found to be altered by neuromodulators, including serotonin in a study by harris-warrick and cohen in 1985 and tachykinin in a study by parker et al. in 1998. the lamprey model of cpg for locomotion has been important to the study of cpgs. although sten grillner claims that the locomotor network is characterised, a claim that has seemingly been uncritically accepted by the spinal cord locomotor network field, there are in fact many missing details and grillner cannot provide the evidence he uses to support his claims (parker 2006). however, this neural circuit model of the lamprey cpg, including three classes (one excitatory and two inhibitory) of neurons but omitting sub-cellular details, provides a system level understanding of the cpg-generated locomotion whose speed and direction (swimming forward, backward, or turning) are set by non-rhythmic external inputs (from the brainstem) to the circuit. a general scheme of the lamprey cpg is now being used in the creation of artificial cpgs. for example, ijspeert and kodjabachian used ekeberg's model for the lamprey to create artificial cpgs and simulate swimming movements in a lamprey-like substrate using controllers based on a sgoce encoding. essentially, these are the first steps toward the use of cpgs to code for locomotion in robots. the vertebrate model of cpg has been also developed with both hodgkin-huxley formalism, its variants and control system approaches. for example, yakovenko and colleagues have developed a simple mathematical model that describes basic principles proposed by t.g. brown with integrate-to-threshold units organized with mutually inhibitory connections. this model is sufficient to describe complex properties of behavior, such as different regimes of the extensor- and flexor-dominant locomotion observed during electrical stimulation of the mesencephalic locomotor region (mlr), mlr-induced fictive locomotion. the connections between the cpgs that control each limb manage interlimb coordination and hence the gaits in quadrupedal and possibly also bipedal animals. left right coordination is mediated by commissural and fore-hind as well as diagonal coordination is mediated by long-projecting propiospinal interneurons. the balance of the left-right alternation (mediated genetically identified v0d and v0v neuron classes) to left-synchronization promoting commissural interneurons (potentially mediated v3 neurons) determines whether walk and trot (alternating gaits) or gallop and bound (synchronous gaits) are expressed. this balance changes with increasing speed, potentially because of modulation by supraspinal drive from the mlr and mediated by the reticular formation, and causes speed dependent gait transitions characteristic for quadrupedal animals. the walk to trot transition potentially occurs because of the stronger decrease of extension than flexion phase durations with increasing locomotor speed and could be mediated by descending diagonal inhibition through v0d long propriospinal neurons, which leads to progressively increasing overlap between the diagonal limbs up until diagonal synchronization (trot). commissural and long propriospinal neurons are a likely target of supraspinal and somatosensory afferent inputs to adjust interlimb coordination and gait to different environmental and behavioral conditions. central pattern generators also contribute to locomotion in humans. in 1994, calancie, et al. described the "first well-defined example of a central rhythm generator for stepping in the adult human." the subject was a 37-year-old male who suffered an injury to the cervical spinal cord 17 years prior. after initial total paralysis below the neck, the subject eventually regained some movement of the arms and fingers and limited movement in the lower limbs. he had not recovered sufficiently to support his own weight. after 17 years, the subject found that when lying supine and extending his hips, his lower extremities underwent step-like movements for as long as he remained lying down. "the movements (i) involved alternating flexion and extension of his hips, knees, and ankles; (ii) were smooth and rhythmic; (iii) were forceful enough that the subject soon became uncomfortable due to excessive muscle 'tightness' and an elevated body temperature; and (iv) could not be stopped by voluntary effort." after extensive study of the subject, the experimenters concluded that "these data represent the clearest evidence to date that such a network does exist in man." four years later, in 1998, dimitrijevic, et al. showed that the human lumbar pattern generating networks can be activated by drive to large-diameter sensory afferents of the posterior roots. when tonic electrical stimulation is applied to these fibers in motor complete spinal cord injured individuals (i.e., individuals in whom the spinal cord is functionally isolated from the brain) rhythmic, locomotor-like movement of the lower limbs can be elicited. these measurements were performed in supine position, thus minimizing peripheral feedback. subsequent studies showed that these lumbar locomotor centers can form a large variety of rhythmic movements by combining and distributing stereotypical patterns to the numerous lower limb muscles. a cpg-activating drug treatment called spinalon, active centrally upon oral administration, has also been shown to partially reactivate spinal locomotor neurons in complete or motor-complete spinal cord-injured patients. indeed, a double-blind, randomized, placebo-controlled study in forty-five volunteers with chronic ais a/b injuries (between 3 months and 30 years post-trauma) lying in the supine position for safety reasons, revealed that spinalon below maximum tolerated dose (mtd was 500/125/50 mg/kg l-dopa/carbidopa/buspirone) was well tolerated. preliminary evidence of efficacy was also found using videotape and electromyographic recordings since doses below mtd could acutely induce rhythmic locomotor-like leg movements in groups with spinalon, but not in those with placebo (cornstarch). neuromechanical control of locomotion in mammals if step cycle durations and muscle activations were fixed, it wouldn't be possible to change body velocity and adapt to varying terrain. it has been suggested that the mammalian locomotor cpg comprises a “timer” (possibly in the form of coupled oscillators) which generates step cycles of varying durations, and a “pattern formation layer,” which selects and grades the activation of motor pools. increasing the neural drive from the midbrain locomotor region (mlr) to the spinal cpg increases the step cycle frequency (the cadence). swing and stance phase durations co-vary in a fairly fixed relationship, with stance phases changing more than swing phases. sensory input from the limbs may truncate or extend individual phase durations in a process akin to finite state control (in which "if-then” rules determine when state transitions occur). for example, if a limb that is swinging forward reaches the end of swing in less time than the current cpg-generated flexor phase duration, sensory input would cause the cpg timer to terminate swing and start the stance phase. furthermore, as body velocity increases, the pattern formation layer would increase muscle activation nonlinearly to provide increased load-bearing and thrust forces. it has been posited that in well-predicted movements, cpg-generated phase durations and muscle forces closely match those required by the evolving biomechanical events, minimizing the sensory corrections required. the term ‘‘neuromechanical tuning’’ has been coined to describe this process fig. 1. schematic of the locomotor central pattern generator in the mammalian nervous system. a command signal specifying increasing body velocity descends from deep brain nuclei via the mlr to the spinal cord and drives the timing element of the spinal locomotor cpg to generate cycles of increasing cadence. extensor phase durations change more than flexor phase durations. the command signal also drives the pattern formation layer to generate cyclical activation of flexor and extensor motoneurons. loading of the activated muscles (e.g. supporting the moving body mass) is resisted by the muscles' intrinsic spring-like properties. this is equivalent to displacement feedback. force and displacement sensed by muscle spindle and golgi tendon organ afferents reflexly activate motoneurons. a key role of these afferents is to adjust the timing of phase transitions, presumably by influencing or overriding the cpg timer. modified from fig. 1 provides a simplified schematic that summarizes these proposed mechanisms. a command specifying desired body velocity descends from higher centers to the mlr, which drives the spinal locomotor cpg. the cpg timer produces the appropriate cadence and phase durations and the pattern formation layer modulates the motoneuronal outputs. the activated muscles resist stretch through their own intrinsic biomechanical properties, providing a rapid form of length and velocity feedback control. reflexes mediated by golgi tendon organ and other afferents provide additional load compensation, but the main role of sensory input may be to adjust or override the cpg at stance-swing-stance transitions. as described in neuromodulation, the human locomotive cpg is very adaptable and can respond to sensory input. it receives input from the brainstem as well as from the environment to keep the network regulated. newer studies have not only confirmed the presence of the cpg for human locomotion, but also confirmed its robustness and adaptability. for example, choi and bastian showed that the networks responsible for human walking are adaptable on short and long timescales. they showed adaptation to different gait patterns and different walking contexts. also, they showed that different motor patterns can adapt independently. adults could even walk on treadmills going in a different direction for each leg. this study showed that independent networks control forward and backward walking and that networks controlling each leg can adapt independently and be trained to walk independently. thus, humans also possess a central pattern generator for locomotion that is capable not only of rhythmic pattern generation but also remarkable adaptation and usefulness in a wide variety of situations. respiration further information: respiratory center a three-phase model is the classical view of the respiratory cpg. the phases of the respiratory cpg are characterized by the rhythmic activity of: (1) the phrenic nerve during inspiration; (2) recurrent laryngeal nerve branches that innervate the thyroarytenoid muscle during the last stage of expiration; (3) the internal intercostal nerve branches that innervate the triangularis sterni muscle during the second stage of expiration. the rhythmicity of these nerves is classically viewed as originating from a single rhythm generator. in this model, phasing is produced by reciprocal synaptic inhibition between groups of sequentially active interneurons. nevertheless, an alternative model has been proposed reinforced by certain experimental data. according to this model, respiratory rhythm is generated by two coupled anatomically distinct rhythm generators, one in the pre-boetzinger complex and the other in the retrotrapezoid nucleus / parafacial respiratory group. further survey provided evidence to the hypothesis that one of the networks is responsible for inspiration rhythm and the other for expiration rhythm. therefore, inspiration and expiration are distinct functions and one does not induce the other, as is the common belief, but one of two dominates the behavior by generating a faster rhythm. swallowing swallowing involves the coordinated contraction of more than 25 pairs of muscles in the oropharynx, larynx and esophagus, which are active during an oropharyngeal phase, followed by the primary esophageal peristalsis. swallowing depends on a cpg located in the medulla oblongata, which involves several brain stem motor nuclei and two main groups of interneurons: a dorsal swallowing group (dsg) in the nucleus tractus solitarii and a ventral swallowing group (vsg) located in the ventrolateral medulla above the nucleus ambiguus. neurons in the dsg are responsible for the generation of the swallowing pattern, while those in the vsg distribute the commands to the various motoneuronal pools. as in other cpgs, the functioning of the central network can be modulated by peripheral and central inputs, so that the swallowing pattern is adapted to the size of the bolus. within this network, central inhibitory connections play a major role, producing a rostrocaudal inhibition that parallels the rostrocaudal anatomy of the swallowing tract. thus, when the neurons controlling the proximal parts of the tract are active, those that command more distal parts are inhibited. apart from the type of connection between the neurons, intrinsic properties of the neurons, especially those of nts neurons, probably also contribute to the shaping and timing of the swallowing pattern. the swallowing cpg is a flexible cpg. this means that at least some of the swallowing neurons may be multifunctional neurons and belong to pools of neurons that are common to several cpgs. one such cpg is the respiratory one, which has been observed interacting with the swallowing cpg. rhythm generators central pattern generators can also play a role in rhythm generation for other functions in vertebrates. for example, the rat vibrissa system uses an unconventional cpg for whisking movements. "like other cpgs, the whisking generator can operate without cortical input or sensory feedback. however, unlike other cpgs, vibrissa motoneurons actively participate in rhythmogenesis by converting tonic serotonergic inputs into the patterned motor output responsible for movement of the vibrissae." breathing is