Development of bipedal and quadrupedal locomotion in humans from a dynamical systems perspective

The first phase in the development 0f locomotion, pr,öary variability would occur in normal fetuses and infants, and those with Uner Tan syndrome. The neural networks for quadrupedal locomotion have apparently been transmitted epigenetically through many species since about 400 MYA.\ud The second phase is the neuronal selection process. During infancy, the most effective motor pattern(s) and their associated neuronal group(s) are selected through experience.\ud The third phase, secondary or adaptive variability, starts to bloom at two to three years of age and matures in adolescence. This third phase may last much longer in some patients with Uner Tan syndrome, with a considerably delay in selection of the well-balanced quadrupedal locomotion, which may emerge very late in adolescence in these cases

Üner Tan Syndrome: Review and Emergence of Human Quadrupedalism in Self-Organization,\ud Attractors and Evolutionary Perspectives\ud

The first man reported in the world literature exhibiting habitual quadrupedal locomotion was discovered by a British traveler and writer on the famous Baghdat road near Havsa/Samsun on the middle Black-Sea coast of Turkey (Childs, 1917). Interestingly, no single case with human quadrupedalism was reported in the scientific literature after Child's first description in 1917 until the first report on the Uner Tan syndrome (UTS: quadrupedalism, mental retardation, and impaired speech or no speech)in 2005 (Tan, 2005, 2006). Between 2005 and 2010, 10 families exhibiting the syndrome were discovered in Turkey with 33 cases: 14 women (42.4%) and 19 men (57.6%). Including a few cases from other countries, there were 25 men (64.1%)and 14 women (35.9%). The number of men significantly exceeded the number of women (p < .05). Genetics alone did not seem to be informative for the origins of many syndromes, including the Uner Tan syndrome. From the viewpoint of dynamical systems theory, there may not be a single factor including the neural and/or genetic codes that predetermines the emergence of the human quadrupedalism.Rather, it may involve a self-organization process, consisting of many decentralized and local interactions among neuronal, genetic, and environmental subsystems. The most remarkable characteristic of the UTS, the diagonal-sequence quadrupedalism is well developed in primates. The evolutionarily advantage of this gait is not known. However, there seems to be an evolutionarily advantage of this type of locomotion for primate evolution, with regard to the emergence of complex neural circuits with related highly complex structures. Namely, only primates with diagonal-sequence quadrupedal locomotion followed an evolution favoring larger brains, highly developed cognitive abilities with hand skills, and language, with erect posture and bipedal locomotion, creating the unity of human being. It was suggested that UTS may be considered a further example for Darwinian diseases, which may be associated with an evolutionary understanding of the disorders using evolutionary principles, such as the natural selection. On the other hand, the human quadrupedalism was proposed to be a phenotypic example of evolution of reverse, i.e., the reacquisition by derived populations of the same character states as those of ancestor populations. It was also suggested that the emergence of the human quadrupedalism may be related to self-organizing processes occurring in complex systems, which select or attract one preferred behavioral state or locomotor trait out of many possible attractor states. Concerning the locomotor patterns, the dynamical systems in brain and body of the developing child may prefer some kind of locomotion, according to interactions of the internal components and the environmental conditions, without a direct role of any causative factor(s), such as genetic or neural codes, consistent with the concept of self-organization, suggesting no single element may have a causal priority

Uner Tan Syndrome: History, Clinical Evaluations, Genetics, and the\ud Dynamics of Human Quadrupedalism

Abstract: This review includes for the first time a dynamical systems analysis of human quadrupedalism in Uner Tan syndrome, which is characterized by habitual quadrupedalism, impaired intelligence, and rudimentary speech. The first family was discovered in a small village near Iskenderun, and families were later found in Adana and two other small villages near Gaziantep and Canakkale. In all the affected individuals dynamic balance was impaired during upright walking,and they habitually preferred walking on all four extremities. MRI scans showed inferior cerebellovermian hypoplasia with slightly simplified cerebral gyri in three of the families, but appeared normal in the fourth. PET scans showed a decreased glucose metabolic activity in the cerebellum, vermis and, to a lesser extent the cerebral cortex, except for one patient,\ud whose MRI scan also appeared to be normal. All four families had consanguineous marriages in their pedigrees,\ud suggesting autosomal recessive transmission. The syndrome was genetically heterogeneous. Since the initial discoveries\ud more cases have been found, and these exhibit facultative quadrupedal locomotion, and in one case, late childhood onset. It has been suggested that the human quadrupedalism may, at least, be a phenotypic example of reverse evolution. From the viewpoint of dynamic systems theory, it was concluded there may not be a single factor that predetermines human quadrupedalism in Uner Tan syndrome, but that it may involve self-organization, brain plasticity, and rewiring, from the many decentralized and local interactions among neuronal, genetic, and environmental subsystems

Preclinical evidence supporting the clinical development of central pattern generator-modulating therapies for chronic spinal cord-injured patients

Ambulation or walking is one of the main gaits of locomotion. In terrestrial animals, it may be defined as a series of rhythmic and bilaterally coordinated movement of the limbs which creates a forward movement of the body. This applies regardless of the number of limbs - from arthropods with six or more limbs to bipedal primates. These fundamental similarities among species may explain why comparable neural systems and cellular properties have been found, thus far, to control in similar ways locomotor rhythm generation in most animal models. The aim of this article is to provide a comprehensive review of the known structural and functional features associated with central nervous system (CNS) networks that are involved in the control of ambulation and other stereotyped motor patterns - specifically Central Pattern Generators (CPGs) that produce basic rhythmic patterned outputs for locomotion, micturition, ejaculation, and defecation. Although there is compelling evidence of their existence in humans, CPGs have been most studied in reduced models including in vitro isolated preparations, genetically-engineered mice and spinal cord-transected animals. Compared with other structures of the CNS, the spinal cord is generally considered as being well-preserved phylogenetically. As such, most animal models of SCI should be considered as valuable tools for the development of novel pharmacological strategies aimed at modulating spinal activity and restoring corresponding functions in chronic spinal cord-injured patients

Multilevel Analysis of Locomotion in Immature Preparations Suggests Innovative Strategies to Reactivate Stepping after Spinal Cord Injury

Locomotion is one of the most complex motor behaviors. Locomotor patterns change during early life, reflecting development of numerous peripheral and hierarchically organized central structures. Among them, the spinal cord is of particular interest since it houses the central pattern generator (CPG) for locomotion. This main command center is capable of eliciting and coordinating complex series of rhythmic neural signals sent to motoneurons and to corresponding target-muscles for basic locomotor activity. For a long-time, the CPG has been considered a black box. In recent years, complementary insights from in vitro and in vivo animal models have contributed significantly to a better understanding of its constituents, properties and ways to recover locomotion after a spinal cord injury (SCI). This review discusses key findings made by comparing the results of in vitro isolated spinal cord preparations and spinal-transected in vivo models from neonatal animals. Pharmacological, electrical, and sensory stimulation approaches largely used to further understand CPG function may also soon become therapeutic tools for potent CPG reactivation and locomotor movement induction in persons with SCI or developmental neuromuscular disorder

Development in a biologically inspired spinal neural network for movement control

In two phases, we develop neural network models of spinal circuitry which self-organises into networks with opponent channels for the control of an antagonistic muscle pair. The self-organisation is enabled by spontaneous activity present in the spinal cord. We show that after the process of self-organisation, the networks have developed the possibility to independently control the length and tension of the innerated muscles. This allows the specification of joint angle independent from the specification of joint stiffness. The first network comprises only motorneurons and inhibitory interneurons through which the two channels interact. The inhibitory interneurons prevent saturation of the motorneuron pools, which is a necessary condition for independent control. In the second network, however, the neurons in the motorneuron pools obey the size-principle, which is a threat to the desired invariance of joint angle for varying joint stiffness, because of the different amplification of inputs in the case these inputs are not equal. To restore the desired invariance the second network ha.s been expanded with Renshaw cells. The manner in which they are included in the circuitry corrects the problem caused by the addition of the size-principle. The results obtained from the two models compare favourably with the FLETE-model for spinal circuitry (Bullock & Grossberg, 1991; Bullock et al., HJ93; Bullock & Contreras-Vidal, 1993) which has been successful in explaining several phenomena related to motor control.Fulbright Scholarship; Office of Naval Research (N00014-92-J-1309, N00014-95-1-0409

Excitatory Motor Neurons are Local Central Pattern Generators in an Anatomically Compressed Motor Circuit for Reverse Locomotion [preprint]

Central pattern generators are cell- or network-driven oscillators that underlie motor rhythmicity. The existence and identity of C. elegans CPGs remain unknown. Through cell ablation, electrophysiology, and calcium imaging, we identified oscillators for reverse locomotion. We show that the cholinergic and excitatory class A motor neurons exhibit intrinsic and oscillatory activity, and such an activity can drive reverse locomotion without premotor interneurons. Regulation of their oscillatory activity, either through effecting an endogenous constituent of oscillation, the P/Q/N high voltage-activated calcium channel UNC-2, or, via dual regulation, inhibition and activation, by the descending premotor interneurons AVA, determines the propensity, velocity, and sustention of reverse locomotion. Thus, the reversal motor executors themselves serve as oscillators; regulation of their intrinsic activity controls the reversal motor state. These findings exemplify anatomic and functional compression: motor executors integrate the role of rhythm generation in a locomotor network that is constrained by small cell numbers

Developing an In Vitro Assay for Detection and Characterization of Functional Connectivity within Transplantation Candidate Embryonic Stem Cell-Derived V2a Interneuron Networks

Facilitating plasticity after spinal cord injury tends to be the focus of most modern interventions for this condition. In particular, stem cell therapies attempt to both modulate and mimic some of the native plasticity after injury through multiple mechanisms. One such mechanism, the creation of new exogenous relay circuits bridging the injury, has been explored extensively, revealing serious impediments to its optimization and adoption for clinical settings. Our collaborator, the Sakiyama-Elbert group, has spent years addressing the first limitation, the variability of cellular graft composition, by perfecting protocols to generate embryonic stem cell (ESC)-derived populations of neurons with pre-determined genetic identity. Recently, they developed a protocol to develop highly-enriched populations of Chx10-expressing V2a interneurons (INs), a ventral interneuron population that has garnered recent interest due to its role in central pattern generating function and favorable phenotypic properties. This predominantly glutamatergic and long, ipsilaterally projecting population appears to be a prime candidate for transplantation therapies for SCI, especially for the creation of relay circuits that can potentially circumnavigate injuries. The research documented in this thesis attempts to begin to address the second limitation of stem cell transplantation therapy, our minimal understanding of intra-graft network connectivity after transplantation. Due to the limitations of current techniques for evaluating the connectivity of populations like ESC-derived V2a INs, the relationship between functional recovery and the functional properties of the novel circuits formed within the graft still eludes researchers. This thesis focuses on the development of an assay capable of rapidly detecting connectivity within ESC-derived candidate populations. By extending previous work in the stem cell field, we combine in vitro multi-electrode arrays (MEAs) with an extensively studied metric of functional connectivity, cross-correlation, to detect and characterize individual functional connections between ESC-derived neurons. We first validated this assay by culturing ESC-derived populations differentiated for increased expression of Chx10 on MEAs. We found that both dissociated and aggregated cultures formed functional busting networks with significant functional connectivity detected with the use of Between-Sample Analysis of Connectivity, a methodology originally developed for in vitro circadian networks. Aggregated networks, however, had much more consistent electrode coverage and individual neuron detection that dissociated networks. After this validation study, we characterized the functional connectivity within highly-enriched populations of ESC-V2a INs, comparing their connectivity to populations of ESC-MN/glia and mixed populations of ESC-V2a/MN/glia. We found that ESC-MN/glia aggregates formed active networks with a variety of activity and functional connectivity that was dependent on the transmission of glutamate. ESC-V2a INs could only survive out to the 4-week time point if they were grown in media conditioned with glial factors, but these cultures still lacked spontaneous extracellular activity. Mixed ESC-V2a/MN/glia populations formed the most active networks and had thousands of detectable connections which were also dependent on glutamate transmission. Application of glycine antagonist modulated network activity but the underlying cause is fairly inconclusive due to possible secondary effects. High growth factor concentrations in the growth media actually decreased network activity and detectable functional connections in the mixed populations. All of these findings in this proof of concept study collectively suggest that a mixture of ESC-V2a INs and ESC-MN/glia may be the most viable candidate for transplantation and sets the stage for future investigations into the manipulability of their connectivity with electrical stimulation, as well as scaled versions of this assay performed in combination with animal studies