Pioneers in CNS inhibition: 2. Charles Sherrington and John Eccles on inhibition in spinal and supraspinal structures.

This article reviews the contributions of the English neurophysiologist, Charles Scott Sherrington [1857-1952], and his Australian PhD trainee and collaborator, John Carew Eccles [1903-1997], to the concept of central inhibition in the spinal cord and brain. Both were awarded Nobel Prizes; Sherrington in 1932 for "discoveries regarding the function of neurons," and Eccles in 1963 for "discoveries concerning the ionic mechanisms involved in excitation and inhibition in central portions of the nerve cell membrane." Both spoke about central inhibition at their Nobel Prize Award Ceremonies. The subsequent publications of their talks were entitled "Inhibition as a coordinative factor" and "The ionic mechanism of postsynaptic inhibition", respectively. Sherrington's work on central inhibition spanned 41 years (1893-1934), and for Eccles 49 years (1928-1977). Sherrington first studied central inhibition by observing hind limb muscle responses to electrical (peripheral nerve) and mechanical (muscle) stimulation. He used muscle length and force measurements until the early 1900s and electromyography in the late 1920s. Eccles used these techniques while working with Sherrington, but later employed extracellular microelectrode recording in the spinal cord followed in 1951 by intracellular recording from spinal motoneurons. This considerably advanced our understanding of central inhibition. Sherrington's health was poor during his retirement years but he nonetheless made a small number of largely humanities contributions up to 1951, one year before his death at the age of 94. In contrast, Eccles retained his health and vigor until 3 years before his death and published prolifically on many subjects during his 22 years of official retirement. His last neuroscience article appeared in 1994 when he was 91. Despite poor health he continued thinking about his life-long interest, the mind-brain problem, and was attempting to complete his autobiography in the last years of his life.

Discharge characteristics of motor units during long-duration contractions.

The purpose of the study was to determine how long humans could sustain the discharge of single motor units during a voluntary contraction. The discharge of motor units in first dorsal interosseus of subjects (27.8 ± 8.1 years old) was recorded for as long as possible. The task was terminated when the isolated motor unit stopped discharging action potentials, despite the ability of the individual to sustain the abduction force. Twenty-three single motor units were recorded. Task duration was 21.4 ± 17.8 min. When analysed across discharge duration, mean discharge rate (10.6 ± 1.8 pulses s(-1)) and mean abduction force (5.5 ± 2.8% maximum) did not change significantly (discharge rate, P = 0.119; and abduction force, P = 0.235). In contrast, the coefficient of variation for interspike interval during the initial 30 s of the task was 22.2 ± 6.0% and increased to 31.9 ± 7.0% during the final 30 s (P < 0.001). All motor units were recruited again after 60 s of rest. Although subjects were able to sustain a relatively constant discharge rate, the cessation of discharge was preceded by a gradual increase in discharge variability. The findings also showed that the maximal duration of human motor unit discharge exceeds that previously reported for the discharge elicited in motor neurons by intracellular current injection in vitro.

Pioneers in CNS inhibition: 1. Ivan M. Sechenov, the first to clearly demonstrate inhibition arising in the brain.

This article reviews the contributions of Ivan Michailovich Sechenov [1829-1905] to the neurophysiological concept of central inhibition. He first studied this concept in the frog and on himself. Later his trainees extended the study of central inhibition to other mammalian species. Outside his own country, Sechenov is better known for his prescient contributions to physiological psychology. In Russia, however, he is also revered as "the father of Russian physiology," because of his contributions to neurophysiology and other aspects of physiology including blood gases and respiration, the physiology and biomechanics of movement, and general physiology concepts that appeared in his textbooks and later works he helped translate from largely German sources. After graduation from Moscow University Medical School in 1856 he spent 3½ years in Germany and Austria where he attended lectures and conducted research under the direction of several prominent physiologists and biochemists. In his subsequent academic career he held positions at universities in St. Petersburg (1860-1870; 1876-1888), Odessa (1871-1876) and Moscow (1890-1905). From 1860 onwards he was acclaimed as a physiologist in academic circles. He was also well known in Russian society for his public lectures on physiology and his views on physiological psychology. The latter resulted in him being branded "politically unreliable" by the tsarist bureaucracy from 1863 onwards. Sechenov's first (1862) study on central inhibition remains his most memorable. He delayed the withdrawal of a frog's foot from a weak acid solution by chemical or electrical stimulation of selected parts of the central nervous system. He also noted similar effects on his own hand during co-activation of other sensory inputs by tickling or teeth gnashing.

The beginning of intracellular recording in spinal neurons: facts, reflections, and speculations.

Intracellular (IC) recording of action potentials in neurons of the vertebrate central nervous system (CNS) was first reported by John Eccles and two colleagues, Walter Brock and John Coombs, in Dunedin, NZL in 1951/1952 and by Walter Woodbury and Harry Patton in Seattle, WA, USA in 1952. Both groups studied spinal cord neurons of the adult cat. In this review, we discuss the precedents to their notable achievement and reflect and speculate on some of the scientific and personal nuances of their work and its immediate and later impact. We then briefly discuss early achievements in IC recording in the study of CNS neurobiology in other laboratories around the world, and some of the methods that led to enhancement of CNS IC-recording techniques. Our modern understanding of CNS neurophysiology directly emanates from the pioneering endeavors of the five who wrote the seminal 1951/1952 articles.

Whither motoneurons?

In the preceding series of articles, the history of vertebrate motoneuron and motor unit neurobiological studies has been discussed. In this article, we select a few examples of recent advances in neuroscience and discuss their application or potential application to the study of motoneurons and the control of movement. We conclude, like Sherrington, that in order to understand normal, traumatized, and diseased human behavior, it is critical to continue to study motoneuron biology using all available and emerging tools. This article is part of a Special Issue entitled Historical Review.

Reflections on Jacques Paillard (1920-2006)--a pioneer in the field of motor cognition.

This article reviews the scientific contributions of Jacques Paillard (1920-2006), who strengthened substantially the role of physiological psychology in the field of movement neuroscience. His research began in 1947 under the direction of the French neurophysiologist, Alfred Fessard (1900-1982), with whom he then collaborated for 9 years while an undergraduate and then graduate student and junior faculty member in psychology at the University of Paris (the Sorbonne). Paillard moved to the University of Marseille in 1957 as a Professor of Psychophysiology. In parallel, he became a founding member and administrator of the Institute of Neurophysiology and Psychophysiology, which began in 1963 on the Marseille campus of the National Center of Scientific Research (CNRS). Paillard retired from his university and CNRS positions in 1991 but he continued seminal research until his demise. Paillard advanced understanding of higher brain influences on human spinal motor mechanisms and the functional role of proprioception as revealed in patients deprived of such sensibility. He remains best known, however, for his work on human motor cognition. He reasoned that brain "maps" of the external world are constructed by the body's own movements and the central effects of their resulting central and peripheral feedback. He proposed two levels of interactive brain processing for the planning and/or execution of a reaching movement: 1) a sensorimotor level, using body posture as a key reference; and 2) a "higher" cognitive level for accurate movement performance, using learned representations of the position and shape of the environmental components, including the body, itself.

Thomas Graham Brown (1882--1965), Anders Lundberg (1920-), and the neural control of stepping.

Thomas Graham Brown (1882--1965) undertook experiments on the neural control of stepping in the University of Liverpool laboratory of Charles Sherrington (1857--1952) in 1910--13 and his own laboratory in 1913--15 at the University of Manchester. His results revealed the intrinsic capability of the spinal cord in the guinea pig and cat to generate a stepping output pattern whose timing did not depend upon descending or sensory inputs. This idea was then revolutionary because the prevailing viewpoint was that the stepping rhythm was generated by spinal reflexes. Sadly, Graham Brown's GBR peers gave little credence to this seminal accomplishment, except perhaps Sherrington, who waxed but largely waned on the potential significance of the work. It remained for the Swedish neuroscientist, Anders Lundberg (1920-), to rescue Graham Brown's concepts from obscurity: in seminars presented in several countries between 1957 and 1980, and in widely read articles and reviews (1965--1981). Graham Brown had proposed mutually inhibitory connections between a pair of intrinsically active flexor and extensor "half-centers" on each side of the spinal cord, with the rhythmic output modulated by sensory proprioceptive input. Lundberg, Elzbieta Jankowska (1930-), and their colleagues provided seminal, compelling evidence for spinal half-center interneuronal circuitry implicated in the control of stepping and Lundberg and Ingemar Engberg (1935--2005) made behavioral EMG observations on unrestrained cats that supported a central generation of the rhythm. Subsequently, models of the spinal pattern generators for mammalian locomotion have become progressively more complex but they mostly still include a half-center component.

Does motoneuron adaptation contribute to muscle fatigue?

To help reduce the gap between the cellular physiology of motoneurons (MNs) as studied "bottom-up" in animal preparations and the "top-down" study of the firing patterns of human motor units (MUs), this article addresses the question of whether motoneuron adaptation contributes to muscle fatigue. Findings are reviewed on the intracellularly recorded electrophysiology of spinal MNs as studied in vivo and in vitro using animal preparations, and the extracellularly recorded discharge of MUs as studied in conscious humans. The latter "top-down" approach, combined with kinetic measurements, has provided most of what is currently known about the neurobiology of muscle fatigue, including its task and context dependencies. It is argued that although the question addressed is still open, it should now be possible to design new "bottom-up" research paradigms using animal preparations that take advantage of what has been learned with the use of relatively noninvasive quantitative procedures in conscious humans.

Reflections on integrative and comparative movement neuroscience.

Integrative movement neuroscience involves blending "inside-out" and "outside-in" approaches in the study of posture and movement. The former is characterized by determining the properties of single cells within the central nervous system (CNS) and then ascertaining how these properties influence the operation of CNS microcircuits, single reflexes, groups of reflexes, and generators of central pattern. This information is then used to theorize about CNS control of overt motor behavior. In contrast, the outside-in approach begins with analysis of the biomechanics of posture and movement and then uses this information to theorize how the mechanics are solved by the CNS and its pathways, circuitry, and even single cells. Studies conducted in the 1960s on CNS circuitry generating locomotor patterns in several invertebrate and vertebrate species, together with work on the treadmill locomotion of brain-stimulated decerebrate cats, led to a subsequent convergence of inside-out and outside-in understanding of the neural control of locomotion in invertebrates, nonmammalian vertebrates, and mammalian vertebrates, even including humans. This convergence of integrative and comparative approaches has been facilitated by modeling and simulation studies. These developments have important implications for doctoral and postdoctoral training programs in movement neuroscience. They can profit greatly by use of a multidisciplinary university-wide faculty who place a strong emphasis on integrative and comparative biology. Furthermore, the next generation of movement neuroscientists will require more familiarity with modeling and simulation than are being provided in most current training programs. To achieve the above, it will be advantageous if university culture and structure truly champion university-wide interdisciplinary research.

The academic lineage of Sir John Carew Eccles (1903-1997).

This report reviews the academic lineage of Sir John Eccles; who trained him, whom he then trained and with whom he collaborated, and the subsequent impact of his trainees and collaborators on neuroscience and other areas. In a post-training career at five institutions in four countries (Great Britain, Australia, New Zealand, back to Australia, USA) and during retirement in Switzerland, Eccles trained and collaborated with over 180 people (mostly neuroscientists) from 21 countries. Most of them have had stellar research and training records that span the cellular-behavioral-philosophical spectrum of neuroscience, with a focus from peripheral neuromuscular issues to the forebrain. Some have been equally distinguished in other areas of biomedical science. Eccles' academic contributions and lineage are a valuable colloquium topic in a neuroscience training program. His experimental work spanned much of the 20th C before the recent emphasis on the application of the techniques of molecular biology. He continually sought to integrate information from the cellular to the systems and behavioral levels of analysis and synthesis. He also devoted a substantial amount of his intellectual effort to the mind-brain and other philosophical issues. Eccles' prodigious working hours and enthusiasm for his projects were a role model for such trainees. Hard-working trainees often ask how can they retain their all-round interests, and indeed their humanity and citizenry, as they focus more and more on their necessarily narrowly focused neuroscience research. Again, Eccles' writings and overall behavior show that it can indeed be done, but only by the application of extraordinary effort and dedication.

Integration of posture and movement: contributions of Sherrington, Hess, and Bernstein.

Neural mechanisms that integrate posture with movement are widespread throughout the central nervous system (CNS), and they are recruited in patterns that are both task- and context-dependent. Scientists from several countries who were born in the 19th century provided essential groundwork for these modern-day concepts. Here, the focus is on three of this group with each selected for a somewhat different reason. Charles Sherrington (1857-1952) had innumerable contributions that were certainly needed in the subsequent study of posture and movement: inhibition as an active coordinative mechanism, the functional anatomy of spinal cord-muscle connectivity, and helping set the stage for modern work on the sensorimotor cortex and the corticospinal tract. Sadly, however, by not championing the work of his trainee and collaborator, Thomas Graham Brown (1882-1965), he delayed progress on two key motor control mechanisms: central programming and pattern generation. Walter Hess (1881-1973), a self-taught experimentalist, is now best known for his work on CNS coordination of autonomic (visceral) and emotional behavior. His contributions to posture and movement, however, were also far-reaching: the coordination of eye movements and integration of goal-directed and "framework" (anticipatory set) motor behavior. Nikolai Bernstein (1896-1966), the quintessence of an interdisciplinary, self-taught movement neuroscientist, made far-reaching contributions that were barely recognized by Western workers prior to the 1960s. Today, he is widely praised for showing that the CNS's hierarchy of control mechanisms for posture and movement is organized hand-in-hand with distributed and parallel processing, with all three subject to evolutionary pressures. He also made important observations, like those of several previous workers, on the goal focus of voluntary movements. The contributions of Sherrington, Hess, and Bernstein are enduring. They prompt thought on the philosophical axioms that appear to have driven their research, and the continual need for emphasis on interdisciplinary, comparative, and transnational approaches to advance movement neuroscience.

Slow-tonic muscle fibers and their potential innervation in the turtle, Pseudemys (Trachemys) scripta elegans.

A description is provided of the ratio of slow-tonic vs. slow- and fast-twitch fibers for five muscles in the adult turtle, Pseudemys (Trachemys) scripta elegans. The cross-sectional area of each fiber type and an estimation of the relative (weighted) cross-sectional area occupied by the different fiber types are also provided. Two hindlimb muscles (flexor digitorum longus, FDL; external gastrocnemius, EG) were selected on the basis of their suitability for future motor-unit studies. Three neck muscles (the fourth head of testo-cervicis, TeC4; the fourth head of retrahens capitus collique, RCCQ4; transversalis cervicis, TrC) were chosen for their progressively decreasing oxidative capacity. Serial sections were stained for myosin adenosine triphosphatase (ATPase), NADH-diaphorase, and alpha-glycerophosphate dehydrogenase (alpha-GPDH). Conventional fiber-type classification was then performed using indirect markers for contraction speed and oxidative (aerobic) vs. glycolytic (anaerobic) metabolism: i.e., slow oxidative (SO, including slow-twitch and possibly slow-tonic fibers), fast-twitch, oxidative-glycolytic (FOG), and fast-twitch glycolytic (Fg) fibers. Slow-tonic fibers in the SO class were then revealed by directing the monoclonal antibody, ALD-58 (raised against the slow-tonic fiber myosin heavy chain of chicken anterior latissimus dorsi), to additional muscle cross sections. All five of the tested muscles contained the four fiber types, with the ATPase-stained fibers including both slow-tonic and slow-twitch fibers. The extreme distributions of SO fibers were in the predominately glycolytic TrC vs. the predominately oxidative TeC4 muscle (TrC-SO, 9%; FOG, 20%; Fg, 71% vs. TeC4-SO, 58%: FOG, 16%; Fg, 25%). Across the five muscles, the relative prevalence of slow-tonic fibers (4-47%) paralleled that of the SO fibers (9-58%). TeC4 had the highest prevalence of slow-tonic fibers (47%). The test muscles exhibited varying degrees of regional concentration of each fiber type, with the distribution of slow-tonic fibers paralleling that of the SO fibers. In the five test muscles, fiber cross-sectional area was usually ranked Fg > FOG > SO, and slow-twitch always > slow-tonic. In terms of weighted cross-sectional area, which provides a coarse-grain measure of each fiber type's potential contribution to whole muscle force, all five muscles exhibited a higher Fg and lower SO contribution to cross-sectional area than suggested by their corresponding fiber-type prevalence. This was also the case for the slow-twitch vs. slow-tonic fibers. We conclude that slow-tonic fibers are widespread in turtle muscle. The weighted cross-sectional area evidence suggested, however, that their contribution to force generation is minor except in highly oxidative muscles, with a special functional role, like TeC4. There is discussion of: 1) the relationship between the present results and previous work on homologous neck and hindlimb muscles in other nonmammalian species, and 2) the potential motoneuronal innervation of slow-tonic fibers in turtle hindlimb muscles.

Fatigue of rat hindlimb motor units: biochemical-physiological associations.

Associations between fatigability and biochemical properties within motor unit (MU) types were explored in two hindlimb muscles of the adult rat. Type FF MUs in extensor digitorum longus and type S units in soleus were subjected either to a moderate (type FF) or severe (type S) 6-min, fatigue-inducing stimulation protocol. For both MU types, the range of values for their fatigability was considerably greater than the ranges in the activity levels of three enzymes in the units' constituent muscle fibers (MFs). These enzymes represented major energy-yielding pathways: adenylokinase, for high-energy phosphate metabolism; lactate dehydrogenase, for anaerobic glycolysis; and malate dehydrogenase, for oxidative metabolism. There were also relatively weak associations between the fatigue indices of the MUs and the activity levels of the three enzymes. Thus, this work supports previous conclusions that the force decline exhibited by MUs during electrically evoked contractions depends on both MF biochemistry and other intracellular mechanisms. Electromyographic measurements suggested that these other mechanisms are distal to the intramuscular branches of the axon in type FF units, and distal to excitation-contraction coupling in type S units.

Associations between the morphology and physiology of ventral-horn neurons in the adult turtle.

This study compared some morphologic and physiological properties of adult turtle spinal motoneurons (MNs) vs. interneurons (INs). Reconstructions were made of 20 biocytin-stained cells, which had been previously studied physiologically in 2-mm-thick slices of lumbosacral spinal cord. The intracellularly measured physiological properties included resting potential, input resistance (R(N)), threshold (rheobase, I(Rh)), and slope of the stimulus current (I) -spike frequency (f) relation. The seven morphologic properties that were quantified for each cell included three indices of somal size (diameter, area, volume), and four of dendritic size: the number of first- and last-order branches, rostrocaudal extent, and sigma individual lengths. Significant differences were shown between all seven morphologic parameters for MNs vs. INs. Despite the small sample size, significant differences were also shown for five of seven parameters for high-threshold vs. low-threshold MNs, and three of seven for low-threshold MNs vs. INs. These latter three parameters were the number of terminal dendritic branches, their rostrocaudal extent, and the sigma dendritic lengths. Linear associations for the MN + IN and the MN samples were stronger between the four dendritic parameters than between soma-dendritic ones. Exponential associations between morphologic and physiological properties were mostly significant (28 of 30), and their strength was in the order I(Rh) < R(N) < f/I slope for the MN +IN sample and I(Rh) < R(N) = f/I slope for the MN sample. There is discussion of the relevance of the above findings to the provisional classification of turtle ventral-horn neurons on the basis of electrophysiology alone.

Reflections on spinal reflexes.

Over the past four decades, the understanding of proprioceptive spinal reflexes has advanced far more rapidly than generally considered. This problem could be largely obviated in undergraduate and graduate training programs if the topic of reflexes was introduced subsequent to the concept and mechanisms of pattern generation within the central nervous system. The key advantage would then be that the neuroscience community as a whole would gain appreciation of the fact that proprioceptive reflexes are not hard-wired but rather are context- and phase-dependent, with the central nervous system selecting input-output pathways appropriate for the task at hand.

Effects of excitatory modulation on intrinsic properties of turtle motoneurons.

The purpose of this study was to quantify the effects of excitatory modulation on the intrinsic properties of motoneurons (MNs) in slices of spinal cord taken from the adult turtle. Responses were noted following application of an excitatory modulator: serotonin (5-HT), muscarine, trans-1-amino-1,3-cyclopentane dicarboxylic acid (tACPD), or all three combined. A sample of 44 MNs was divided into 2 groups, on the basis of whether MNs did (28/44) or did not (16/44) demonstrate a nifedipine-sensitive acceleration of discharge during a 2-s, intracellularly injected stimulus pulse. Such acceleration indicates the development of a plateau potential (PP). Excitatory modulation lowered the MNs' resting potential, increased input resistance, decreased rheobase, reduced several afterhyperpolarization values, and shifted the conventional, one-phase stimulus current-spike frequency (I-f) relation to the left. For both MN groups, the relative efficacy of excitatory modulation on both non-PP and PP MNs was generally in the following order: combined application > 5-HT approximately muscarine > tACPD. In many instances, the effects of modulation differed significantly for non-PP versus PP MNs, the most pronounced being in their I-f relation. To describe this difference, it was necessary to measure a two-phase relation. In PP MNs, excitatory modulation considerably increased the slope of the first (initial) phase and flattened the second (later) phase of this relation. The latter result bore similarities to that obtained in a previous study, which addressed MN firing behavior during fictive locomotion of the high-decerebrate cat.

Motoneurons: A preferred firing range across vertebrate species?

The term "preferred firing range" describes a pattern of human motor unit (MU) unitary discharge during a voluntary contraction in which the profile of the spike-frequency of the MU's compound action potential is dissociated from the profile of the presumed depolarizing pressure exerted on the unit's spinal motoneuron (MN). Such a dissociation has recently been attributed by inference to the presence of a plateau potential (PP) in the active MN. This inference is supported by the qualitative similarities between the firing pattern of human MUs during selected types of relatively brief muscle contraction and that of intracellularly stimulated, PP-generating cat MNs in a decerebrate preparation, and turtle MNs in an in vitro slice of spinal cord. There are also similarities between the stimulus-response behavior of intracellularly stimulated turtle MNs and human MUs during the elaboration of a slowly rising voluntary contraction. This review emphasizes that there are a variety of open issues concerning the PP. Nonetheless, a rapidly growing body of comparative vertebrate evidence supports the idea that the PP and other forms of non-linear MN behavior play a major role in the regulation of muscle force, from the lamprey to the human.