is present in immature cats and monkeys before any exercise of visual function, and therefore must be innately determined. However, the innately determined functioning of the visual system is disrupted by lack, reduction, or distortion of normal visual experience during critical postnatal periods. Similar limitations or manipulations of visual experience occurring after the critical periods have little or no damaging effects on visual behavior, attesting the essential participation of early visual experience in the maintenance of the selective connections laid down by developmental factors alone. Moreover, Hubel and Wiesel provided definitive evidence that the damaging absence of early visual experience can operate, as expected, because of disuse, but also, and even more effectively, because of a competition between deprived and non-deprived portions of the visual system (Hubel and Wiesel, 2005). Their discovery of the respective roles of development and experience in the organization of the visual cortex lay to rest the old philosophical nature-versus-nurture controversy, forcing extremely strict nativists and empiricists alike to concede that neither the genes plus development alone, nor experience alone, can give rise to and maintain functioning neural structures.

Sperry and the corpus callosum Sperry’s second great contribution to neurophysiology and clinical neurology was the discovery of the functions of the corpus callosum. One of the cornerstones of Lashley’s anti-connectionist stance had been his inability to find any demonstrable function for the corpus callosum, which he was inclined to regard as a mere “skeletal structure.” Lashley (1951) was impressed by findings suggesting that surgical callosal sections did not appear to cause clear-cut behavioral signs of interhemispheric disconnection in experimental animals, as well as in human patients submitted to callosotomy for controlling drug-refractory epileptic seizures. Thanks to better planned tests, Sperry’s

THE CONTRIBUTIONS OF NEUROPHYSIOLOGY TO CLINICAL NEUROLOGY (1961) split brain studies in cats and monkeys showed instead that the corpus callosum, far from being a mere mechanical link between the two hemispheres, is the essential route for the exchange of sensory, motor, and higher-order information between the two hemispheres. When new callosotomized epileptic patients became available for experimental studies, Sperry et al., (1969) found that sensory inputs restricted to and perceived by a single hemisphere became inaccessible to the conscious experience of the other hemisphere. From a neurophysiological standpoint, this was compelling proof that information acting on the mind is transmitted in the brain primarily, if not exclusively, via orthodox neuronal connections. This is true also of high frequency pathological discharges in epilepsy, whereby the corpus callosum is a major avenue for the interhemispheric spread of seizures (Moruzzi, 1939; Berlucchi, 1990). Electrical fields propagating through the brain as a volume conductor or chemical volume transmission may play some part in normal or pathological information processing, but such mechanisms are clearly insufficient by themselves to sustain interhemispheric communication in the absence of direct fiber connections between the two sides. The real existence of disconnection syndromes not only between the hemispheres, but also within a hemisphere, was also supported, in confirmation and rehabilitation of the so-called diagram-makers, by Geschwind (1965a, b; see Absher and Benson, 1993).

Hemispheric specialization as opposed to cerebral dominance Another bonus from the research on the effects of corpus callosum section in humans was the discovery of parallel and largely independent conscious processes in the two hemispheres, with language mainly or exclusively on the left and non-verbal abilities mainly on the right (Sperry, 1982). However, the initial claim that there are two separate conscious minds and free wills under the cranial vault of a split-brain patient was undoubtedly an exaggeration. Yet split-brain research rekindled the interest of clinical neurologists and neuropsychologists in the different cognitive abilities of the two hemispheres, previously based on the effects of unilateral lesions. The research of Henry He´caen and Oliver Zangwill on patients with unilateral brain lesions in the late 1940s and early 1950s had ushered in the modern era of investigation of hemispheric cerebral dominance (see Benton, 1991). As a partial consequence of split-brain research, the 1960s saw an explosive increase of studies on differential deficits following right and left hemispheric lesions. Congruent evidence from unilateral lesions

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and split-brain patients led to a definitive rejection of the classical overall left cerebral dominance in favor of a complementary functional specialization of the two hemispheres. The unique specialization of the left hemisphere for all language functions was confirmed not only in right-handers but also in most left-handers, but the right hemisphere was in turn found to be predominant in various cognitive tasks that cannot be aided by verbal mediation, like the exploration and cognition of space, the discrimination and recognition of unfamiliar and familiar faces, and the perception and memory of colors, and complex visual shapes. Lesions of the right hemisphere were attributed a special role in the unilateral hemineglect syndrome, as well as in emotional and affective disorders such as anosognosia, e.g., the denial of illness, and the flattening of affect (Geschwind and Galaburda, 1987). As a match to hemispheric asymmetries of functions in brain-injured patients, a multitude of tests with different sensory inputs channeled into single hemispheres of normal observers provided complementary evidence on various aspects of interhemispheric transfer and cognitive differences based on simple or choice reaction times (Milner, 1971). The time-honored methodology of mental chronometry was also applied to the analysis of attentional modulation of cognitive processes, allowing important distinctions between automatic and voluntary orienting mechanisms, as well as between the allocation of attention to spatial locations and that to objects (Posner, 2005). In turn, results in normal observers prompted similar studies in brain damaged patients, and in clear opposition to behavioristic tendencies, it became again acceptable for neurophysiology and clinical neurology to study the brain correlates of consciousness and mental processes in general.

Plausibility of a neuroscience of consciousness and memory For much of its history, neurophysiology has shied away from difficult psychological problems, such as the neural bases of memory and consciousness. A prudent separation between neurophysiology and all psychological sciences was constantly advocated in the past by famous neurophysiologists, including Pavlov and Adrian. Pavlov managed to avoid psychological terms in describing his conditioned reflexes, because he thought that the physiologist is lost when he uses the psychologist’s lexicon. For his part, Adrian always maintained that, although sensory signals could be traced by his techniques in the intact brain, their effect on the mind was scarcely one for the physiologist to settle (Adrian, 1947a).

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On the psychology side, radical behaviorists have traditionally prided themselves on an intentional policy of eschewing any attempt to correlate the pattern of behavioral effects under examination with causative changes in cerebral organization (Skinner, 1938). Such an attitude is shared by present-day ultracognitive neuropsychologists, who declare themselves to be interested in how the mind works but not in how the brain works (Coltheart, 2002). A few years ago the term consciousness was conspicuously absent in the analytical index of the first edition of a popular neuroscience textbook (Kandel and Schwartz, 1981), yet the same term appears 32 times in the analytical index of the 4th edition of that same handbook (Kandel et al., 2000). Fresh views emerging in the years separating the two editions must have turned cognition into a proper subject matter for neurophysiology and the neurosciences in general, including clinical neurology. Indeed the neurological problem of consciousness can now be tackled with the enormous technological achievements of the last decades. The changing patterns of brain activities and states in awake, mentally active humans can be imaged in a noninvasive way with a variety of methods, based on the recording of spontaneous or evoked electrical activities, as well as on the monitoring of changes in local blood flow related to metabolic and electrical activities of neurons and glia (Frackowiak, 1998; Raichle and Mintun, 2006). However, even the old method of searching for associations between brain lesions and cognitive deficits is still viable, since a new life has accrued to it by the possibility of an in vivo localization of brain lesions linkable with cognitive deficits. As examples, a few lines of investigations can be singled out as especially effective in providing some glimpses of the neural bases of consciousness and memory. As regards the neurology of memory, the field was revolutionized by the work of Brenda Milner on the famous patient H.M., who had been submitted to a bilateral medial temporal removal for epilepsy control. The resulting extremely severe anterograde amnesia was associated with normal short-term memory and fair-to-good long-term memory for preoperatory facts and events. The demonstration that this patient could learn at a nomal rate and retain skills of which he was totally unaware made a definitive case for a fractionation of memory into components, which had been postulated mainly on theoretical grounds but never revealed with such compelling evidence (Milner, 1962; Milner et al., 1968). The subdivision of long-term memory into the declarative and non-declarative categories, in their turn subdivided into different subcategories, has been given a solid neurological basis by the evidence that forms of memory distinguishable at the cognitive level are also associated with distinct neural

substrates at cortical and subcortical sites (Milner et al., 1998; Squire, 2004). Further, that different knowledge categories are represented in different regions of the cortex has been made clear by the existence of strikingly selective agnostic disorders that affect information processing of some categories of objects or living beings but not of other categories (Warrington and Shallice, 1984; Damasio, 1990). Finally, possible approaches to the neurology of consciousness have been furnished by the discovery of dissociations between conscious and unconscious forms of vision, as occur in blindsight and other special conditions in both brain-damaged patients and normal observers, and by the proposed distinction between an occipito-temporal brain system for conscious visual perception and an occipito-parietal brain system for visually-guided action, unaccompanied by awareness (Goodale and Milner, 2004). The term blindsight was originally coined to denote appropriate motor or verbal reactions of patients with primary visual cortex lesions to visual inputs from the supposedly blind contralesional part of their visual field (Stoerig and Cowey, 1997; Weiskrantz, 2004). Such appropriate reactions associated with the patients’ self-proclaimed unawareness of those inputs conflict with responses to visual inputs from the normal field, accompanied by full conscious awareness of the stimuli. This dramatic dissociation between those forms of visually guided behavior which are accompanied by consciousness and those which are not can be found in other pathological conditions as well as in normal observers in special testing conditions (Marzi et al., 2004). The blindsight phenomenon has therefore offered the opportunity to study the brain during conscious and unconscious information processing, where conscious and unconscious can be defined operatively (Stoerig and Cowey, 1997; Weiskrantz, 2004).

IONS, RECEPTORS, CHANNELS, AND SYNAPSES: DISCOVERIES IN NEUROPHYSIOLOGY AND APPLICATIONS IN CLINICAL NEUROLOGY If the year 1953 marked the triumphal birth of molecular biology with the discovery of DNA, 1952 was a similarly successful, if less clamorous, year for neurophysiology, with its spectacular advances in the understanding of neuronal excitability and synaptic transmission at a subcellular level.

Ionic bases of excitability and chemical nature of central synaptic transmission A series of papers by Hodgkin, Huxley, and Katz published in 1952 (Hodgkin and Huxley, 1952a, b, c, d; Hodgkin et al., 1952) presented a masterly quantitative

THE CONTRIBUTIONS OF NEUROPHYSIOLOGY TO CLINICAL NEUROLOGY description of the selective changes in the permeability of the membrane of the squid giant axon, which account for the generation and propagation of the action potential. The resulting “ionic hypothesis” of the action potential argued indirectly, though very convincingly, for the existence of separate pores or transporters. These would respond to decreases in the resting membrane potential by allowing sodium and potassium to flow across the membrane with different kinetics along their respective electrochemical gradients. Another epochal paper published in the same year announced the conversion of Eccles, perhaps the most distinguished pupil of Sherrington, to the acceptance of the chemical nature of the synaptic transmission between central neurons (Brock et al., 1952). For years Eccles had headed the so-called sparks faction, supporting the notion that impulses are transmitted between neurons by electrical induction, in the battle against the so-called soups faction, led by Sir Henry Dale, who instead believed in chemical synaptic transmission (Valenstein, 2005). In their 1952 paper, Eccles and coworkers reported that intracellular recordings from the cat spinal cord had falsified Eccles’ own hypothesis of an electrical synaptic inhibition of motoneurons, and therefore that the inhibitory synaptic action had to be mediated by a specific inhibitory transmitter released from the terminals of the inhibitory terminals.* Since the experimental evidence had left the chemical transmitter hypothesis as the only likely explanation for inhibition, it seemed reasonable to attribute synaptic excitation to a chemical transmitter as well. Subsequent experiments in Eccles’ own laboratory and in other laboratories established that synapses between central neurons did indeed work according to the general principles of chemical transmission previously discovered by Loewi and Dale in the automatic nervous system and the neuromuscular junction (Katz, 1966; Eccles, 1974). Put simply, presynaptic active fibers release a transmitter which binds to receptors on the postsynaptic membrane, and such binding changes the electrical state of the postsynaptic cell. In the same year, Fatt and Katz (1952) described the phenomenon of quantal release of acetylcholine at the neuromuscu*

[Note: The use of the verb “to falsify” in the paper by Brock et al., (1952) reflects the influence exerted on Eccles by the philosopher Karl Popper, who had befriended Eccles in the 1930s (Eccles, 1974). Popper had convinced Eccles that the best scientists must always endeavor to disprove (falsify) their own favorite scientific hypotheses by means of experiments. The long-standing association between the two culminated in their joint publication of the controversial book The Self and Its Brain (Popper and Eccles, 1977).]

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lar junction, which eventually led to another general principle of synaptic transmission, namely the vesicular release of synaptic transmitters as an electrically controlled form of neurosecretion, invariably requiring the entrance of calcium ions into the presynaptic terminal (Katz, 1966).

Voltage- and ligand-gated channels The ionic hypothesis of the action potential and the generality of chemical synaptic transmission in the peripheral and central nervous system started a massive search for the identification of molecules acting as ionic channels, receptors, and transmitters up to this day (Numa, 1987-88; Hille et al., 1999). Voltage-gated ionic channels were identified as integral proteins whose molecular configuration is sensitive to changes in the electrical field across the membrane, so as to allow appropriate opening and closing of channels. In contrast with voltage-gated channels, ligand-gated channels are also integral membrane proteins, but open in response to the binding of a chemical messenger (usually a synaptic transmitter) to a specific site of their molecule. The prototypic ligand-gated ion channel is the channel linked to a nicotinic receptor in the muscle plate, which opens upon the binding of acetylcholine to the molecular receptor site, allowing sodium and potassium to flow simultaneously through it along their electrochemical gradients (Colquhoun and Sakman, 1998). Families of voltage-gated and ligandgated ionic channels selective not only for sodium and potassium, but also for calcium, chloride, and for other small ions have now been identified. Many developments were generated by the discovery of glutamate as a central neurotransmitter, as well as by the identification of a third general type of ionic channel sensitive both to the electrical potential across the membrane and to the binding of glutamate to the receptor associated with the channel. The so-called NMDA receptor (Dingledine, 1986) opens when both conditions are present, but not when only one or the other of them is present alone (Collingridge et al., 1988). Before Eccles and the neurophysiologists accepted the concept of central chemical synaptic transmission, the list of ascertained or suspected synaptic transmitters was limited to those identified in the peripheral nervous system, i.e., acetylcholine and the catecholamines adrenaline and noradrenaline. Subsequently several molecules have gained recognition as synaptic transmitters in the central nervous system, for each of which there exist specific postsynaptic receptors linked to ionic channels. Ascertained central synaptic transmitters include acetylcholine, the aminoacid group (glutamate, glycine, and gamma-aminobutyric acid or

180 G. BERLUCCHI GABA), the amine group (adrenaline, noradrenaline, voltage-gated calcium channels in presynaptic termdopamine, serotonin, histamine), and ATP. There are inals and cerebellar neurons are in turn held responsiin addition many neuroactive peptides whose status ble for familial hemiplegic migraine and different as synaptic transmitters is as yet incompletely demonforms of episodic and spinocerebellar ataxia. Other strated. Glutamate, the most common excitatory forms of epilepsy and benign familial neonatal contransmitter in the brain, acts on various types of vulsions have been associated with mutations and receptors. malfunctioning of ligand-gated channels linked to glycine, GABA, and nicotinic cholinergic receptors Pharmacological revolutions in neurology (Kullmann, 2002).

and psychiatry The identification of molecules acting as ionic channels, receptors, and transmitters, and the clarification of their physiological roles in the working of the nervous system have been of enormous importance for clinical neurology. A number of neurological or psychiatric disorders can now be ascribed to damage, malfunctioning, or absence of a specific class of molecules in one or the other of the three categories. Typical examples include myasthenia gravis, due to loss of acetylcholine receptors of the muscle plate (Fambrough et al., 1973), and Parkinson’s disease, due to loss of the dopamine transmitter in the nigro-striatal pathway (Carlsson, 2000; Hornykiewicz, 2002). The serendipitous discovery in the magic year, 1952, of the calming effect of chlorpromazine on agitated schizophrenics (Delay et al., 1952) has revolutionized neuropsychiatry by suggesting that the major psychoses may be caused by abnormalities in one or more transmitter–receptor aminergic brainstem systems projecting to diencephalon and cortex. Transmitter– receptor malfunctioning in the cholinergic system may be involved in Alzheimer’s dementia. Knowledge of the molecular physiopathological bases of some of the above conditions has led to at least partially successful therapeutic interventions, such as the administration of l-dopa to Parkinsonian patients (Carlsson, 2000; Hornykiewicz, 2002) and the use of psychotropic drugs acting on the brainstem aminergic systems in the major psychoses. Grafts of embryonic dopaminergic neurons into the striatum of Parkinsonian patients have also been tried, so far with mixed results (Bjo¨rklund et al., 2003; Olanow, 2004). More recently, the concept of neuronal channelopathies (Kullmann, 2002) has been introduced to refer to neural dysfunctions amenable to inherited or acquired mutations of both voltage-gated and ligand-gated ionic channels, with consequent alterations of channel function. Neuronal channelopathies associated with mutations affecting different voltage-gated sodium and potassium channels are now held responsible for various forms of infantile and adult epilepsy, previously regarded as idiopathic, as well as for episodic ataxia and neuromyotonia. Further, mutations of

Developments in the understanding of neural plasticity William James (1890) was the first to use the word plasticity with regard to the hypothetical changes in nervous activity that underlie the formation of habits, and the psychiatrist Tanzi (1893) was the first to postulate that plastic neural changes involved in learning and memory are likely to occur as physical modifications of the interneuronal articulations subsequently called synapses by Sherrington. Many decades later, still from a theoretical point of view, Hebb’s (1949) book The Organization of Behavior made a strong impact on neurological thinking by suggesting that learning and memory could be based on changes in effectiveness of transmission at given synapses in orthodox “Sherringtonian” circuits. Only in the second half of the 20th century did it become possible to test the synaptic hypothesis of memory experimentally, thanks to reductionistic approaches combining electrophysiological and molecular analyses of cellular and synaptic changes induced in the simple nervous systems of invertebrates. Eric Kandel, one of the pioneers of the field (Kandel and Spencer, 1968; Kandel, 2000) with his studies of synaptic plasticity mediating simple forms of learning and memory in the mollusk Aplysia californica, was awarded the Nobel Prize in Physiology or Medicine in 2000, along with Carlsson and Greengard for their discoveries concerning signal transduction in the nervous system. A relatively simple model of synaptic plasticity in the nervous system of mammals was provided by the discovery of the electrical phenomenon called long-term potentiation (LTP) and the role played in it by the NMDA receptors. LTP is a long-lasting change in the efficacy of synaptic transmission due to repeated stimulation of the same or different synaptic inputs to a neuron. It was discovered by Terje Lmo in 1968 (see Lmo, 2003) and subsequently analyzed in detail by Timothy Bliss and Lmo himself (Bliss and Lmo, 1973) at the Institute of Neurophysiology, Oslo University. LTP and the converse phenomenon of long-term depression (LTD) of synaptic transmission activity are thought to be basic forms of neural plasticity heavily implicated

THE CONTRIBUTIONS OF NEUROPHYSIOLOGY TO CLINICAL NEUROLOGY not only in normal learning and memory, but also in functional recovery following brain lesions, as well as in abnormal neural reactions leading to diseases. NMDA-mediated pathological changes in synaptic transmission may indeed occur in a variety of neurologic diseases, which include epilepsy and ischemic brain damage, and perhaps also neurodegenerative disorders such as Parkinson’s, Alzheimer’s, and Huntington’s diseases, and amyotrophic lateral sclerosis. Some less severe disorders of human cognition can be ascribed to LTP-related dysfunctions in brain regions known to be critical for memory. Employment of repetitive transcranial magnetic stimulation is now being proposed for restoring LTP to normal levels in amnesic patients, as well as for obtaining beneficial results from appropriately induced LTP effects in brain regions of patients with Parkinson’s disease, epilepsy, or chronic neuropathic pain. Putative LTP effects have also proven to be effective in some cases of depression, where repetitive transcranial magnetic stimulation has been used as a substitute for electroconvulsive therapy. There is also considerable interest in the development of pharmacological agents active at NMDA receptors as new therapeutic agents in various neurological disorders (Cooke and Bliss, 2006).

THE CONTRIBUTIONS OF CLASSICAL NEUROPHYSIOLOGY TO ELECTROENCEPHALOGRAPHY, ELECTROMYOGRAPHY, NEUROGRAPHY, AND OTHER INSTRUMENTAL APPROACHES IN CLINICAL NEUROPHYSIOLOGY The initial developments of clinical neurophysiology centered on the techniques of electroencephalography (EEG) and evoked potentials, electromyography (EMG), and nerve conduction studies.

Berger, Adrian, and the birth of electroencephalography The introduction of electroencephalography and electrocorticography into basic and clinical research is usually associated with the name of a psychiatrist, Hans Berger, from Jena. Berger carried out a long series of competent investigations on brain electrical potentials in animals and humans, but published his results only partially and in some cases several years after obtaining them. He must be credited for correctly describing and naming the fundamental electrical phenomena that can be recorded from the scalp in various physiological and pathological conditions, from the alpha waves at rest to their blockade upon sensory stimulation (Berger, 1929; Berger, 1932; Berger, 1933–1934; Berger, 1935). It

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is therefore indisputable that a position of primary importance in the history of electroencephalography must be assigned to a psychiatrist, yet there is no doubt that some neurophysiologists made timely and crucial contributions to the field of EEG. Indeed Berger was preceded by Richard Caton, lecturer and then Professor of Physiology in Liverpool, who briefly reported in 1875 that electrical activities can be generated at the brain surface of animals, both spontaneously and in response to sensory stimuli. In a sense he may thus be considered the discoverer of both EEG and sensory-evoked brain potentials (Caton, 1875; see Brazier, 1959). However, even more crucial contributions from neurophysiology to electroencephalography were due to Adrian. He very effectively defended the validity of Berger’s interpretation of the EEG waves against those who did not believe that the tiny electrical currents of the brain could cross the skull and the scalp. Adrian dispelled all doubts about the actual neuronal genesis of the EEG waves in experiments on animals (Adrian and Matthews, 1934), which along with the cerveau and encephale isolé EEG studies by Bremer (1936, 1974) is considered by some (e.g., Cobb, 1969) the marker of the real beginning of the electroencephalography and clinical neurophysiology era. In addition, Adrian showed that the alpha waves of man originate mainly in the occipital cortex, and duly recognized Berger’s fundamental work by naming those waves “Berger’s rhythm” (Adrian and Yamagiwa, 1935). Adrian thought that the EEG waves were due to a summation of the activities of individual neurons, and in collaboration with Moruzzi he showed that the EEG waves from the motor cortex are indeed associated with discharges of action potentials along single fibers of the pyramidal tract (Adrian and Moruzzi, 1939). The proposal that the EEG waves are envelopes of action potentials from groups of neighboring cortical neurons is now known to be at least partially incorrect, but Adrian’s concepts of synchronization and desynchronization are still in current use for relating the EEG waves to electrical events at the neuronal level.

The EEG as a means of clinical investigation As regards the clinical use of the EEG, there is evidence that Berger had already seen abnormal EEG discharges in petit-mal epilepsy by recording with intracortical needles in the early 1930s. Yet his overcautious attitude kept him from publishing the results, because he was afraid of a contamination of the EEG recordings by muscle artifacts from the myoclonic twitches accompanying the attack (Jung, 1974). The first EEG study of epilepsy and impaired consciousness was thus published by Gibbs, Davis, and Lennox

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in 1935. One of the authors, Hallowell Davis, was a neurophysiologist working under Forbes, a pupil of Sherrington, in the Department of Physiology of Harvard University headed by Cannon. Davis’ students had read Berger’s papers and, after some skepticism, Davis had confirmed the presence of the alpha waves on his own scalp with a home-made “brain wave” apparatus. The neurologists William Lennox and Fred and Erna Gibbs, working at the Boston City Hospital, asked Davis to organize a brain-wave recording session on one of their patients with petit-mal epilepsy. The spike-and-wave EEG pattern, which is now known to be an electrical hallmark of that condition, was discovered in a single recording session in the Physiology Department in December 1934, during an attack with loss of consciousness (Gibbs et al., 1935). With this historical event, clinical electroencephalography was born in a Physiology Department with the midwifery help of a neurophysiologist (Davis, 1974). Shortly thereafter the clinical usefulness of the EEG for the localization of brain tumors was established by Grey Walter (1936), a former member of the Physiology Department of Cambridge University, and, in brief, EEG became a lasting indispensable diagnostic tool for clinical neurology, as well as for research on normal brain mechanisms.

The use of evoked and event-related potentials in neurophysiology and clinical neurology Since the 1930s, neurophysiologists have investigated in depth the various discrete electrical EEG changes that can be produced by natural activation of the sense organs, or by electrical stimulation at various locations along the afferent pathways to the cortex. The method has proved useful for establishing correlations between structure and function, such as the general localization of a sensory modality in the cortex, the topographic representation of the peripheral sensory periphery on the specialized cortical areas, the relative importance of each portion of the peripheral field in the cortical representation, and the possible existence of multiple cortical representations of the same sensory modality. Among the pioneering neurophysiological contributions one can mention: (1) Kornmu¨ller’s (1933) finding that visual cortex mapped with evoked potentials coincides with the citoarchitectonically defined area striata; (2) Bishop and O’Leary’s (1938) study of the different waves produced in the visual cortex by electrical stimulation of the optic pathway; and (3) Adrian’s demonstration that areas of skin preferentially used in the exploration of the outside space, such as the snout in pigs, the nostrils in horses, and the hands in monkeys,

have a proportionally greater representation in the somatosensory cortex compared to less-used peripheral parts (Adrian, 1947a). Other early neurophysiological contributions using evoked potentials include Talbot and Marshall’s (1941) demonstration of the retinotopic organization of the visual cortex, Woolsey’s (1952) exhaustive mapping of sensory areas of the cerebral cortex from a comparative point of view, and the socalled strychnine neuronography used by Dusser de Barenne and McCulloch (1939) for tracing connections between cortical areas. After the first neurophysiological studies in normal humans (Brazier, 1984), the evoked potential method has found applications in clinical neurology, especially for the early diagnosis of neurological disorders and for their localization in the nervous system. As an example, the pattern-reversed stimulation of the visual system was developed and is still useful for the early diagnosis of optic neuritis in multiple sclerosis, based on an increased latency of the evoked response (Halliday et al., 1973). Abnormalities of auditory evoked potentials (Robinson and Rudge, 1977) and somatosensory potentials evoked in the spinal cord and somatosensory cortex on stimulation of the median and posterior tibial nerves (Small et al., 1978) are also useful to detect demyelinating lesions in the brainstem and cord. Abnormality of the latency and amplitude of the evoked response are also seen in a variety of conditions including compression and degeneration. Event-related potentials originally discovered in normal observers by physiologists or neurologists with physiological training include the contingent negative variation (CNV) or expectancy wave (Walter et al., 1964), the Bereitschaftspotential or readiness potential (Kornhuber and Deecke, 1965), the P300 wave (Sutton et al., 1965), the mismatch negativity (Na¨a¨ta¨nen et al., 1978), and other brain electrical phenomena. These have subsequently been variously employed in investigations in normal observers for basic research (Rugg and Coles, 1995), as well as in neurological patients for assessing disorders of attention, arousal, motor preparation, and other sensory and cognitive functions (Regan, 1989).

Neurophysiological and clinical uses of electromyography Like the EEG, electromyography (EMG) is currently an essential diagnostic tool in clinical neurology for investigating the severity, the pathophysiology, and the distribution of neuromuscular disorders (Sta˚lberg and Falck, 1997). Neurophysiologists rank prominently among those who established the theoretical and empirical bases for the development of the EMG technique. The possibility of recording muscle electrical

THE CONTRIBUTIONS OF NEUROPHYSIOLOGY TO CLINICAL NEUROLOGY potentials with surface electrodes positioned on the skin overlying the muscles was already known in the 19th century, but the groundwork for a full exploitation of the EMG in experimental and clinical tests was done in 1929 by Adrian and Bronk. They were able to record from single motor units by means of a concentric electrode that they had developed for the purpose and that is still of much use in present-day EMG tests. Based on the Sherringtonian concept of the motor unit, they could indirectly measure for the first time the discharge of single motoneurons as muscle unit potentials during a voluntary contraction of their own arm muscles. By this approach they established the two basic principles of muscle force regulation: as contractions become more powerful, the discharge frequency within a single unit rises, and so does the number of units coming into play (Adrian and Bronk, 1929). Neurophysiologists were also strongly involved in the first clinical applications of the EMG technique with single muscle unit recording. In 1938, Derek Denny-Brown, a former pupil of Sherrington who worked at the National Hospital in London (see above), reported the first EMG characteristics of fasciculation and fibrillation in skeletal muscles (Denny-Brown and Pennybacker, 1938), and in 1941 Buchthal and Clemmesen described characteristic EMG indexes of neuropathy and muscle atrophy in poliomyelitis. Fritz Buchthal, founder and director of the Institute of Neurophysiology in Copenhagen, contributed in many ways to the understanding of the physiological and pathological EMG bases by promoting important technical advances such as quantitative EMG (e.g., Buchthal and Pinelli, 1953; Buchthal et al., 1955). Another neurophysiologist who made pioneering contributions to clinical EMG was Eric Kugelberg, who described the EMG alterations in muscular dystrophy for the first time (Kugelberg, 1949). Kugelberg had started his scientific career at the Karolinska Institute in Stockholm in the neurophysiological laboratory of Ragnar Granit, who was awarded the Nobel Prize in Physiology or Medicine in 1967, along with Haldan Hartline and George Wald for their discoveries concerning the primary physiological and chemical processes in the eye. Kugelberg then went on to found one of the first clinical neurophysiology laboratories at the Karolinska Institute.

Combined use of EEG and EMG in polisomnography Polysomnography is the combined recording of EEG and other physiological parameters (such as ocular movements, EMG activities, blood pressure, respiration, and so forth) during sleep in humans. Recordings of the EEG during sleep in humans were first obtained by Berger (1929) followed by neurophysiologists

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including Blake and Gerard (1937) and Hallowell Davis, his wife Pauline and their collaborators (Davis et al., 1938). Nathaniel Kleitman, a professor of physiology at the University of Chicago, was responsible for starting systematic investigations on the phenomenology of sleep in humans. With Aserinsky (Aserinsky and Kleitman, 1953) and Dement (Dement and Kleitman, 1957a, b) he identified various stages of sleep and particularly the stage associated with dreaming and rapid eye movements. These findings in humans were linked with those of experiments in animals (Jouvet, 1967; Moruzzi, 1972; see also above, page 175), engendering one of the most lively developments of neurophysiology in the 20th century. The clinical applications of polysomnography resulted in the foundation of a specialty called sleep medicine, dealing not only with sleep disorders, but also with sleep as an activator of pathological expressions such as epilepsy and circulatory and respiratory dysfunctions (Dement, 2005; also see sleep chapter in this volume).

Neuron conduction studies Two physiologists from Berlin, Piper and Hoffmann, pioneered the method of electrical stimulation of peripheral nerves in man, in order to record direct and reflex motor responses with skin electrodes overlying the contracting muscles. By using this method, Piper (1907) made the first assessment of conduction speed in myelinated motor fibers. His assistant, Hoffmann (1910), who later taught physiology in Freiburg im Breisgau, was able to demonstrate (mostly on himself) two kinds of muscle responses in the calf to electrical stimulation of the tibial nerve in the posterior popliteal fossa: a fast one due to direct stimulation of motor fibers, and a delayed one due to stimulation of afferent fibers. The delayed response is now known as the H-reflex, a near electrical equivalent of the myotatic reflex. The technique inaugurated by Hoffmann is still widely used in clinical neurology for bypassing the receptors in tests of various reflex centers and pathways in normal and pathological conditions (see Pierrot-Deseilligny and Mazevet, 2000). A later major contribution of neurophysiology to clinical neurography was the classification of single fibers of peripheral sensory and motor nerves into categories with different conduction velocities and specific functions. This classification was made possible by the first employment of the cathode-ray oscillograph in nerve recording studies by the American physiologists Erlanger and Gasser (1937), who shared the 1944 Nobel Prize in Physiology or Medicine for their discoveries relating to the highly differentiated functions of single nerve fibers. Nerve conduction studies are currently employed in clinical neurology for the

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diagnosis of focal neuropathies and polyneuropathies, allowing the distinction between demyelinations, axonal degenerations, and conduction blocks. A relatively recent development in electrical studies on peripheral nerves is microneurography, a technique initiated in Uppsala by clinical neurophysiologists Hagbarth, Vallbo, and their coworkers, who had trained in neurophysiology at the Karolinska Institute in Stockholm with Granit. They were able to record from and stimulate single fibers in human peripheral nerves with percutaneously inserted needle electrodes, and to correlate their activities with perception and other functions (Hagbarth and Vallbo, 1968; Vallbo and Hagbarth, 1968; Vallbo, 1981). In clinical neurology, the microneurographic method has allowed and allows one to obtain evidence on spindle function and more generally on proprioceptive, tactile, nociceptive, and autonomic mechanisms in normal observers and in patients with spasticity or rigidity and other neurological disorders (Vallbo et al., 2003).

Newer instrumental technologies The new technologies presently applied in basic neuroscience and in clinical neurology include magnetoencephalography, positron emission tomography, magnetic resonance imaging, and transcranial magnetic stimulation. These techniques have evolved in fields different from classical neurophysiology, such as radiology, medical physics, and engineering, and highly specialized clinical neurophysiology, although in a few cases certain basic premises for their development were foreseen by traditional neurophysiologists. For example, the coupling between brain work and blood flow, which is the foundation of modern brain imaging with functional magnetic resonance, was already predicted in the afore mentioned studies of Mosso (1880) and Roy and Sherrington (1890) and later elaborated by Sokoloff and Kety (1960) and Lassen and Ingvar (1961). However, on the whole it seems fair to say that neurophysiological inquiry has benefited from the new instrumental techniques far more than neurophysiology has contributed to their development.

ACKNOWLEDGMENTS The preparation of this chapter has been aided by grants FIRB and PRIN from the Ministero dell’Universit a e della Ricerca of Italy. Thanks are due to Mr. Marco Veronese for preparing the figures and to Prof. Paolo Moruzzi for supplying Fig. 13.2.

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