ゼツカ シンケイ ト サンサ シンケイ ウンドウ ニューロン 二 オケル シンケイ カソセイ 二 ツイテ ノ ケンキュウ

this is the author’s version of a work that was accepted for publication in Brain Research. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Brain Research, VOL1541, (2013-12-06) DOI : 10.1016/j.brainres.2013.10.01

THE PSYCHOMOTOR THEORY OF HUMAN MIND

This study presents a new theory to explain the neural origins of human mind. This is the psychomotor theory. The author briefly analyzed the historical development of the mind-brain theories. The close relations between psychological and motor systems were subjected to a rather detailed analysis, using psychiatric and neurological examples. The feedback circuits between mind, brain, and body were shown to occur within the mind-brain-body triad, in normal states, and psycho-neural diseases. It was stated that psychiatric signs and symptoms are coupled with motor disturbances; neurological diseases are coupled with psychological disturbances; changes in cortico-spinal motor-system activity may influence mind-brain-body triad, and vice versa. Accordingly, a psychomotor theory was created to explain the psychomotor coupling in health and disease, stating that, not themind-brain duality or unity, but themind-brain-body triad as a functional unit may be essential in health and disease, because mind does not end in the brain, but further controls movements, in a reciprocal manner; mental and motor events share the same neural substrate, cortical, and spinalmotoneurons;mental events emerging from the motoneuronal system expressed by the human language may be closely coupled with the unity of the mind-brain-body triad. So, the psychomotor theory rejects the mind-brain duality and instead advances the unity of the psychomotor system, which will have important consequences in understanding and improving the human mind, brain, and body in health and disease

Effects of Selective Deafferentation on the Discharge Characteristics of Medial Rectus Motoneurons

Medial rectus motoneurons receive two main pontine inputs: abducens internuclear neurons, whose axons course through the medial longitudinal fasciculus (MLF), and neurons in the lateral vestibular nucleus, whose axons project through the ascending tract of Deiters (ATD). Abducens internuclear neurons are responsible for conjugate gaze in the horizontal plane, whereas ATD neurons provide medial rectus motoneurons with a vestibular input comprising mainly head velocity. To reveal the relative contribution of each input to the oculomotor physiology, single-unit recordings from medial rectus motoneurons were obtained in the control situation and after selective deafferentation from cats with unilateral transection of either the MLF or the ATD. Both MLF and ATD transection produced similar short-term alterations in medial rectus motoneuron firing pattern, which were more drastic in MLF of animals. However, long-term recordings revealed important differences between the two types of lesion. Thus, while the effects of the MLF section were permanent, 2 months after ATD lesioning all motoneuronal firing parameters were similar to the control. These findings indicated a more relevant role of the MLF pathway in driving motoneuronal firing and evidenced compensatory mechanisms following the ATD lesion. Confocal immunocytochemistry revealed that MLF transection produced also a higher loss of synaptic boutons, mainly at the dendritic level. Moreover, 2 months after ATD transection, we observed an increase in synaptic coverage around motoneuron cell bodies compared with short-term data, which is indicative of a synaptogenic compensatory mechanism of the abducens internuclear pathway that could lead to the observed firing and morphological recovery. SIGNIFICANCE STATEMENT Eye movements rely on multiple neuronal circuits for appropriate performance. The abducens internuclear pathway through the medial longitudinal fascicle (MLF) and the vestibular neurons through the ascending tract of Deiters (ATD) are a dual system that supports the firing of medial rectus motoneurons. We report the effect of sectioning the MLF or the ATD pathway on the firing of medial rectus motoneurons, as well as the plastic mechanisms by which one input compensates for the lack of the other. This work shows that while the effects of MLF transection are permanent, the ATD section produces transitory effects. A mechanism based on axonal sprouting and occupancy of the vacant synaptic space due to deafferentation is the base for the mechanism of compensation on the medial rectus motoneuron

Neuromechanical Tuning for Arm Motor Control

Movement is a fundamental behavior that allows us to interact with the external world. Its importance to human health is most evident when it becomes impaired due to disease or injury. Physical and occupational rehabilitation remains the most common treatment for these types of disorders. Although therapeutic interventions may improve motor function, residual deficits are common for many pathologies, such as stroke. The development of novel therapeutics is dependent upon a better understanding of the underlying mechanisms that govern movement. Movement of the human body adheres to the principles of classic Newtonian mechanics. However, due to the inherent complexity of the body and the highly variable repertoire of environmental contexts in which it operates, the musculoskeletal system presents a challenging control problem and the onus is on the central nervous system to reliably solve this problem. The neural motor system is comprised of numerous efferent and afferent pathways with a hierarchical organization which create a complex arrangement of feedforward and feedback circuits. However, the strategy that the neural motor system employs to reliably control these complex mechanics is still unknown. This dissertation will investigate the neural control of mechanics employing a “bottom-up” approach. It is organized into three research chapters with an additional introductory chapter and a chapter addressing final conclusions. Chapter 1 provides a brief description of the anatomical and physiological principles of the human motor system and the challenges and strategies that may be employed to control it. Chapter 2 describes a computational study where we developed a musculoskeletal model of the upper limb to investigate the complex mechanical interactions due to muscle geometry. Muscle lengths and moment arms contribute to force and torque generation, but the inherent redundancy of these actuators create a high-dimensional control problem. By characterizing these relationships, we found mechanical coupling of muscle lengths which the nervous system could exploit. Chapter 3 describes a study of muscle spindle contribution to muscle coactivation using a computational model of primary afferent activity. We investigated whether these afferents could contribute to motoneuron recruitment during voluntary reaching tasks in humans and found that afferent activity was orthogonal to that of muscle activity. Chapter 4 describes a study of the role of the descending corticospinal tract in the compensation of limb dynamics during arm reaching movements. We found evidence that corticospinal excitability is modulated in proportion to muscle activity and that the coefficients of proportionality vary in the course of these movements. Finally, further questions and future directions for this work are discussed in the Chapter 5

Afferent Input Induced by Rhythmic Limb Movement Modulates Spinal Neuronal Circuits in an Innovative Robotic In Vitro Preparation

Locomotor patterns are mainly modulated by afferent feedback, but its actual contribution to spinal network activity during continuous passive limb training is still unexplored. To unveil this issue, we devised a robotic in vitro setup (Bipedal Induced Kinetic Exercise, BIKE) to induce passive pedaling, while simultaneously recording low-noise ventral and dorsal root (VR and DR) potentials in isolated neonatal rat spinal cords with hindlimbs attached. As a result, BIKE evoked rhythmic afferent volleys from DRs, reminiscent of pedaling speed. During BIKE, spontaneous VR activity remained unchanged, while a DR rhythmic component paired the pedaling pace. Moreover, BIKE onset rarely elicited brief episodes of fictive locomotion (FL) and, when trains of electrical pulses were simultaneously applied to a DR, it increased the amplitude, but not the number, of FL cycles. When BIKE was switched off after a 30-min training, the number of electrically induced FL oscillations was transitorily facilitated, without affecting VR reflexes or DR potentials. However, 90 min of BIKE no longer facilitated FL, but strongly depressed area of VR reflexes and stably increased antidromic DR discharges. Patch clamp recordings from single motoneurons after 90-min sessions indicated an increased frequency of both fast- and slow-decaying synaptic input to motoneurons. In conclusion, hindlimb rhythmic and alternated pedaling for different durations affects distinct dorsal and ventral spinal networks by modulating excitatory and inhibitory input to motoneurons. These results suggest defining new parameters for effective neurorehabilitation that better exploits spinal circuit activity

Direct current stimulation modulates the excitability of the sensory and motor fibres in the human posterior tibial nerve, with a long-lasting effect on the H-reflex

Several studies demonstrated that transcutaneous direct current stimulation (DCS) may modulate central nervous system excitability. However, much less is known about how DC affects peripheral nerve fibres. We investigated the action of DCS on motor and sensory fibres of the human posterior tibial nerve, with supplementary analysis in acute experiments on rats. In forty human subjects, electric pulses at the popliteal fossa were used to elicit either M-waves or H-reflexes in the Soleus, before (15 min), during (10 min) and after (30 min) DCS. Cathodal or anodal current (2 mA) was applied to the same nerve. Cathodal DCS significantly increased the H-reflex amplitude; the post-polarization effect lasted up to ~ 25 min after the termination of DCS. Anodal DCS instead significantly decreased the reflex amplitude for up to ~ 5 min after DCS end. DCS effects on M-wave showed the same polarity dependence but with considerably shorter after-effects, which never exceeded 5 min. DCS changed the excitability of both motor and sensory fibres. These effects and especially the long-lasting modulation of the H-reflex suggest a possible rehabilitative application of DCS that could be applied either to compensate an altered peripheral excitability or to modulate the afferent transmission to spinal and supraspinal structures. In animal experiments, DCS was applied, under anaesthesia, to either the exposed peroneus nerve or its Dorsal Root, and its effects closely resembled those found in human subjects. They validate therefore the use of the animal models for future investigations on the DCS mechanisms

Inhibition and oscillatory activity in human motor cortex

Using transcranial magnetic stimulation (TMS) important information can be obtained about the function of motor cortical circuitry during performance of voluntary movements by conscious human subjects. In particular, pairs of TMS pulses can probe inhibitory pathways projecting onto corticospinal neurones, which themselves project to motoneurones innervating hand muscles. This allows investigation of inhibitory circuitry involved in the performance of specific motor tasks, such as the precision grip. Previous studies have shown that pronounced synchronous oscillatory activity within the hand motor system is present at both cortical and muscular level when subjects maintain steady grasp of an object in a precision grip. The origin of this synchronous activity is unknown. However modelling studies have suggested that inhibitory pathways are likely to play an important role in the generation of cortical oscillations, and therefore TMS was used in this Thesis to investigate the origin of synchrony present during the precision grip task. In the first study, parameters of the paired-pulse test used to measure intracortical inhibition were examined. It was found that by modifying the intensities of the stimuli, and the interval between the paired-pulses, different phases of inhibition could be measured. This enabled specific use of TMS to investigate inhibitory pathways. Both single and paired-pulse TMS were then delivered to the motor cortex of subjects performing a precision grip task. It was found that low intensity TMS could reset the phase of muscle oscillatory activity, consistent with corticospinal neurones being part of the circuitry that generates the oscillatory rhythm. When, in the paired-pulse test, a low intensity stimulus was followed a few milliseconds later with a larger TMS stimulus, in the paired-pulse test, strong intracortical inhibition could be measured. This suggested that inhibitory interneurones activated by low intensity TMS could play an important role in the rhythm-generating network. An additional study looked at the importance of cutaneous receptor feedback on synchrony, by studying the effects of local anaesthesia of the index finger and thumb. Whereas low intensity TMS was shown to enhance synchronous activity between muscle pairs, suppression of cutaneous feedback from the digits reduced it. Results in this Thesis suggest that inhibitory interneurones within the motor cortex are important in the generation of synchronous activity within the hand motor system. This synchrony is also under the influence of cutaneous afferent input

Plasticity in ascending long propriospinal and descending supraspinal pathways in chronic cervical spinal cord injured rats

The high clinical relevance of models of incomplete cervical spinal cord injury (SCI) creates a need to address the spontaneous neuroplasticity that underlies changes in functional activity that occur over time after SCI. There is accumulating evidence supporting long projecting propriospinal neurons as suitable targets for therapeutic intervention after SCI, but focus has remained primarily oriented toward study of descending pathways. Long ascending axons from propriospinal neurons at lower thoracic and lumbar levels that form inter-enlargement pathways are involved in forelimb-hindlimb coordination during locomotion and are capable of modulating cervical motor output. We used non-invasive magnetic stimulation to assess how a unilateral cervical (C5) spinal contusion might affect transmission in intact, long ascending propriospinal pathways, and influence spinal cord plasticity. Our results show that transmission is facilitated in this pathway on the ipsilesional side as early as 1 week post-SCI. We also probed for descending magnetic motor evoked potentials (MMEPs) and found them absent or greatly reduced on the ipsilesional side as expected. The frequency-dependent depression (FDD) of the H-reflex recorded from the forelimb triceps brachii was bilaterally decreased although H(max)/M(max) was increased only on the ipsilesional side. Behaviorally, stepping recovered, but there were deficits in forelimb–hindlimb coordination as detected by BBB and CatWalk measures. Importantly, epicenter sparing correlated to the amplitude of the MMEPs and locomotor recovery but it was not significantly associated with the inter-enlargement or segmental H-reflex. In summary, our results indicate that complex plasticity occurs after a C5 hemicontusion injury, leading to differential changes in ascending vs. descending pathways, ipsi- vs. contralesional sides even though the lesion was unilateral as well as cervical vs. lumbar local spinal networks

The Dominant Role of the Hip in Multijoint Reflex Responses in Human Spinal Cord Injury

Following a spinal cord injury (SCI), people often experience exaggerated reflexes, such that mild provocations can cause prolonged and uncontrolled muscle activity throughout the entire leg. These reflexes can be problematic and are known to interfere with functional tasks, such as transferring to and from a wheelchair, and they may interfere with locomotor function by prolonging muscle activity and/or inappropriately activating muscles during attempts to walk. While these multijoint reflexes have been shown to originate from several afferent cues, hip afferent input is a particularly potent sensory signal that readily triggers multijoint reflexes. The overall objective of this dissertation was to understand the role of hip sensory cues and the potential mechanisms associated with multijoint reflex behavior in human SCI. To evaluate this, a custom -built robot was used to impose movement of the legs about the hip joint. Joint torque and muscle activity were used as quantitative measures of reflex activity in SCI subjects. The findings from this suggest that the mutability of reflexes triggered by hip-mediated sensory signals is reduced. Voluntary effort and stretch-sensitive sensory feedback impart weak signals that do not significantly alter multijoint reflex patterns. Additionally, reflex behaviors presented with a distinct temporal response that has been associated with the disregulation of voltage-dependent depolarizing persistent inward currents (PICs). These results further elucidate the underlying mechanisms associated with hyperexcitable multijoint reflexes to help guide rehabilitation techniques for controlling unwanted muscle activity and for increasing functional gains in human SCI

Activity of leg motoneurons during single leg walking of the stick insect: From synaptic inputs to motor performance

In the single middle leg preparation of the stick insect, leg motoneurons were recorded intracellularly during stepping movements on a treadmill. This preparation allows investigating the synaptic drive from local sense organs and central pattern generating networks to motoneurons. The synaptic drive comprises rhythmic (�phasic�) excitation and inhibition and a sustained (�tonic�) depolarization. This general scheme was found to be true for all motoneurons innervating the muscles of the three major leg joints. A comparison e.g. with results obtained from deafferented and pharmacologically activated preparations of the stick insect suggests that both tonic depolarization and phasic inhibition originate from central networks, while the phasic excitation is mainly generated by local sense organs. Recruitment of motoneurons was studied on the flexor tibiae muscle as an example of a complexly innervated muscle. It is innervated by ~14 slow, semifast and fast motoneurons that are firing action potentials during the stance phase of the step cycle. During slow steps or steps under small load, less motoneurons are recruited than during fast steps or steps under high load. Fast flexor motoneurons are recruited later during stance phase than slow motoneurons. All motoneurons receive substantial common synaptic drive during walking. They are recruited in an orderly fashion due to the more negative resting membrane potential of the fast motoneurons, which thus require a larger and longer lasting depolarization to reach the threshold for the generation of action potentials. Because walking is not invariable but needs to be adjusted to the behavioral requirements, it was investigated how these adjustments are implemented at the motoneuronal level. The activity of flexor and extensor tibiae motoneurons was analyzed during steps with different velocities. Extensor motoneuron activity during the extension phase of the step cycle (i.e. swing phase) is rather stereotypic and invariant with stance velocity. Flexor motoneurons show two distinct periods of depolarization at the beginning of stance. The initial depolarization is also stereotypic and most likely generated by a release from inhibition that allows the underlying tonic excitation to depolarize the neuron. The subsequent depolarization is larger and faster during fast steps than during slow steps. This indicates that in the single insect leg during walking, mechanisms for altering stepping velocity are becoming effective only during already ongoing stance phase motor output. Since a large portion of the phasic excitation arises from sense organs, it is conceivable that for the generation of different stepping velocities the effectiveness of these pathways are centrally modulated, for example by variations in the degree of presynaptic inhibition