I have developed "tennis elbow" from lugging this book around the past four weeks, but it is worth the pain, the effort, and the aspirin. It is also worth the (relatively speaking) bargain price. Including appendixes, this book contains 894 pages of text. The entire panorama of the neural sciences is surveyed and examined, and it is comprehensive in its scope, from genomes to social behaviors. The editors explicitly state that the book is designed as "an introductory text for students of biology, behavior, and medicine," but it is hard to imagine any audience, interested in any fragment of neuroscience at any level of sophistication, that would not enjoy this book. The editors have done a masterful job of weaving together the biologic, the behavioral, and the clinical sciences into a single tapestry in which everyone from the molecular biologist to the practicing psychiatrist can find and appreciate his or

Principles of Neural Science

Muscle fatigue is an exercise-induced reduction in maximal voluntary muscle force. It may arise not only because of peripheral changes at the level of the muscle, but also because the central nervous system fails to drive the motoneurons adequately. Evidence for “central” fatigue and the neural mechanisms underlying it are reviewed, together with its terminology and the methods used to reveal it. Much data suggest that voluntary activation of human motoneurons and muscle fibers is suboptimal and thus maximal voluntary force is commonly less than true maximal force. Hence, maximal voluntary strength can often be below true maximal muscle force. The technique of twitch interpolation has helped to reveal the changes in drive to motoneurons during fatigue. Voluntary activation usually diminishes during maximal voluntary isometric tasks, that is central fatigue develops, and motor unit firing rates decline. Transcranial magnetic stimulation over the motor cortex during fatiguing exercise has revealed focal cha...

Spinal and Supraspinal Factors in Human Muscle Fatigue

中枢神経系疾患の治療は正常細胞（ニューロン）の機能維持を目的とするが，脳血管障害のように機能障害の原因が細胞の死滅に基づくことは多い．一方，脳腫瘍の治療においては薬物療法や放射線療法といった腫瘍細胞の死滅を目標とするものが大きな位置を占める．いずれの場合にも，細胞死の機序を理解することは各種病態や治療法の理解のうえで重要である．現在のところ最も研究の進んでいる細胞死の型はアポトーシスである．そのなかで重要な位置を占めるミトコンドリアにおける反応および抗アポトーシス因子について概要を紹介する．

Neuroscience 細胞死：最近の知見

Locomotion results from intricate dynamic interactions between a central program and feedback mechanisms. The central program relies fundamentally on a genetically determined spinal circuitry (central pattern generator) capable of generating the basic locomotor pattern and on various descending pathways that can trigger, stop, and steer locomotion. The feedback originates from muscles and skin afferents as well as from special senses (vision, audition, vestibular) and dynamically adapts the locomotor pattern to the requirements of the environment. The dynamic interactions are ensured by modulating transmission in locomotor pathways in a state- and phase-dependent manner. For instance, proprioceptive inputs from extensors can, during stance, adjust the timing and amplitude of muscle activities of the limbs to the speed of locomotion but be silenced during the opposite phase of the cycle. Similarly, skin afferents participate predominantly in the correction of limb and foot placement during stance on uneven terrain, but skin stimuli can evoke different types of responses depending on when they occur within the step cycle. Similarly, stimulation of descending pathways may affect the locomotor pattern in only certain phases of the step cycle. Section ii reviews dynamic sensorimotor interactions mainly through spinal pathways. Section iii describes how similar sensory inputs from the spinal or supraspinal levels can modify locomotion through descending pathways. The sensorimotor interactions occur obviously at several levels of the nervous system. Section iv summarizes presynaptic, interneuronal, and motoneuronal mechanisms that are common at these various levels. Together these mechanisms contribute to the continuous dynamic adjustment of sensorimotor interactions, ensuring that the central program and feedback mechanisms are congruous during locomotion.

https://www.physiology.org/doi/pdf/10.1152/physrev.00028.2005

Dynamic Sensorimotor Interactions in Locomotion

Freezing of gait (FoG) is a unique and disabling clinical phenomenon characterised by brief episodes of inability to step or by extremely short steps that typically occur on initiating gait or on turning while walking. Patients with FoG, which is a feature of parkinsonian syndromes, show variability in gait metrics between FoG episodes and a substantial reduction in step length with frequent trembling of the legs during FoG episodes. Physiological, functional imaging, and clinical-pathological studies point to disturbances in frontal cortical regions, the basal ganglia, and the midbrain locomotor region as the probable origins of FoG. Medications, deep brain stimulation, and rehabilitation techniques can alleviate symptoms of FoG in some patients, but these treatments lack efficacy in patients with advanced FoG. A better understanding of the phenomenon is needed to aid the development of effective therapeutic strategies.

Freezing of gait: Moving forward on a mysterious clinical phenomenon

1. The effects of stimulating hindlimb extensor nerves (100-200 ms trains, 100 Hz, < or = 2 times threshold) during the flexor and extensor phases of the locomotor step cycle were analysed in the decerebrate, paralysed cat during fictive locomotion evoked by stimulation of the mesencephalic locomotor region. 2. Stimulation during extension of either the medial gastrocnemius (MG), lateral gastrocnemius-soleus (LGS) or plantaris (Pl) nerves was equally effective in increasing the duration and amplitude of electroneurogram (ENG) activity recorded in ipsilateral ankle, knee and hip extensor nerves. Enhancement of extensor ENG activity could be evoked with near threshold stimulation intensity and appeared within 10-40 ms of the onset of ankle extensor nerve stimulation. Stimulation of anterior biceps during extension occasionally evoked a modest increase in the duration of activity of hip, knee and ankle extensors. Stimulation of quadriceps during extension enhanced the activity of proximal extensors and soleus, but inhibited other ankle extensors. 3. Selective activation of ankle extensor Ia spindle afferents by muscle stretch also enhanced ipsilateral extension. It is argued that both muscle spindle and tendon organ afferents can contribute to the increase in extensor nerve activity evoked by group I stimulation intensity during fictive locomotion. 4. During flexion, stimulation of either the MG, Pl or LGS nerves at group I strength terminated on-going activity in ipsilateral flexors and initiated a burst of activity in ipsilateral hip, knee and ankle extensors, i.e. reset the step cycle to extension. 5. Low strength stimulation of the mixed muscle and cutaneous nerve innervating the plantar aspect of the foot produced extension enhancement and resetting similar to that evoked by group I muscle afferent stimulation. Stimulation of the cutaneous nerve supplying the dorsal aspect of the foot during extension enhanced extensor activity, and during flexion, enhanced the activity of flexors. 6. The effects reported here during fictive locomotion may also occur during overground locomotion with natural activation of group I muscle spindle and tendon organ afferents. Extensor spindle and tendon organ afferents may thus serve as an excitatory reflex system helping to shape the amplitude, duration and timing of ipsilateral extensor activity. Increased or unexpected activation of group I ankle extensor afferents or plantar foot afferents during locomotion could also compensate for increased loading of the limb.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.1995.sp020871

Ankle extensor group i afferents excite extensors throughout the hindlimb during fictive locomotion in the cat

http://www.pgedf.ufpr.br/Referencias08/CGP%20e%20locomocao%20BILL.pdf

The mammalian central pattern generator for locomotion

This article provides a perspective on major innovations over the past century in research on the spinal cord and, specifically, on specialized spinal circuits involved in the control of rhythmic locomotor pattern generation and modulation. Pioneers such as Charles Sherrington and Thomas Graham Brown have conducted experiments in the early twentieth century that changed our views of the neural control of locomotion. Their seminal work supported subsequently by several decades of evidence has led to the conclusion that walking, flying, and swimming are largely controlled by a network of spinal neurons generally referred to as the central pattern generator (CPG) for locomotion. It has been subsequently demonstrated across all vertebrate species examined, from lampreys to humans, that this CPG is capable, under some conditions, to self-produce, even in absence of descending or peripheral inputs, basic rhythmic, and coordinated locomotor movements. Recent evidence suggests, in turn, that plasticity changes of some CPG elements may contribute to the development of specific pathophysiological conditions associated with impaired locomotion or spontaneous locomotor-like movements. This article constitutes a comprehensive review summarizing key findings on the CPG as well as on its potential role in Restless Leg Syndrome, Periodic Leg Movement, and Alternating Leg Muscle Activation. Special attention will be paid to the role of the CPG in a recently identified, and uniquely different neurological disorder, called the Uner Tan Syndrome.

/pdf/central-pattern-generator-for-locomotion-anatomical-5bkh07gu26.pdf

Central Pattern Generator for Locomotion: Anatomical, Physiological, and Pathophysiological Considerations

1. This study examines the effects of electrical stimulation of hindlimb flexor nerves on the fictive locomotion pattern. Locomotion was initiated by stimulation of the mesencephalic locomotor region in the decerebrate paralysed cat and monitored by recording the electroneurogram from selected hindlimb flexor and extensor muscle nerves. Flexor nerves were stimulated using short trains (20-50 stimuli at 100 Hz) during either the flexor or the extensor phase of the fictive locomotor cycle. 2. Stimulation of tibialis anterior (TA), posterior biceps and semitendinosus (PBSt) or sartorius (Sart) nerves at 5 times threshold (T) during the flexor phase of the fictive locomotor cycle terminated on-going activity in flexor nerves and initiated activity in extensors. Thus, flexor nerve stimulation during flexion shortened the locomotor cycle by resetting to extension. The failure of lower intensity (2T) stimulation of PBSt or Sart nerves to reset the step cycle to extension suggests that group II afferents are responsible for these actions. Resetting evoked by 2T stimulation of the TA nerve may be due to a high proportion of group II afferents with low electrical threshold. 3. During extension, stimulation of TA and PBSt nerves at 5T did not perturb the locomotor rhythm whereas Sart stimulation prolonged the locomotor cycle. 4. Stimulation of cutaneous or knee joint afferents failed to produce effects similar to those evoked by stimulation of flexor muscle nerves at group II strength. These findings are at odds with those obtained elsewhere in the acute spinal, DOPA fictive locomotion preparation. The possibility that group II resetting during fictive locomotion is not mediated by flexion reflex pathways but by previously unknown pathways released in the present preparation is discussed. 5. Since many of the flexor afferents recruited by 5T electrical stimulation are the length-sensitive group II fibres, spindle secondaries may act to regulate the duration and onset of flexor and extensor activity during real locomotion. The resetting from flexion to extension also suggests that unexpected or enhanced activity of flexor secondaries during swing would promote a switch of the step cycle to stance.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.1995.sp020872

Effects of stimulation of hindlimb flexor group II afferents during fictive locomotion in the cat.

The ability of dedicated spinal circuits, referred to as central pattern generators (CPGs), to produce the basic rhythm and neural activation patterns underlying locomotion can be demonstrated under specific experimental conditions in reduced animal preparations. The existence of CPGs in humans is a matter of debate. Equally elusive is the contribution of CPGs to normal bipedal locomotion. To address these points, we focus on human studies that utilized spinal cord stimulation or pharmacological neuromodulation to generate rhythmic activity in individuals with spinal cord injury, and on neuromechanical modeling of human locomotion. In the absence of volitional motor control and step-specific sensory feedback, the human lumbar spinal cord can produce rhythmic muscle activation patterns that closely resemble CPG-induced neural activity of the isolated animal spinal cord. In this sense, CPGs in humans can be defined by the activity they produce. During normal locomotion, CPGs could contribute to the activation patterns during specific phases of the step cycle and simplify supraspinal control of step cycle frequency as a feedforward component to achieve a targeted speed. Determining how the human CPGs operate will be essential to advance the theory of neural control of locomotion and develop new locomotor neurorehabilitation paradigms.

Pierre A. Guertin

Papers

Ankle extensor group i afferents excite extensors throughout the hindlimb during fictive locomotion in the cat

The mammalian central pattern generator for locomotion

Central Pattern Generator for Locomotion: Anatomical, Physiological, and Pathophysiological Considerations

Effects of stimulation of hindlimb flexor group II afferents during fictive locomotion in the cat.

The Human Central Pattern Generator for Locomotion: Does It Exist and Contribute to Walking?